Conditions: Lung Non-Small Cell Carcinoma Stage I Lung Cancer AJCC v8 Stage IA1 Lung Cancer AJCC v8 Stage IA2 Lung Cancer AJCC v8 Stage IA3 Lung Cancer AJCC v8 Stage IB Lung Cancer AJCC v8 Stage II Lung Cancer AJCC v8 Stage IIA Lung Cancer AJCC v8 Stage IIB Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This trial studies the side effects of sirolimus and durvalumab and to see how well they work in treating patients with stage I-IIIA non-small cell lung cancer. Sirolimus is an oral medication that blocks the mTOR cellular pathway which may help the immune system work better. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sirolimus before durvalumab may help the immune system get rid of cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of sirolimus followed by durvalumab as neoadjuvant treatment II. To evaluate the efficacy of sirolimus followed by durvalumab as neoadjuvant treatment for stage I, II, and IIIA non-small cell lung cancer (NSCLC)

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of sirolimus in combination with durvalumab as neoadjuvant treatment for stage I, II, and IIIA NSCLC II. To evaluate response to sirolimus in combination with durvalumab in patients with PD-L1-positive versus (vs.) PD-L1-negative tumors III. To evaluate the association between blood mutation burden and response to sirolimus and durvalumab

EXPLORATORY OBJECTIVES:

I. To evaluate the immune-mediated effects of combination sirolimus and durvalumab II. To investigate tumor and immune microenvironment changes in tissue samples

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD) on days 1-21 in the absence of disease progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab intravenously (IV) over 1 hour. Treatment with durvalumab repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within a 2-3 week period after the second dose of durvalumab, but not earlier than two weeks after the administration of durvalumab, patients undergo standard of care surgery.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Arms:
arm 1: Patients receive sirolimus PO QD on days 1-21 in the absence of disease progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab IV over 1 hour. Treatment with durvalumab repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within a 2-3 week period after the second dose of durvalumab, but not earlier than two weeks after the administration of durvalumab, patients undergo standard of care surgery.

Interventions: intervention 1: Durvalumab intervention 2: Sirolimus
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 1 of 129
Investigational Drug 
Substance(s)
Durvalumab (MEDI4736) 
Sirolimus (Rapamune)
Study Number
19-20015
Version Number
4
Date
11 February 2022
A Phase 1b Neoadjuvant Trial of Sirolimus Followed by Durvalumab 
(MEDI4736) in Resectable Non-small Cell Lung Cancer
Supporter: AstraZeneca/MedImmune


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 2 of 129
PROTOCOL SYNOPSIS
Clinical Protocol ESR 19-20015 
Study Title: A Phase 1b Neoadjuvant Trial of Sirolimus followed by Durvalumab (MEDI4736) in 
Resectable Non-small Cell Lung Cancer
Protocol Number: 19-20015
Clinical Phase: Ib
Study Duration: 4 years, which will include survival follow-up for up to 2 years after the last patient 
receives the last dose of neoadjuvant durvalumab
Investigational Product(s) and Reference Therapy:
Durvalumab (MEDI4736) solution for infusion after dilution will be supplied in glass vials containing 
500 mg of liquid solution durvalumab at a concentration of 50 mg/mL infusion after dilution.
Sirolimus (Rapamune) will be supplied in 1 mg, white, triangular-shaped tablets marked 
“RAPAMUNE 1 mg” on one side; bottle containing 100 tablets.
Research Hypothesis
We hypothesize that administration of sirolimus, an mTOR inhibitor, followed by durvalumab, an 
engineered human IgG1 kappa monoclonal antibody targeting PD-1, will demonstrate a good safety 
profile and produce objective responses in clinical Stage I-IIIA NSCLC. We plan to assess established 
markers that correlate with response including PD-L1 expression in the tumors and tumor mutation 
burden by next generation sequencing. As these markers are not perfect and some patients with low PD-
L1 and mutational burden may derive benefit, additional study of immune mechanisms is needed. 
Moreover, there is significant interest in developing combination therapy regimens that enhance the 
immune system response to cancer of patients that are PD-L1 and mutational burden low. Our focus on 
biomarkers of response will help identify patients who will benefit from this treatment strategy.
Objectives:
Co-Primary Objectives:
• To evaluate the safety and tolerability of sirolimus followed by durvalumab as neoadjuvant treatment 


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 3 of 129
• To evaluate the efficacy of sirolimus followed by durvalumab as neoadjuvant treatment for Stage I, II, 
and IIIA NSCLC
Secondary Objective(s):
• To evaluate the efficacy of sirolimus followed by durvalumab as neoadjuvant treatment for Stage I, II, 
and IIIA NSCLC
• To evaluate response to sirolimus followed by durvalumab in patients with PD-L1
positive vs. PD-L1-negative tumors 
• To evaluate the association between blood mutation burden and response to sirolimus followed by 
durvalumab
Exploratory Objective(s):
• To evaluate the immune-mediated effects of sirolimus followed by durvalumab 
• To investigate tumor and immune microenvironment changes in tissue samples
Study Design:
Up to 31 patients with NSCLC will be enrolled in this study at Emory University Winship Cancer 
Institute and associated clinical sites. Eligible patients will complete 3 weeks of daily oral sirolimus 
followed by 2 cycles of durvalumab treatment prior to proceeding to standard of care surgical resection. 
Durvalumab will be administered at a dose of 1500mg Q 3 weeks starting on C1D1 for up to 2 cycles 
that are 21 days in length. Pharmacodynamic analysis will be done using PD samples collected at 
baseline (tissue) and with blood samples on day 1, day 22 C1 prior to durvalumab, day 43 C2 
durvalumab, and at the time of surgery (blood and tissue). Additional post surgery blood samples will 
be collected at 1-, 3-, and 6-months post-surgery. See Appendix D for schedule of Biomarker collection. 
Patients will proceed to surgery within a 2–3-week period post 2nd dose of durvalumab but not earlier 
than two weeks after the administration of durvalumab i.e. not earlier than C2D14. Additionally, as an 
optional study, patients will self-administer heavy water (D2O) 50ml orally three times a day from day 
22 C1 through day 27 followed by 50ml orally twice a day through the day prior to surgery in order to 
label dividing cells for research tracking purposes.
Number of Centers: Emory University Winship Cancer Institute and affiliated hospitals
Number of Patients: 31
Study Population: Resectable Stage 1-3A NSCLC
Inclusion Criteria:

Pathologically documented NSCLC who are candidates for surgical resection

Capable of signing informed consent


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 4 of 129

 Age > 18 years at time of study entry.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 

Life expectancy of > 26 weeks

Body weight >30 kg 

Adequate normal organ and marrow function as defined in protocol

Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-
menopausal patients.

Measurable disease defined by RECIST v 1.1. 

Patient is able to take oral medications

Patient consents to heavy water (D2O) self-administration, if enrolling in optional heavy water 
study

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.
Exclusion Criteria:

Prior therapy for lung cancer including chemotherapy, hormonal therapy, or radiotherapy.

Concurrent enrolment in another clinical study, unless it is observational 

Prior treatment with anti-PD-1, anti-PDL-1, including durvalumab other PD-1/PDL-1 pathway 
targeting agents, or mTOR inhibition. 

History of allogenic organ transplantation.

Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc]). Exceptions listed in protocol below. 

Uncontrolled intercurrent illness

History of another primary malignancy with exceptions noted in protocol

QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms

History of active primary immunodeficiency 

Active infection including tuberculosis, hepatitis B, hepatitis C

Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab. There are exceptions to this criterion listed below in the protocol

Receipt of live attenuated vaccine within 30 days prior to the first dose of study medications 


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 5 of 129

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 screening to 90 days after the 
last dose of durvalumab

Known allergy or hypersensitivity to any of the study drugs or excipients.

Patients with a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan 

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:
Patients will receive 1500 mg durvalumab via IV infusion Q3W for up to a maximum of 2 cycles prior 
to curative resection surgery. Weight-based dosing (20 mg/kg) should be utilized for patients whose 
body weight falls to <30 kg while on study.
Patient will self-administer sirolimus 6 mg orally once on day 1, followed by once daily dosing of 
2mg, continuously through day 21, which is one day prior to C1 of durvalumab. The dose should be 
taken each morning, with or without food. 
Study Assessments and Criteria for Evaluation:
Safety Assessments:
• Incidence of adverse events, with severity per NCI CTCAE v5.0 
• Length of hospital stay after surgery
Efficacy Assessments:
• Complete pathologic response, scored by a pathologist, based on surgical resection as defined by prior 
studies 
• Investigator-assessed response rate per RECIST v1.1 
• DFS and OS
• Pathological response in PD-L1-positive and PD-L1-negative groups
• Overall response rate in PD-L1-positive and PD-L1-negative groups based on mutational burden
Statistical Methods and Data Analysis:
Safety Analyses:
All enrolled patients will be evaluable for safety analyses from the time of their first treatment with 
sirolimus. After study complete, DLTs will be summarized and tabulated by type and grade. DLT rate 


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 6 of 129
by dose level will be calculated as proportion (Patients with DLT/Total patients) along with 95% 
confidence intervals using the Clopper-Pearson method. Chi-square test or Fisher’s exact test will be 
used to compare the probability of DLT between the different other factors, such as PD-L1 status, dose 
levels, etc. respectively.
Other adverse events (toxicity) will be listed and summarized overall and by dose level. Adverse events 
will also be listed by severity, seriousness, and by system organ class. The number and percentage of 
subjects who experience AEs will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. No formal statistical comparison between the dose levels or PD-L1 will 
be performed. AEs will be presented with and without regard to causality based on the investigator’s 
judgment. The frequency of overall toxicity, categorized by toxicity grades 1 through 5, will be 
described. Additional summaries will be provided for AEs that are observed with higher frequency.
Efficacy Analyses:
The primary and secondary efficacy analyses will include all enrolled patients who have received at least 
one dose of durvalumab, underwent resection and who do not have EGFR mutant tumors (efficacy 
population).
Primary Efficacy Endpoint
The effectiveness of sirolimus followed by durvalumab will be assessed by complete pathologic response 
rate in the efficacy population. If the null hypothesis is rejected then this is evidence that the response 
rate exceeds 10% when sirolimus followed by durvalumab is given before resection. The one-sided 95% 
confidence interval (CI) for complete pathologic response will be reported. Exact binomial test will be 
used to compare the estimated complete pathologic response rate to the historical reference. 
Secondary Efficacy Endpoints
The complete pathologic response rates for PDL-1 negative and PDL-1 positive patients in the efficacy 
population will be presented separately. 
A comparison of both the complete pathologic response and investigator assessed response rates per 
RECIST v1.1 rates between the PD-L1 positive and PD-L1 negative groups will be performed by 
calculating the lower bound of a one-sided 80% CI for the difference, complete pathologic response for 
PDL-1 positive patients − complete pathologic response for PDL-1 negative patients. Chi-square test or 
Fisher’s exact test will be used to compare the efficacy in term of response rate between the different 
groups stratified by other factors, respectively. Logistics regression model will be further employed to 
test the adjusted effect of each other factor on the response rate after adjusting for other clinical factors 
and demographic factors, respectively. Correlation of response will be performed for tumor mutation 
burden using spearman correlation coefficient and tested with Wald’s test.


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 7 of 129
Sample Size Determination:
Pathologic complete response is rare following neoadjuvant chemotherapy but was reported in 0-8% of 
cases39.  The current study is designed to test improved rate of pathologic complete response from 10% 
to 25% with sequential treatment with sirolimus and durvalumab. Using a MinMax 2-stage design, a 
total of 31 patients will be enrolled in 2 stages. At the end of stage I, at least 2 of 16 patients must achieve 
complete pathologic complete response in order for the study to enroll 15 additional patients. The 
regimen of sirolimus followed by durvalumab will be considered to have sufficient efficacy to warrant 
further testing in this patient population if 6 or more of the 31 patients achieve a pathologic CR at the 
end of stage II. The study has 80% power at a 1-sided alpha of 0.1 to show a compelling 25% pCR 
compared to a less compelling rate of 10%. Because this is a signal finding study, an alpha of 0.1 is 
considered reasonable since any promising signal will be confirmed in a larger follow-up study.


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 8 of 129
SCHEDULE OF STUDY ASSESSMENTS
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Informed Consent
Informed consent: study proceduresb
X
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ce 
source 
not 
found. 
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ce 
source 
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found.


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 9 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Consent: genetic sample and analysis 
(optional)
X
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ce 
source 
not 
found.
Study Procedures
Physical exam (full)
X
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source 
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found.
Targeted physical exam (symptom driven)
X
X
X
X
X
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ce 
source 
not 
found.


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 10 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Vital signsc
X
X
X
X
X
X
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source 
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found.
ECGd
X
As clinically indicated
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found.
Concomitant medications
<------------------------------------------------------------------------------------------->
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Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 11 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Demography, including baseline 
characteristics and tobacco use
X
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Eligibility criteria
X
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and 
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Laboratory Assessments


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 12 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Clinical chemistrye
X
Xf
X
X
X
X
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Hematologye
X
Xf
X
X
X
X
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found.
TSHg, (reflex free T4h)
X
X
X
X
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found.


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 13 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Hepatitis B and C and HIV
X
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source 
not 
found.
Pregnancy testi
X
X
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source 
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found.
Sirolimus level for batch analysis
X
8.1.2
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
10.1.1


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 14 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
AE/SAE assessment j
<------------------------------------------------------------------------------------------------------->
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IP administration
Sirolimus
X
5.1
Durvalumabk
X
X
5.2
Optional Heavy Water (D2O)
X
X
X


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 15 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Other assessments and assays
Blood biomarker samples for immunologic 
analysis
X
X
X
X
X
Xm
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Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 16 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Tumor biopsy (newly acquired/fresh if 
amenable to core biopsy)
X
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rror! 
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found.
Tumor biopsy (archival, required for 
diagnosis and PD-L1 assessment)
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Fresh tumor and lymph node samples for 
immunologic analysis
X
Efficacy evaluations


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 17 of 129
Screening
Sirolimus
Durvalumab
C1
Durvalumab
C2
Pre-
surgery
Surgery
Study 
DC
Follow-
up
Week
-4 to 0
0
3
6
8-9
Day
-28 to 0
1-21
22
+/- 3 daysa
43
+/- 3 daysa
57-64
+/- 10 days
Post 
Surgery 
30 +/- 7 
days
Every 3 
months 
for 2 
years
For 
details 
see 
Section
Tumor evaluation (CT or MRI) 
(RECIST 1.1) l within 6 weeks of C1D1
Xn
X
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source 
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found.
Pathologic response assessment
X
a
If cycle 2 day 1 visit is delayed, all subsequent visits will be delayed accordingly
b           Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy sample 
acquisition and analysis prior to randomization.  The collection of tumor biopsies at the time of progression prior to retreatment is mandated; the Investigator must consult with 
the Study Physician if such sampling is not feasible. 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 study assignment.
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 T4 may only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 18 of 129
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 
j
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed 
k
Results for LFTs, electrolytes, full blood count and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or 
Investigator prior to dosing.
l
RECIST assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest, abdomen (including liver and adrenal glands) 
and pelvis. Pelvic imaging is 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.  Repeat assessments will be performed as close as possible to surgery date. 
m       Peripheral blood collection for biomarker analysis will be obtained at 3- and 6-months post-surgery
n      Screening/Baseline Cross-sectional Imaging (CT, PET, or MRI) for RECIST should be within 6 weeks of starting C1D1 of trial therapy 
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; T4  Thyroxine; TSH  Thyroid-stimulating hormone.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 19 of 129
TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS .........................................................................................................2
SCHEDULE OF STUDY ASSESSMENTS ............................................................................8
TABLE OF CONTENTS .......................................................................................................12
ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................17
1.
INTRODUCTION..................................................................................................22
1.1
Disease background ...............................................................................................22
1.1.1 
Immunotherapy in NSCLC ....................................................................................22
1.1.2
Potential role of mTOR inhibition in NSCLC and immunologic effects...............23
1.2
Durvalumab background/non-clinical and clinical experience..............................25
1.3
Sirolimus background/non-clinical and clinical experience ..................................25
1.4
Research hypothesis...............................................................................................26
1.5
Rationale for conducting this study........................................................................26
1.6
Benefit/risk and ethical assessment........................................................................31
1.6.1
Potential benefits....................................................................................................31
1.6.2
Overall risks ...........................................................................................................31
2.
STUDY OBJECTIVES..........................................................................................38
2.1
Co-Primary objective(s).........................................................................................38
2.2
Secondary objective(s)...........................................................................................38
2.3
Exploratory objective(s).........................................................................................38
3.
STUDY DESIGN...................................................................................................39
3.1
Overview of study design.......................................................................................39
Table 1: Neoadjuvant Study Treatment dosing regimen ........................................................40
3.2
Study schema .........................................................................................................41
3.3
Surgical Resection..................................................................................................42
3.4
Study oversight for safety evaluation.....................................................................42
4.
PATIENT SELECTION ........................................................................................43


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4.1
Inclusion criteria.....................................................................................................43
4.2
Exclusion criteria ...................................................................................................45
4.3
Withdrawal of patients from study treatment and/or study....................................47
4.4
Replacement of patients .........................................................................................49
5.
INVESTIGATIONAL PRODUCT(S)...................................................................50
5.1
Durvalumab............................................................................................................50
5.1.1
Formulation/packaging/storage..............................................................................50
5.1.2
Durvalumab doses and treatment regimens ...........................................................50
5.1.3
Study drug preparation...........................................................................................50
5.1.4
Monitoring of dose administration.........................................................................51
5.1.5
Accountability and dispensation ............................................................................52
5.1.6
Disposition of unused investigational study drug ..................................................52
5.2
Sirolimus ................................................................................................................52
5.2.1
Formulation/packaging/storage..............................................................................52
5.2.2
Doses and treatment regimens ...............................................................................53
5.2.3
Dose administration ...............................................................................................53
5.2.4
Monitoring of dose administration.........................................................................53
5.2.5
Disposition of unused investigational study drug ..................................................53
5.3
Heavy Water (D2O) ...............................................................................................53
6.
TREATMENT PLANT..........................................................................................54
6.1
Patient enrollment ..................................................................................................54
6.2
Dosage and administration.....................................................................................54
6.3
Definition of DLT ..................................................................................................54
6.4
Toxicity management guidelines ...........................................................................56
6.4.1
Durvalumab............................................................................................................56
6.4.2
Sirolimus ................................................................................................................57
6.4.3
Potential Overlapping Toxicites.............................................................................58
7.
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S)...................................................................................................59


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7.1
Restrictions during the study..................................................................................59
7.2
Concomitant treatment(s).......................................................................................61
7.2.1
Permitted concomitant medications .......................................................................61
7.2.2
Excluded concomitant medications........................................................................62
8.
STUDY PROCEDURES .......................................................................................65
8.1
Schedule of study procedures.................................................................................65
8.1.1
Screening phase......................................................................................................65
8.1.2
Treatment phase .....................................................................................................66
8.1.3
End of treatment.....................................................................................................66
8.2
Biological sampling procedures.............................................................................67
8.2.1
Biomarker/pharmacodynamic sampling and evaluation methods .........................67
8.2.2
Blood-based Studies for immunologic analysis.....................................................71
8.2.3 Sirolimus Level Collection............................................................................................72
8.2.3
Estimate of volume of blood to be collected..........................................................73
8.2.4
Archival tumor samples and fresh tumor biopsies use beyond PD-L1..................74
8.2.5
Archival tumor samples .........................................................................................74
8.2.6
Withdrawal of informed consent for donated biological samples .........................74
9.
DISEASE EVALUATION AND METHODS ......................................................74
9.1.1
Pathologic Response Assessment ..........................................................................74
9.1.2
Radiographic Response Assessment of Anti-tumor effect.....................................75
10.
ASSESSMENT OF SAFETY................................................................................82
10.1.1
Clinical laboratory tests..........................................................................................82
10.1.2
Physical examinations............................................................................................84
10.1.3
Vital signs...............................................................................................................85
10.1.4
Early patient review for safety ...............................................................................85
10.1.5
WHO/ECOG performance status...........................................................................85
10.1.6
Other safety assessments........................................................................................86
10.2
Safety parameters...................................................................................................86
10.2.2
Definition of serious adverse events ......................................................................87


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10.2.3
Definition of adverse events of special interest (AESI).........................................88
10.2.4
Safety data to be collected following the final DCO of the study .........................90
10.3
Assessment of safety parameters ...........................................................................91
10.3.1
Assessment of severity...........................................................................................91
10.4
Recording of adverse events and serious adverse events.......................................92
10.4.1
Study recording period and follow-up for adverse events and serious 
adverse events ........................................................................................................93
10.4.2
Causality collection................................................................................................93
10.4.3
Relationship to protocol procedures.......................................................................94
10.4.4
Adverse events based on signs and symptoms.......................................................94
10.4.5
Adverse events based on examinations and tests...................................................94
10.4.6
Hy’s Law................................................................................................................95
10.4.7
Disease progression................................................................................................95
10.4.8
New cancers ...........................................................................................................95
10.4.9
Deaths.....................................................................................................................95
10.4.10
Follow-up of unresolved adverse events................................................................96
10.4.11
Post-study events....................................................................................................96
10.5
Reporting of serious adverse events.......................................................................97
10.5.1
Reporting of deaths to AstraZeneca.......................................................................98
10.5.2
Other events requiring reporting ............................................................................98
10.5.3
Overdose ................................................................................................................98
10.5.4
Hepatic function abnormality.................................................................................98
10.5.5
Pregnancy...............................................................................................................99
10.5.6
Maternal exposure..................................................................................................99
10.5.7
Paternal exposure .................................................................................................100
10.6
Medication error...................................................................................................100
11.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ..........102
11.1
Description of analysis sets..................................................................................102
11.1.1
Safety analysis set ................................................................................................102


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11.1.2
Efficacy analysis set.............................................................................................102
11.2
Methods of statistical analyses.............................................................................102
11.2.1
Safety analyses.....................................................................................................102
11.2.2
Efficacy analyses..................................................................................................103
11.2.3
Exploratory analyses ............................................................................................103
11.2.4
Interim analyses ...................................................................................................103
11.3
Determination of sample size...............................................................................104
12.
ETHICAL AND REGULATORY REQUIREMENTS.......................................105
12.1
Ethical conduct of the study.................................................................................105
12.2
Ethics and regulatory review................................................................................105
12.3
Informed consent and confidentiality...................................................................105
12.4
Changes to the protocol and informed consent form ...........................................106
12.5
Audits and inspections .........................................................................................107
13.
STUDY MANAGEMENT...................................................................................108
13.1
Training of study site personnel...........................................................................108
13.2
Monitoring of the study........................................................................................108
13.2.1
Source data...........................................................................................................108
13.3
Study timetable and end of study.........................................................................108
14.
DATA MANAGEMENT.....................................................................................108
15.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ..................109
15.1
Identity of investigational product(s)...................................................................109
16.
LIST OF REFERENCES .....................................................................................110
LIST OF TABLES
TABLE 1: Neoadjuvant Study Treatment regimens………………………………………
TABLE 2: Criteria for interruption and reinitiation of Sirolimus…………………………..
TABLE 3: Highly Effective Methods of Contraception (<1% Failure Rate)………………..
TABLE 4: Permitted Supportive Medications………………………………………………
TABLE 5: Prohibited Concomitant Medications……………………………………………


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Date:  11 February 2022
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TABLE 6: List of CYP3A4 strong and moderate inhibitors and inducers
TABLE 7: Hematology Laboratory Tests…………………………………………………...
TABLE 8: Clinical Chemistry (Serum or Plasma) Laboratory Tests……………………….
TABLE 9: Urinalysis Tests…………………………………………………………………
TABLE 10: Volume of Blood to be Drawn From Each Patient………………………………
LIST OF FIGURES
Figure 1. Study Schema.............................................................................................................46
LIST OF APPENDICES
Appendix 1.
Dosing Modification and Toxicity Management Guidelines for Immune-
Mediated, Infusion- Related, and Non-Immune–Mediated Reactions 
(MEDI4736 Therapy) 
Appendix 2.
Schedule of Study Procedures: Follow-Up for Patients Who Have Completed 
Durvalumab  Treatment and Achieved Disease Control (Until Confirmed 
Progression of Disease) and  Patients Who Have Discontinued Durvalumab 
Due to Toxicity in the Absence of Confirmed  Progression of Disease ..........123
Appendix 3.
American Joint Committee on Cancer Non-small cell Lung Cancer Staging, 8th 
Edition
Appendix 4. 
Information on Possible Drug Interactions
Appendix 5. 
Memory Aid for Heavy Water
Appendix 6. 
Trial Outline Patient Handouts
 ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody


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Date:  11 February 2022
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Abbreviation or 
special term
Explanation
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APC
Antigen-presenting cells
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CL
Clearance
Cmax
Peak concentration
Cmax,ss
Peak concentration at steady state
Cmin
Trough concentration
Cmin,ss
Trough concentration at steady state
CNS
Central nervous system
CR
Complete response
CT
Computed tomography
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
DC
Disease control
DCR
Disease control rate
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
Disodium edetate dihydrate


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Abbreviation or 
special term
Explanation
Fc
Fragment crystallizable
FFPE
Formalin fixed paraffin embedded
FSH
Follicle-stimulating hormone
FTIH
First-time-in-human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GLP
Good Laboratory Practice
HCl
Hydrochloride
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IGF
Insulin-like growth factor
IgG1
Immunoglobulin G1
IgG2
Immunoglobulin G2
IGSF
Immunoglobulin superfamily
IHC
Immunohistochemistry 
IL
Interleukin
imAE
Immune-mediated adverse event
IRB
Institutional Review Board
IV
Intravenous(ly)
MAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
Micro ribonucleic acid
MRI
Magnetic resonance imaging


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Abbreviation or 
special term
Explanation
mRNA
Messenger ribonucleic acid
MTD
Maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NK
Natural killer
NOAEL
No-observed-adverse-effect level
NSCLC
Non-small cell lung cancer
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
PVC
Polyvinyl chloride
Q2W
Every 2 weeks
Q3M
Every 3 months
Q3W
Every 3 weeks
Q4W
Every 4 weeks
Q12W
Every 12 weeks
QoL
Quality of life


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Abbreviation or 
special term
Explanation
QTc
Time between the start of the Q wave and the end of the T wave corrected 
for heart rate
QTcF
QT interval on ECG corrected using the Frederica’s formula
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
Serious adverse event
SD
Stable disease
SID
Subject identification
sPD-L1
Soluble programmed cell death ligand 1
SOCS3
Suppressor of cytokine signaling 3
SUSAR
Suspected unexpected serious adverse reaction
t½
Half life
TEAE
Treatment-emergent adverse event
TIL
Tumor infiltrating lymphocyte
Tmax
Time to peak concentration
Tmax,ss
Time to peak concentration at steady state
TNF-α
Tumor necrosis factor alpha
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
USA
United States of America
WFI
Water for injection
WHO
World Health Organization


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1.
INTRODUCTION
1.1
Disease background
Lung cancer is the number one cause of cancer-related death in men and women in the United 
States. Based on Surveillance Epidemiology and End Results Program (SEER) data, there will 
be an estimated 222,500 new cases and 155,870 lung cancer deaths in the United States in 20171. 
Unfortunately, only 16% of patients are diagnosed with localized disease, and despite this early 
stage, 5-year survival is less than 60%. Another 22% of patients are diagnosed with lymph-node 
positive disease and again despite the potential for cure, less than 30% are alive five years later1. 
Non-small cell lung cancer (NSCLC), accounts for over 80% of lung cancer diagnoses, and 
adenocarcinoma and squamous cell carcinoma are the two most common histologic subtypes. 
In an effort to reduce the risk of local and distant recurrences after resection, both adjuvant and 
neoadjuvant systemic therapies have been tested in NSCLC. Adjuvant cisplatin-based doublet 
chemotherapy for up to 4 cycles has been shown in multiple trials to provide a benefit to patients 
with stage II-III NSCLC2-4. The LACE meta-analysis of 5 large trials showed there was an 
absolute 5-year overall survival benefit of 5.4%5. Patients without nodal involvement, but large 
tumors ≥ 4 cm in diameter were also found to have a statistically significant survival advantage6, 
indicating patients with stage Ib disease can also benefit from systemic therapy. There is fewer 
data on neoadjuvant chemotherapy because the positive adjuvant data led to the early closure 
of some neoadjuvant studies7. A meta-analysis of 13 trials in 2010 demonstrated survival benefit 
with chemotherapy8 and a more recent meta-analysis of 15 randomized studies with over 2000 
patients with NSCLC showed a survival benefit similar to the adjuvant chemotherapy trials9. 
1.1.1 
Immunotherapy in NSCLC
Currently, there are ongoing trials testing immunotherapy as a potential neoadjuvant +/- 
adjuvant treatment for resectable NSCLC10, 11, based on the benefit of such treatment seen in 
patients with unresectable or metastatic disease. Four phase III randomized clinical trials 
demonstrated improved overall survival with immunotherapy targeting the Programmed death 
1 (PD-1)/Programmed death ligand 1 (PD-L1) immune checkpoint when compared to docetaxel 
as second line therapy for advanced NSCLC12-15. While some patients have a remarkable 
clinical response, the majority of NSCLC patients treated with single agent immunotherapies 
do not benefit; response rates ranged from 18%-30% in the metastatic setting12-15. In the 
neoadjuvant setting major pathologic response (MPR) rates have ranged from 45% with 
nivolumab10 and 21% with atezolizumab11. Combination neoadjuvant regimens are also being 
tested; in a phase 2 trial of neoadjuvant nivolumab or nivolumab + ipilimumab, combination 


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PD-1 and CTLA-4 blockade was associated with numerically higher MPR and side effects than 
PD-1 blockade alone16. Ongoing research efforts are underway to both identify biomarkers that 
can predict response to checkpoint inhibitor therapy in NSCLC and develop novel combination 
treatment strategies that enhance the therapeutic efficacy of cancer immunotherapy.
Useful but not entirely predictive or prognostic markers established to date include PD-L1 
expression on the tumor and tumor mutation burden. Comparison across trials of PD-L1 
expression is complicated by different companion diagnostic tests that have been developed 
along with technical variables including biopsy source, processing, detection antibodies, and 
immunohistochemistry cutoffs17. In general, patients with higher tumor PD-L1 expression 
showed improved response rates and overall survival compared to patients with low PD-L1 
expression18. However, patients with low or no PDL-1 expression can still derive a benefit, and 
therefore other markers are being studied. Interestingly, the number of mutations identified in 
the tumor may predict response. Rizvi et al. demonstrated with whole exome sequencing that 
improved response rates and PFS were seen in patients with higher mutational burdens treated 
with pembrolizumab19. Similar findings were seen using next generation sequencing of patients 
treated with PD-1 or PD-L1 directed monotherapy or combination immunotherapy20. The 
development of reliable biomarkers would further improve the ability to interrogate the 
effectiveness of combination therapies in both preclinical and clinical studies. 
Ideal agents to combine with PD-1/PDL-1 checkpoint inhibitor therapy would include well-
tolerated, easy to administer drugs with single agent anti-cancer activity that have a 
complementary effect on the immune system. The mammalian target of rapamycin (mTOR) is 
one such therapeutic target in cancer based on its diverse roles in cell proliferation, metabolism, 
and survival. There are currently three FDA approved inhibitors of mTOR: rapamycin 
(sirolimus) and two rapamycin analogs or rapalogs, everolimus and temsirolimus. Sirolimus has 
long been used as an immunosuppressant in organ transplantation, temsirolimus is approved for 
use in renal cell carcinoma21 and everolimus has FDA indications for multiple solid organ 
malignancies including the treatment of hormone receptor positive HER-2 negative breast 
cancer, neuroendocrine tumors of the pancreas22, lung, or GI tract, and renal cell carcinoma 
(RCC)23. Additionally, single agent neoadjuvant everolimus was tested in resectable NSCLC. 
In this window of opportunity study 23 patients were treated with everolimus (5 or 10mg daily) 
for 3 to four weeks, followed by resection, with evidence of dose dependent, metabolic, and 
anticancer activity24. 
1.1.2
Potential role of mTOR inhibition in NSCLC and immunologic effects


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Pharmacological inhibition of the mTOR pathway can modulate both innate and adaptive 
immunity. Modulation of the innate immune system by mTOR inhibition can be seen in the 
known inflammatory side effects including fever, pneumonitis, anemia of inflammation as well 
as the promotion of inflammatory cytokines IL-1B and IL-1225. Rapamycin has been shown to 
decrease plasmacytoid dendritic cell production of interferon26. Additionally, there is 
accumulating understanding of rapamycin and rapalogs impact on T cell activation and 
differentiation. Using a well described mouse model, Araki et al. showed increased numbers of 
virus specific memory CD8 T-cells following treatment with rapamycin. Low doses of 
rapamycin led to increased numbers of memory T cell precursors and regulation of memory T 
cell differentiation occurs through the mTORC1 pathway27.  The mTOR pathway is involved in 
the regulation of FOXP3 expression in regulatory T cells28, 29. In a study of metastatic RCC 
patients on everolimus, better clinical responses were seen in patients that developed high 
expression of tumor specific Th1 cells and lower regulatory T cells (Tregs)30. 
The interaction of mTOR inhibition with PD-1/PDL-1 pathway has been studied in preclinical 
models. In genetically engineered mouse models of lung cancer, mTOR inhibition led to 
decreased tumor growth, increased tumor-infiltrating lymphocytes (TILSs) and decreased 
Tregs31, but there is some controversy over the mechanism. In that paper mTOR activation 
reportedly up-regulated PD-L1 while mTOR pathway inhibition with rapamycin decreased PD-
L131. A subsequent study using a murine model of RCC and human RCC cells showed that 
everolimus in combination with anti-PDL1 therapy up-regulated PD-L1 on the cell surface, 
indicating this mechanism underlies the therapeutic benefit of combination therapy32. 
Additionally, rapamycin was shown to enhance anti-PD-L1 treatment with durable tumor 
control in an immunogenic model of oral cavity cancer33. These preclinical studies provide 
evidence of significantly enhanced antitumor activity with combined mTOR plus PD-1/PD-L1 
targeted therapy over single agent immunotherapy in 3 different solid tumor models (RCC, 
NSCLC, and oral cancer).
The purpose of this study is to evaluate the ability of the mTOR inhibitor sirolimus given prior 
to durvalumab, an engineered human IgG1 kappa monoclonal antibody targeting PD-L1, to 
produce pathologic responses in the neoadjuvant setting in patients with early stage NSCLC 
who have a pretreatment biopsy.  Clinical staging of NSCLC is based on computed tomography 
(CT) of the chest and upper abdomen, positron emission tomography (PET) and brain CT or 
magnetic resonance imaging (MRI) to rule out metastatic disease. These studies and any 
necessary additional functional assessments by attending thoracic surgeons will be used to 
assess the potential for curative-intent resection. The study will only include patients with 
surgically resectable early stage NSCLC (I, II, or IIIA disease) and who are deemed suitable for 
surgical resection without metastatic disease and have sufficient initial biopsy material to 


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analyze biomarkers. The subsequent surgical tumor resection from these patients will allow 
determination of pathologic response rates and investigation of potential predictive biomarkers 
from the pretreatment biopsy. Additional peripheral blood immune-phenotyping by flow 
cytometry will describe the evolution of immune related markers associated with response in 
the tumor biopsy specimen after treatment. 
1.2
Durvalumab background/non-clinical and clinical experience
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure. 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune 
for use in the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). ). 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-γ49.  In vivo 
studies have shown that durvalumab inhibits tumor growth in xenograft models via a 
T-cell-dependent mechanism49. Based on these data, durvalumab is expected to stimulate the 
patient’s 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. 
To date durvalumab has been given to more than 8000 patients as part of ongoing studies 
either as monotherapy or in combination with other anti-cancer agents.  Details on the safety 
profile of durvalumab monotherapy are summarized in Section 0 and Section 6.3. Refer to the 
current durvalumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics. 
1.3
Sirolimus background/non-clinical and clinical experience
Sirolimus inhibits mTOR, a highly conserved serine-threonine kinase that is a master regulator 
of protein synthesis, cell growth, cell proliferation, angiogenesis and cell survival. mTOR forms 
two distinct complexes (mTORC-1 with raptor and mTORC-2 with rictor)36. Signaling via 
mTORC-1 leads to activation of p70 S6 kinase and suppression of 4EBP1, initiating translation 


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of cyclin D1, C-myc, and Mcl-1, which are known oncogenic proteins. The mTORC-2 complex 
is known to be involved in survival via AKT/PI3 kinase pathways as well as cytoskeletal 
regulation via protein kinase C36. Sirolimus binds to FK Binding Protein-12 (FKBP-12), which 
then binds to and inhibits mTOR thereby preventing T cell activation and suppresses cytokine-
driven T cell proliferation. Additionally, mTOR blockade with sirolimus may up regulate AKT 
via a negative feedback loop37.  
Rapamycin is currently FDA approved for the prophylaxis of kidney transplant rejection and 
the treatment of lymphangioleiomyomatosis. Dosing as an immunosuppressant for the 
aforementioned indications ranges from 6-15 gm loading dose and 2-5 mg daily doses 
thereafter, with adjustments made based on trough levels for goal 12-20ng/ml34. Interestingly, 
a dosing scheme on the higher range was recently studied for its direct anti-cancer effects in a 
window of opportunity head and neck cancer trial35. Patients received a loading dose of 15mg 
followed by 5mg daily dosing, with down titration if troughs were > 20 ng/ml for 21 day 
treatment prior to curative intent surgery in 15 patients and chemo-radiation in 1 patient. Five 
patients experienced a > 25% tumor shrinkage including one complete response, and there were 
no significant changes in CD3, CD4, CD8 or CD19+ circulating lymphocytes35. This dose led 
to dramatic reduction in pS6 and pAKTS473 and was well tolerated with mostly grade 1-2 
thrombocytopenia and neutropenia, and only one grade three adverse event, hypokalemia35. 
1.4
Research hypothesis
We hypothesize that administration of sirolimus, an mTOR inhibitor prior to durvalumab, an 
engineered human IgG1 kappa monoclonal antibody targeting PD-1, will demonstrate a good 
safety profile and produce objective responses in clinical Stage I-IIIA NSCLC. We plan to 
assess established markers that correlate with response including PD-L1 expression in the 
tumors and tumor mutation burden by next generation sequencing. As these markers are not 
perfect and some patients with low PD-L1 and mutational burden may derive benefit, additional 
study of immune mechanisms is needed. Moreover, there is significant interest in developing 
combination therapy regimens that enhance the immune system response to cancer of patients 
that are PD-L1 and mutational burden low. Our focus on biomarkers of response will help 
identify patients who will benefit from this treatment strategy.
1.5
Rationale for conducting this study
Given the significant mortality associated with potentially resectable NSCLC, additional 
treatment options are desperately needed. Checkpoint inhibitor therapy has shown remarkable 
efficacy in some patients, but unfortunately the majority of patients do not benefit from this 
modality of therapy. Recent murine models and translational studies suggest that mTOR 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
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Date:  11 February 2022
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pathway inhibition can enhance immunity and may increase PD-L1 targets on cancer cells. 
Furthermore, sirolimus, an FDA approved mTOR inhibitor, is safe and well tolerated. These 
findings lay the foundation for the use of sequential therapies that enhance the function of PD-
1/PDL-1 targeted therapies. We therefore propose to conduct a phase Ib trial to evaluate the 
safety and tolerability as well as efficacy of sirolimus followed by durvalumab for neoadjuvant 
treatment of resectable NSCLC.
 
1.5.1.1
Role of neo-adjuvant studies in biomarker discovery
Neoadjuvant treatment protocols such as this allow a unique window of opportunity to assess 
biologic effects of novel combination or sequential therapies and limit confounding effects. 
Commonly, patients with heavily pre-treated or refractory disease are treated with new agents 
or regimens, but prior therapy may induce cellular and immunologic alterations that impact 
treatment responses. We have shown at the Winship Cancer Institute that this neoadjuvant 
paradigm is feasible, from a patient willingness perspective to delay surgery as well as 
logistically keeping to defined timelines for biopsy, staging, treatment, and surgical resection24. 
Furthermore, there is institutional expertise in the areas of T cell exhaustion, checkpoint 
inhibitor therapy, and chronological immune assessment of peripheral blood and tissue. As 
such, neoadjuvant trials will enable us to evaluate sequential therapies utilizing checkpoint 
inhibitors where one can assess the immune environment before and after treatment. It is critical 
to develop highly predictive biomarkers of response and to study the evolution of immune-
related markers with treatment with sirolimus followed by durvalumab. 
1.5.1.2
Correlative studies rationale
Cancer can escape the immune system through multiple mechanisms including the manipulation 
of cells with immunosuppressive phenotypes. In addition, it has been shown that elements of 
both the innate and adaptive immune systems have anti-tumor functions. Therefore, it is 
necessary to study the global immune modulatory effects of combination durvalumab and 
sirolimus therapy to further elucidate mechanisms of action in different patients with lung 
cancer. 
Tumor based and systemic markers have been evaluated, but no definitive biomarker has been 
established. The predictive value of PDL-1 expression on the tumor as measured by 
immunohistochemistry (IHC) varies across tumor types, line of therapy, and even among trials 
with similar patients40. Furthermore, PDL-1 expression may: change over time, not be uniform 
across the tumor, and be influenced by other cancer therapies. Tissue samples will be obtained 
pre-treatment and at resection for immunohistochemistry, immunofluorescence microscopy, 
and RNA sequencing.


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Peripheral blood will be collected at baseline, and pre-specified time-points during treatment, 
at resection, and at follow-up in order to perform multiple investigational assays. Flow 
cytometric analysis of peripheral blood of patients on checkpoint inhibitor therapies has shown 
promise in interrogating mechanisms of response. Specifically, a significant transient rise in 
Ki67+ PD1+ CD8 T-cells has been correlated with clinical response to pembrolizumab in 
metastatic melanoma patients41. Similar findings were seen in NSCLC patients that responded 
to anti-PD-1 therapy42 and additional study elucidated the importance of the co-stimulatory 
receptor CD28 in mediating this response43. The role of inflammatory cytokines as predictive 
and/or prognostic variables is also being studied and high levels correlated with poor response 
in melanoma patients on pembrolizumab41.  
Recent murine studies have furthered our understanding of the proliferative burst that occurs in 
CD8 T-cells after PD1 blockade. Im et al. showed that the proliferative burst is dependent on a 
stem-like CD8 T cell population44. When the stem-like cells are activated, they both self-renew, 
and undergo differentiation into a Tim3+ effector cell that has high expression of effector 
molecules. Importantly, treatment with anti-PD1 greatly enhances the rate of this differentiation 
process, and without the stem-like CD8 T-cell, no expansion of the T-cell pool occurs44. We 
plan to localize and characterize the phenotype and function of analogous stem-like CD8 T-
cells present in NSCLC by analyzing resected tissue and peripheral blood from patients with 
stage I-III disease. 
Additionally, the novel technique of in vivo deuterium labeling (also termed heavy water) may 
be used to evaluate T cell dynamics in study patients. This technique, pioneered by Dr. 
Hellerstein at the University of California Berkley, uses the naturally occurring stable, non-
radioactive isotope deuterium (2H) to measure DNA replication and hence cell proliferation in 
humans. This method has been effectively utilized at Emory University to understand CD8 T 
cell homeostasis. Healthy subjects consumed deutierated water during the first two weeks after 
vaccination with yellow fever virus (YFV)45. Deuterium was incorporated into the DNA of 
dividing YFV-specific effector CD8 T cells thus marking all the YFV-specific CD8 T cells 
responding to the vaccine virus. Tracking the deuterium label in these marked cells revealed 
that substantial CD8 T cell proliferation continues to occurs after viral genomes are no longer 
seen in the blood and YFV-specific memory CD8 T cells exhibited a long-intermitotic interval, 
dividing approximately once in ~500 days45. This novel method will enable us to track the 
dynamics of T cell populations in NSCLC patients treated with combination mTOR and 
Durvalumab therapy in vivo as part of an optional labelling study. 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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1.5.1.3
Durvalumab dose rationale
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with 
advanced solid tumors and from a Phase I trial performed in Japanese patients with advanced 
solid tumor (D4190C00002).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached 
linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a particular 
regimen given the linearity seen at doses higher than 3 mg/kg. The expected half-life with doses 
≥3 mg/kg Q2W is approximately 17 days. A dose-dependent suppression in peripheral sPD-L1 
was observed over the dose range studied, consistent with engagement of durvalumab with PD-
L1. A low level of immunogenicity has been observed. No patients have experienced immune-
complex disease following exposure to durvalumab (For further information on 
immunogenicity, please see the current IB). 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W47. Multiple simulations indicate that a similar overall exposure is 
expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by AUCss 
(4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median 
Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold). Clinical activity with the 
20 mg/kg Q4W dosing regimen is anticipated to be consistent with 10 mg/kg Q2W with the 
proposed similar dose of 20 mg/kg Q4W expected to (a) achieve complete target saturation in 
majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and 
clinical activity in diverse cancer populations; (c) maintain sufficient PK exposure in case of 
ADA impact; and (d) achieve PK exposure that yielded maximal antitumor activity in animal 
models.
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg 
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg Q4W. 


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Study Number 19-20015
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Clinical data
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical 
information including safety, efficacy and pharmacokinetics at the 20mg/kg Q4W regimen.
1.5.1.4
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 ≤0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg. Simulation 
results demonstrate that body WT-based and fixed dosing regimens yield similar median steady 
state PK concentrations with slightly less overall between-patient variability with fixed dosing 
regimen. 
Similar findings have been reported by others48, 50, 51, 52. Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies50. 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 parameters51.  
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 Q3W durvalumab is included in the current study. A 3 week interval 
is chosen to keep within neoadjuvant window. 
1.5.1.5
Sirolimus dose rationale
Rapamycin is currently FDA approved for the prophylaxis of kidney transplant rejection and 
the treatment of lymphangioleiomyomatosis. Dosing as an immunosuppressant for the 
aforementioned indications ranges from 6-15 gm loading dose and 2-5 mg daily doses 
thereafter, with adjustments made based on trough levels for goal 12-20ng/ml34. Interestingly, 
a dosing scheme on the higher range was recently studied for its direct anti-cancer effects in a 
window of opportunity head and neck cancer trial35. Patients received a loading dose of 15mg 
followed by 5mg daily dosing, with down titration if troughs were > 20 ng/ml for 21 day 
treatment prior to curative intent surgery in 15 patients and chemo-radiation in 1 patient. Five 
patients experienced a > 25% tumor shrinkage including one complete response, and there were 


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Study Number 19-20015
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Date:  11 February 2022
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no significant changes in CD3, CD4, CD8 or CD19+ circulating lymphocytes35. This dose led 
to dramatic reduction in pS6 and pAKTS473 and was well tolerated with mostly grade 1-2 
thrombocytopenia and neutropenia, and only one grade three adverse event, hypokalemia35. 
1.6
Benefit/risk and ethical assessment
1.6.1
 Potential benefits
1.6.1.1
Durvalumab
Durvalumab is currently FDA approved for use in patients with unresectable stage III NSCLC 
who completed at least two cycles of concurrent platinum-based chemotherapy and definitive 
radiation within 42 days, based on the PACIFIC study (NCT02125461). This was a multicenter, 
double-blind, placebo-controlled study of patients with WHO performance status of 0-1 and no 
prior documented autoimmune disease or need for systemic immunosuppression, and excluded 
those who progressed following concurrent chemotherapy and radiation. Patients were 
randomized 2:1 to receive durvalumab or placebo every 2 weeks for up to 12 months, 
unacceptable toxicity or progression. Durvalumab was well tolerated and improved both 
progression free53 and overall survival54.
1.6.1.2
Sirolimus
There are no known benefits of sirolimus in patients with NSCLC. 
1.6.1.3
Heavy Water
There are no known benefits of low dose heavy water in patients with NSCLC. 
1.6.2
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 immunosuppressants 
and/or endocrine therapy. These immune mediated effects can occur in nearly any organ system, 


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 39 of 129
and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, 
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 
hyper-thyroidism.
Neo-adjuvant studies additionally pose the risk of delaying or preventing surgery due to 
treatment related toxicities that may make surgery not feasible. Neoadjuvant PD-1 pathway 
targeting therapies have not significantly precluded surgery in ongoing single agent studies. 
Furthermore, neoadjuvant everolimus was well tolerated prior to surgery in NSCLC and 
neoadjuvant sirolimus was well tolerated prior to surgery in head and neck squamous cell 
carcinoma patients. However, the risks of combination durvalumab and sirolimus are not 
known. The dose limiting toxicity assessment of combination therapy portion of this study must 
be completed as outlined in section 5.1. Furthermore, a low dose of sirolimus, which 
corresponds to the target immunologic dose, will be administered.
1.6.2.1
Risk associated with durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis pneumonitis/ILD, 
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, hypophysitis and 
adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases in creatinine, 
pancreatitis/increases 
in 
amylase 
and 
lipase, 
rash/pruritus/dermatitis, 
myocarditis, 
myositis/polymyositis, other rare or less frequent inflammatory events including 
neurotoxicities, infusion-related reactions, hypersensitivity reactions, and infections/serious 
infections. 
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab IB. Further information on these risks can be found in the 
current version of the durvalumab IB.
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 15% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9.4% of patients experienced an AE that resulted in permanent discontinuation 
of durvalumab and approximately 6.5% of patients experienced an SAE that was considered to 
be related to durvalumab by the study investigator.
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 adverse events (Appendix 1)


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Study Number 19-20015
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A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
1.6.2.2
Risk associated with Sirolimus
The safety profile of sirolimus differs based on indication (renal transplant or 
lymphangioleiomyomatosis) and goal trough range. As there are added complicating medical 
factors in the post-transplant population, detailed below are the reported side effects in patients 
with lymphangiolyomyomatosis. 
Safety was assessed in a controlled trial involving 89 patients with lymphangioleiomyomatosis, 
46 of whom were treated with Rapamune. The adverse drug reactions observed in this trial were 
consistent with the known safety profile for renal transplant patients receiving Rapamune, with 
the addition of weight decreased which was reported at a greater incidence with Rapamune 
when compared to placebo. Adverse reactions occurring at a frequency of ≥ 20% in the 
Rapamune treatment group and greater than placebo include stomatitis, diarrhea, abdominal 
pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract 
infection, headache, dizziness, myalgia, and hypercholesterolemia. 
Additional warnings and precautions in the FDA package insert based on clinical trials and post 
marketing experience include but are not limited to the following:
• Increased Susceptibility to Infection and the Possible Development of Lymphoma:
Increased susceptibility to infection and the possible development of lymphoma and other 
malignancies, particularly of the skin, may result from immunosuppression. Exposure to 
sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using 
a sunscreen with a high protection factor. Oversuppression of the immune system can also 
increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal 
infections, and sepsis. 
• Lung Transplantation Patients– Bronchial Anastomotic Dehiscence
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung 
transplant patients when Rapamune has been used as part of an immunosuppressive regimen. 
• Hypersensitivity Reactions: 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
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Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, 
exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the 
administration of Rapamune 
• Angioedema:
The concomitant use of Rapamune with other drugs known to cause angioedema, such as 
angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing 
angioedema. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also 
potentiate angioedema. In some cases, the angioedema has resolved upon discontinuation or 
dose reduction of Rapamune. 
• Fluid Accumulation and Impairment of Wound Healing:
There have been reports of impaired or delayed wound healing in patients receiving Rapamune, 
including lymphocele and wound dehiscence. mTOR inhibitors such as sirolimus have been 
shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, 
fibroblast proliferation, and vascular permeability. Appropriate measures should be considered 
to minimize such complications. Patients with a body mass index (BMI) greater than 30 may be 
at increased risk of abnormal wound healing based on data from the medical literature. There 
have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural 
effusion, ascites, and pericardial effusions (including hemodynamically significant effusions 
and tamponade requiring intervention in children and adults), in patients receiving Rapamune. 
•Hyperlipidemia:
Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in 
patients treated with Rapamune compared with azathioprine or placebo controls in clinical 
studies. There were increased incidences of hypercholesterolemia (43-46%) and/or 
hypertriglyceridemia (45-57%) in patients receiving Rapamune compared with placebo controls 
(each 23%). The risk/benefit should be carefully considered in patients with established 
hyperlipidemia before initiating an immunosuppressive regimen including Rapamune. 
Any patient who is administered Rapamune should be monitored for hyperlipidemia. If 
detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as 
outlined by the National Cholesterol Education Program guidelines. During Rapamune therapy 
with or without cyclosporine, patients should be monitored for elevated lipids, and patients 
administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the 
possible development of rhabdomyolysis and other adverse effects, as described in the 
respective labeling for these agents. 


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Study Number 19-20015
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•Interstitial Lung Disease/Non-Infectious Pneumonitis 
Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans 
organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified 
infectious etiology have occurred in patients receiving immunosuppressive regimens including 
Rapamune. In some cases, the ILD was reported with pulmonary hypertension (including 
pulmonary arterial hypertension [PAH]) as a secondary event. In some cases, the ILD has 
resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the 
trough sirolimus concentration increases. 
Additional risks that pertain to the renal transplant population include declines in renal function, 
proteinuria, increased risk of calcineurin associated thrombotic microangiopathy, and additional 
opportunistic infections such as PCP and latent viral infections with BK or others. Please refer 
to full prescribing information in the FDA package insert.
Absorption 
“The mean time to peak concentration after ingestion of the oral solution is approximately 1 
hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic 
availability of sirolimus is low, and was estimated to be approximately 14% after the 
administration of Rapamune Oral Solution. In healthy subjects, the mean bioavailability of 
sirolimus after administration of the tablet is approximately 27% higher relative to the solution. 
Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been 
demonstrated at the 2 mg dose level. To minimize variability in sirolimus concentrations, both 
Rapamune Oral Solution and Tablets should be taken consistently with or without food.”
Distribution 
“The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft 
patients, indicating that sirolimus is extensively partitioned into formed blood elements. The 
mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound 
(approximately 92%) to human plasma proteins, mainly serum albumin (97%).” 
Metabolism 
“Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in 
the intestinal wall and liver and undergoes counter-transport from enterocytes of the small 
intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. 
Inducers of CYP3A4 and P-gp decrease sirolimus concentrations.” 
Excretion 


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Study Number 19-20015
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“After a single dose of [14C] sirolimus oral solution in healthy volunteers, the majority (91%) 
of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in 
urine. The mean ± SD terminal elimination half-life (t1⁄2) of sirolimus after multiple dosing in 
stable renal transplant patients was estimated to be about 62 ± 16 hours.”
Patients with Renal Impairment 
“The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, 
there is minimal (2.2%) renal excretion of the drug or its metabolites in healthy volunteers. The 
loading and the maintenance doses of Rapamune need not be adjusted in patients with renal 
impairment.”
Patients with Hepatic Impairment 
“Rapamune was administered as a single, oral dose to subjects with normal hepatic function 
and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic 
impairment. Compared with the values in the normal hepatic function group, the patients with 
mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values 
for sirolimus AUC, respectively, with no statistically significant differences in mean Cmax. As 
the severity of hepatic impairment increased, there were steady increases in mean sirolimus t1/2, 
and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg). The 
maintenance dose of Rapamune should be reduced by approximately one third in patients with 
mild-to-moderate hepatic impairment and by approximately one half in patients with severe 
hepatic impairment. It is not necessary to modify the Rapamune loading dose in patients with 
mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all 
patients with hepatic impairment.” 
Effects of Age, Gender, and Ethnicity 
“Clinical studies of Rapamune did not include a sufficient number of patients > 65 years of age 
to determine whether they will respond differently than younger patients. After the 
administration of Rapamune Oral Solution or Tablets, sirolimus trough concentration data in 
renal transplant patients > 65 years of age were similar to those in the adult population 18 to 65 
years of age. Sirolimus clearance in males was 12% lower than that in females; male subjects 
had a significantly longer t1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose 
adjustments based on gender are not recommended. In the phase 3 trials for the prophylaxis of 
organ rejection following renal transplantation using Rapamune solution or tablets and 
cyclosporine oral solution and/or cyclosporine capsules there were no significant differences in 
mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 
852) patients during the first 6 months after transplantation.”


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1.6.2.3
Risks associated with heavy water
Deuterium (2H) is a naturally occurring, stable, non-radioactive isotope. Occasional cases of 
transient dizziness have been reported on the first day of drinking heavy water and participants 
are warned not to drive for 30 minutes following the intake of the first dose.  No other known 
side effects have been reported.
1.6.2.4
Overall benefit-risk
Standard of care therapy for resectable stage I-IIIA NSCLC, namely post-operative 
chemotherapy in those patients with at least stage II disease, is associated with significant risk 
of recurrent disease. Multiple ongoing single agent and combination therapy trials of 
immunotherapy are on-going and of a similar design to this trial. Both neoadjuvant agents are 
well tolerated individually and care will be given to close monitoring with safety assessments. 
Overall this study has a good risk-benefit profile to both benefit enrolling patients and inform 
future combination therapies. 


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Study Number 19-20015
Edition Number: 4
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2.
STUDY OBJECTIVES
2.1
Co-Primary objective(s)

To evaluate the safety and tolerability of sirolimus followed by durvalumab as 
neoadjuvant treatment by incidence of adverse events, with severity per NCI CTCAE 
v5.0.

To evaluate the efficacy of sirolimus followed by durvalumab as neoadjuvant treatment 
for Stage I, II, and IIIA NSCLC by complete pathologic response at surgical resection 
scored by a pathologist.
2.2
Secondary objective(s)

To evaluate the efficacy of sirolimus in combination with durvalumab as neoadjuvant 
treatment for Stage I, II, and IIIA NSCLC by Investigator-assessed response rate per 
RECIST v1.1, disease free survival and overall survival

To evaluate response to sirolimus in combination with durvalumab in patients with PD-
L1-positive vs. PD-L1-negative tumors by complete pathologic response rate

To evaluate the association between blood mutation burden and response to sirolimus 
and durvalumab by overall response rate in PD-L1-positive and PD-L1-negative groups 
based on mutational burden.

To evaluate impact of neoadjuvant durvalumab and sirolimus on post-surgical recovery 
by length of hospital stay after surgery
2.3
Exploratory objective(s)

To evaluate the immune-mediated effects of combination sirolimus and durvalumab by 
assessment of immune responses by flow cytometry, cytokine analysis, and genetic 
assessments in serial blood and tissue samples and correlate with clinical outcome

To investigate tumor and immune microenvironment changes in tissue samples by 
pathological analyses (which may include immunohistochemistry immunofluorescence) 
of tissue samples pre- and post- neoadjuvant therapy


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3.
STUDY DESIGN
3.1
Overview of study design
This is a Phase Ib open-label, single-arm study in newly diagnosed stage I-IIIA NSCLC patients, 
to test sirolimus in combination with durvalumab as neoadjuvant treatment prior to curative-
intent surgical resection. The safety and tolerability as well as efficacy of combination sirolimus 
with durvalumab will be evaluated in this treatment setting. The study is also designed to 
investigate a number of laboratory correlative studies to define mechanisms of anti-tumor 
activity of sirolimus + durvalumab and several potential predictive biomarkers, which will help 
identify patients who are more likely to respond to treatment. Finally, the study will also include 
DFS and OS as secondary endpoints.
Up to 31 patients with NSCLC will be enrolled in this study at Emory University Winship 
Cancer Institute and affiliated sites. Enrollment will occur in 2 parts based on simon 2 stage 
design, in which at least 2 of the first 16 patients must achieve pathologic complete response in 
order for the study to enroll 15 additional patients.
Eligible patients will complete 2 cycles of outpatient study treatment prior to proceeding to 
standard of care surgical resection. In order to allow a reliable assessment of the contribution of 
sirolimus versus durvalumab to the observed clinical and PD outcome, treatment will start with 
sirolimus 6mg orally for one loading dose followed by 2mg orally once daily three weeks prior 
to the start of durvalumab. Durvalumab will be administered at a dose of 1500mg Q 3 weeks 
starting on C1D1 for up to 2 cycles that are 21 days in length. Pharmacodynamic analysis will 
be done using PD samples collected at baseline (tissue) and with blood samples on day -7, C1D1 
prior to durvalumab, C1D8, C2D1, C2D8 and at the time of surgery (blood and tissue). 
Additional post surgery blood samples will be collected at 1, 3, and 6 months post-surgery. See 
study schedule of assessments for schedule of Biomarker collection. Patients will proceed to 
surgery within a 4-week period post 2nd dose of durvalumab but not earlier than one week after 
the administration of durvalumab i.e. not earlier than C2D8. Additionally, patients will self-
administer heavy water (D2O) 50ml orally three times a day from C1D1 through C1D5 followed 
by 50ml orally twice a day through the day prior to surgery in order to label dividing cells for 
research tracking purposes.
The dose of sirolimus chosen for this study is based on our pre-clinical data that indicate that a 
lower dose is most likely to result in the desirable pharmacodynamics effects on the immune 
system. For clinical use in the renal transplant setting and high immunologic risk transplants, 
sirolimus is recommended at an initial loading dose of 15 mg followed by 5mg/day 
maintenance, with adjustments based on trough level. In lymphangiolyomyomatosis (LAM), 
the recommended dose is 2 mg daily to block mTOR pathway activation; median whole blood 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 47 of 129
sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day 
was 6.8 ng/mL (interquartile range 4.6 to 9.0 ng/mL; n = 37). As the sirolimus treatment phase 
will be only 3 weeks, a single loading dose of 6mg on day 1 will be followed by 2mg daily. No 
dose changes will be made for individual patients given this short term low dose regimen 
designed to reach levels of 5-15 ng/ml, which was noted in pre-clinical studies to correlate with 
proliferation of memory T cells. This lower dose is also likely to be tolerated better by patients. 
As an added safety measure, the first 6 patients will be monitored through hospital discharge 
following surgical resection to assess for dose limiting toxicities (DLTs) related to sirolimus 
followed by durvalumab therapy. DLTs and safety analysis are described in section 6.4.
Patients will be closely monitored for safety and tolerability throughout the study. Safety 
assessments will include collection and monitoring of adverse events and laboratory 
abnormalities graded per the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0 (NCI CTCAE v5.0). Tumor tissue samples, normal lung 
parenchyma, whole blood samples, and optional lymph node samples will be collected for 
biomarker assessments. 
After study treatment discontinuation, patients will be followed per SOC, but information on 
recurrence and survival will be collected every 6 months for up to 2 years after the last patient 
receives the last dose in the study (in person or by phone). Patients who discontinue the study 
due to adverse events will be followed until resolution or stabilization of the adverse event. 
Appropriate dose modifications are described in Section 6.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy.
Table 1: Neoadjuvant Study Treatment dosing regimen
Regimen Description
Agent
Premedications
Precautions
Dose
Route
Schedule
Cycle 
Length
Sirolimus
Take with or 
without food
6 mg on 
day 1, 
followed 
by 2mg 
PO
Once daily
Start on day 1
21 days 
(3 weeks)


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 48 of 129
daily on 
days 2-21
Durvalumab
None required
1500 mg in 
NS or 
D5W
IV over 1 hr
Once every 3 
weeks, starting 
on day 22
3.2
Study schema
Figure 1. Study Schema
Durva: 1500mg of durvalumab
W: week; M: month; SOC: standard of care; Tx: treatment


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 49 of 129
3.3
Surgical Resection
Following neoadjuvant systemic treatment described above, patients will undergo surgical 
resection of the primary tumor and associated lymph nodes. Repeat chest CT scan and/or PET/CT 
scan will be obtained prior to surgical resection. Resection may be accomplished via an open or 
minimally invasive procedure (i.e., thoracotomy, sternotomy, video assisted thoracic surgery 
(VATS) or robotically assisted VATS.)
Anatomic resection via segmentectomy, lobectomy, bilobectomy or pneumonectomy is strongly 
preferred although wedge resection is acceptable for very small (2 cm or less) tumors located 
peripherally where wedge resection permits a wide margin (at least 1 cm in all directions). 
Hilar and mediastinal lymph node dissection or sampling should be performed whenever possible. 
For right sided resections, the recommended sampling includes lymph nodes from levels 4R, 7, 
10R, and 11R. For left sided resections, the recommended sampling includes lymph nodes from 
levels 5/6, 7, 10L, and 11L. 
Pathologic specimens will undergo standard histopathologic and immunohistochemical evaluation 
for lung cancer. Sections of tumor and normal tissue specimens will be fresh frozen and formalin-
fixed for correlative studies. Sections of lymph nodes will be freshly prepared in media and 
formalin-fixed for correlative studies. Whole blood samples will be collected at the time of surgical 
resection for correlative studies. The blood will be processed for PBMC, plasma, and serum for 
correlative studies. 
At the postoperative follow-up visit, patients whose tumors have not demonstrated evidence of 
pathologic response and who have radiographic progression will have an end-of-study treatment 
visit, after which they will be followed per SOC, as deemed clinically appropriate. Whole blood 
will be collected at postoperative follow-up visit and will be processed for plasma, serum, and 
PBMC for correlative studies.
3.4
Study oversight for safety evaluation
There will be a planned safety assessment of the first 6 patients, who will be monitored through 
hospital discharge following surgical resection to assess for dose limiting toxicities (DLTs) related 
to sirolimus followed by durvalumab therapy. If ≥ 2/6 patients have a DLT then additional 
enrollment will be halted until safety assessment is completed. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 50 of 129
4.
PATIENT SELECTION 
4.1
Inclusion criteria
For inclusion in the study patients must fulfill all of the following criteria:
1.
Patients with pathologically documented NSCLC who are deemed to be candidates for 
definitive surgery: Stage will be categorized based on 8th edition of American Joint 
Committee on Cancer (AJCC) Non-small cell Lung Cancer Staging system; see 
Appendix 3.
2.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. Written informed consent and any locally required authorization (eg, Health 
Insurance Portability and Accountability Act in the US) obtained from the patient/legal 
representative prior to performing any protocol-related procedures, including screening 
evaluations. 
3.
Age > 18 years at time of study entry.
4.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
5.
Life expectancy of > 26 weeks
6.            Body weight >30 kg 
7.
Adequate normal organ and marrow function as defined below: 

Haemoglobin ≥9.0 g/dL

Absolute neutrophil count (ANC) 1.5 x 109/L (> 1500 per mm3)

Platelet count ≥100 x 109/L (>100,000 per mm3)

Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). 

AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤5x ULN

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:


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 51 of 129
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)
8.
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: 

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). 

Women ≥50 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).
9.
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.
10.
Patients must consent to pre-treatment research biopsy and study peripheral blood 
collection. 
11.
Patients must have measurable disease, defined by RECIST v 1.1. 
12.
Patient is able to take oral medications
13.
Patient consents to heavy water (D2O) self-administration if on optional heavy water 
labelling study


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 52 of 129
4.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Patients who have had prior therapy for lung cancer including chemotherapy, hormonal 
therapy, or radiotherapy.
2. Concurrent enrolment in another clinical study, unless it is an observational (non-
interventional) clinical study 
3. Prior treatment with anti-PD-1, anti-PDL-1, including durvalumab other PD-1/PDL-1 
pathway targeting agents, or mTOR inhibition. 
4. History of allogenic organ transplantation.
5. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease],  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
6. 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
7. History of another primary malignancy except for


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 53 of 129
a.
Malignancy treated with curative intent and with no known active disease ≥5 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
8. QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms. Patient 
safety and the cardiac SKG should be consulted as needed. 
9. History of active primary immunodeficiency 
10. 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. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA.
11. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab. 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)
12. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days 
after the last dose of IP.
13. 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 
screening to 90 days after the last dose of durvalumab monotherapy.
14. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 54 of 129
15. Prior randomisation or treatment in a previous durvalumab clinical study regardless of 
treatment arm assignment. 
16. Patients with a history of idiopathic pulmonary fibrosis, pneumonitis (including drug 
induced), organizing pneumonia, or evidence of active pneumonitis on screening chest 
CT scan 
17. Inability to stop prohibited concomitant medications listed in Section 7.7.2.
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
4.3
Withdrawal of patients from study treatment and/or study
Stopping Rules: 
Patients must discontinue study treatment if they experience any of the following: 

Pregnancy 

Radiographic and/or symptomatic deterioration attributed to disease progression disease as 
determined by the investigator

Intolerable toxicity related to sirolimus and/or durvalumab, including development of an 
irAE determined by the investigator to be unacceptable given the individual patient’s 
potential response to therapy and severity of the event 

Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues on study treatment 

Use of another non-protocol-specified anti-cancer therapy 
The primary reason for study treatment discontinuation should be documented on the appropriate 
CRF. 
Additional reasons for patient discontinuation include: 

Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 

Investigator or Sponsor determines it is in the best interest of the patient 

Patient non-compliance 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 55 of 129

The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients. 

Patient enrollment is unsatisfactory. 
Permanent discontinuation of study treatment
Discontinuation of study treatment, for any reason, does not impact the patient’s participation in 
the study. A patient who decides to discontinue durvalumab or sirolimus will always be asked 
about the reason(s) for discontinuation and the presence of any AE. The patient should continue 
attending subsequent study visits, and data collection should continue according to the study 
protocol. If the patient does not agree to continue in-person study visits, a modified follow-up must 
be arranged to ensure the collection of endpoints and safety information. This follow-up could be 
a telephone contact with the patient, a contact with a relative or treating physician, or information 
from medical records. The approach taken should be recorded in the medical records. A patient 
that agrees to modified follow-up is not considered to have withdrawn consent or to have 
withdrawn from the study.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, will 
be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see the SoAs). 
All patients will be followed for survival until the end of the study. 
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs as an alternative. 
Patients who have permanently discontinued from further receipt of IP will need to be discontinued 
from the IVRS/IWRS.
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed, such that there is insufficient information to determine the patient’s status 
at that time. Patients who refuse to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.”  Investigators 
should document attempts to re-establish contact with missing patients throughout the study 
period. If contact with a missing patient is re-established, the patient should not be considered lost 
to follow-up and evaluations should resume according to the protocol.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 56 of 129
In order to support key end points of PFS and OS analyses, the survival status of all patients in the 
full analysis and the safety analysis sets should be re-checked, this includes those patients who 
withdrew consent or are classified as “lost to follow up.”

Lost to Follow up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status. (The applicable CRF modules will be updated.)

In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable CRF modules 
will be updated.)   
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. 
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 (eg, survival contact 
telephone calls)

Withdrawal to the use of any samples 
4.4
Replacement of patients
Patients who withdraw consent prior to administration of durvalumab will be replaced. Patients 
who discontinue study treatment prematurely will not be replaced.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 57 of 129
5.
INVESTIGATIONAL PRODUCT(S)
5.1
Durvalumab
5.1.1
Formulation/packaging/storage
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution.  The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 
275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0 
and density of 1.054 g/mL.  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 Investigational Product 
should be kept in original packaging until use to prevent prolonged light exposure. 
5.1.2
Durvalumab doses and treatment regimens
Regimen Description
Agent
Premedications 
Precautions
Dose
Route
Schedule
Cycle 
Length
Durvalumab
None required
1500 mg in 
NS or 
D5W
IV over 1 hr
Once every 3 
weeks, starting 
on day 22
21 days 
(3 weeks)
5.1.3
Study drug preparation
Patients will receive 1500 mg durvalumab via IV infusion q3w for a maximum of 2 doses. Weight 
based dosing (20 mg/kg) will be utilized for any patient whose body weight drops below to 30 kg 
or below (≤30 kg) while on study. 
Preparation of durvalumab doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator’s or 
site’s designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab (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
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 
15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm filter.  Add 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 58 of 129
30.0 mL of durvalumab  (i.e., 1500 mg of durvalumab) 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.
If weight falls to ≤ 30 kg weight-based dosing at 20 mg/kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging 
from 1 to 15mg/mL and delivered through an IV administration set with a 0.2- or 0.22-μm filter.    
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.  If either preparation time or infusion 
time exceeds the time limits a new dose must be prepared from new vials.  Durvalumab does not 
contain preservatives, and any unused portion must be discarded. 
5.1.4
Monitoring of dose administration
Patients will be monitored before, during and after the infusion with assessment of vital signs at 
the times specified in the Schedule of Assessment. Patients are monitored (pulse rate, blood 
pressure) every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped).
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the 
infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The 
standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 8 hours at room 
temperature (otherwise requires new infusion preparation). For management of patients who 
experience an infusion reaction, please refer to the toxicity and management guidelines in Error! 
Reference source not found..


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 59 of 129
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.
5.1.5
Accountability and dispensation
Administration will occur at the study site (Winship Cancer Institute) or Grady Memorial Hospital 
and recorded in medical record as well as study specific event sheet. 
5.1.6
Disposition of unused investigational study drug
Each site will account for all investigational study drug dispensed and also for appropriate 
destruction. Certificates of delivery and destruction must be signed
5.2
Sirolimus
5.2.1
Formulation/packaging/storage
Sirolimus (Rapamune) is supplied as in both an oral solution and tablets for oral administration. 
This study will preferentially use the tablet formulation from commercial supply:
Rapamune Tablets are available supplied in bottle or blister cards as follows: 

NDC 0008-1040-05, 0.5 mg, tan, triangular-shaped tablets marked “RAPAMUNE 0.5 mg” 
on one side; bottle containing 100 tablets. 

NDC 0008-1040-10, 0.5 mg, tan, triangular-shaped tablets marked “RAPAMUNE 0.5 mg” 
on one side; in of 100 tablets (10 blister cards of 10 tablets each). 

NDC 0008-1041-05, 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” 
on one side; bottle containing 100 tablets. 

NDC 0008-1041-10, 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” 
on one side; in of 100 tablets (10 blister cards of 10 tablets each). 

NDC 0008-1042-05, 2 mg, yellow-to-beige triangular-shaped tablets marked 
“RAPAMUNE 2 mg” on one side; bottle containing 100 tablets. 
Rapamune Tablets should be stored at 20° to 25°C [USP Controlled Room Temperature] (68° 
to 77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, light-
resistant container as defined in the USP. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 60 of 129
5.2.2
Doses and treatment regimens
The dose of sirolimus for this study is 6mg orally daily once on day 1, followed by 2mg orally 
daily from day 2 through 21. 
5.2.3
Dose administration
 Patients will self-administer on a continuous once daily dosing schedule. Patients should be 
instructed to take the dose of sirolimus daily in the morning with or without food at 
approximately the same time each day. However, dietary habits around the time of sirolimus 
intake should be as consistent as possible throughout the study. Patients should swallow the 
tablets as a whole and not chew them. 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before 
the next scheduled dose.  The occurrence and frequency of any vomiting during a treatment cycle 
must be noted as an adverse event. If the patient forgets to take her/his dose and does not 
remember before 6:00 PM, then the dose should be withheld that day and sirolimus resumed the 
following day. 
Patients must avoid consumption of St. John’s Wort, Seville oranges, grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose of 
study medication and during the entire study treatment period due to potential CYP3A4 
interaction with the study medication. Patients must avoid concomitant intake of strong and 
moderate CYP3A4/5 inhibitors and inducers. Orange juice is allowed.
5.2.4
Monitoring of dose administration
The patient will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course.
5.2.5
Disposition of unused investigational study drug
Patients will return any unused medication to their study site for disposal by investigaional 
pharmacy services. 
5.3
Heavy Water (D2O)
Deuterated water is 70% D2O and 30% normal H2O and is manufactured and supplied by 
Cambridge Isotope Laboratories. The Emory research pharmacy will sterilely portion out 
individually labeled 50ml conical tubes and provide to trial patients who agree to optional heavy 
water labelling study. Patients will self-administer 50 ml orally TID for the first 5 days to serve as 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 61 of 129
a loading dose (Day 22, C1 Durvalumab). Subsequently, patients will self-administer 50 ml orally 
BID from day 27 until the day prior to surgery. Previous and ongoing studies have shown high 
compliance among donors. Since compliance with drinking the heavy water is critical to achieve 
adequate deuterium enrichment of body water, participants will be encouraged and rewarded for 
completing the memory aid provided (See Appendix 5) to help keep track of the heavy water 
consumption.
6.
TREATMENT PLANT
6.1
Patient enrollment 
Patients will be enrolled following screening procedures on the open label study. Those patients 
who withdraw consent and discontinue the study prior to a dose of durvalumab will be replaced.  
6.2
Dosage and administration
Refer to Section 5.1.4 and 5.1.5 for the administration and monitoring of administration of durvalumab
Refer to Section 5.2.3 and 0 for the administration and monitoring of any additional study drug(s)
6.3
Definition of DLT
Dose-limiting toxicities (DLTs) will be evaluated in the first 6 patients enrolled on the trial. The 
period for evaluating DLTs will be from the time of first administration of durvalumab until 
discharge from the hospital following surgical resection. Grading of DLTs will follow the 
guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0. Continued enrollment of subsequent patients will be allowed during the DLT monitoring 
period. 
If and when ≥2 DLTs are identified in the first 6 patients, then subsequent enrollment will be 
halted until safety review. Patients already started on therapy will continue per protocol. 
A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to 
the investigational product (IP) or investigational regimen (IR), with two exceptions: any 
grade of vitiligo or alopecia will not qualify as a DLT. AEs that are at least possibly related to 
durvalumab-containing regimens shall be assessed as DLTs if they meet any of the following 
criteria:
Hematologic toxicity:


Clinical Study Protocol
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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 62 of 129

Grade ≥3 neutropenia complicated by fever >38.3°C

Grade 4 neutropenia (lasting more than 7 days)

Grade ≥3 thrombocytopenia with significant bleeding

Grade 4 thrombocytopenia (regardless of duration)

Grade 4 anemia (regardless of duration)
Non-hematologic toxicity:

Any Grade 4 non-immune-mediated AE

Any Grade 4 immune-mediated AE, excluding endocrinopathies

Any Grade 3 non-immune mediated AE that does not resolve to ≤Grade 1 or baseline within 
30 days with optimal medical management

Any Grade 3 immune-mediated AE – excluding diarrhea/colitis, pneumonitis, hepatitis, rash, 
neurotoxicity, myocarditis, myositis/polymyositis, endocrinopathies and nephritis – that does 
not resolve to ≤Grade 1 or baseline within 30 days after onset of the event despite optimal 
medical management including systemic corticosteroids

Grade 3 diarrhea or colitis that does not resolve to ≤Grade 1 within 14 days
[both immune- and non-immune-mediated indicated here; the same is the case if not 
specified in remaining bullet points below]

Grade 3 noninfectious pneumonitis

Grade 2 noninfectious pneumonitis that does not resolve to ≤Grade 1 within 3 days of the 
initiation of maximal supportive care

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN with 
concurrent increase in total bilirubin (TBL) ≥2×ULN without evidence of cholestasis or 
alternative explanations (e.g., viral hepatitis, disease progression in the liver; i.e., “Hy’s 
Law”)

ALT or AST >8×ULN or TBL>5×ULN

Grade 3 immune-mediated rash that does not resolve to ≤Grade 1 or baseline within 30 days

Grade 2 rash covering > 30% BSA that does not resolve to ≤Grade 1 or baseline within 30 
days 

Any grade of immune-mediated rash with bullous formation

Grade 3 immune-mediated neurotoxicity (excluding Guillain-Barre and myasthenia gravis) 
that does not resolve to ≤Grade 1 within 30 days

Grade 2 or 3 immune-mediated peripheral neuromotor syndrome (such as Guillain-Barre and 
myasthenia gravis) that does not resolve to ≤Grade 1 within 30 days or that exhibits signs of 
respiratory insufficiency or autonomic instability

Grade 3 immune-mediated myocarditis

Any symptomatic immune-mediated myocarditis that does not become asymptomatic within 
3 days of initiating optimal medical management including systemic corticosteroids


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 63 of 129

Grade 2 or 3 immune-mediated myositis/polymyositis that does not resolve to Grade ≤1 
within 30 days of initiating optimal medical management including systemic corticosteroids 
or that exhibits signs of respiratory insufficiency regardless of optimal medical management

Immune-mediated increase in creatinine >3×ULN, or >3×baseline for patients with a 
baseline creatinine elevated above ULN

Delay in administration of scheduled doses of sirolimus greater than 2 weeks because of 
drug-related toxicity of any grade.
Any treatment-related toxicities that first occurred during the DLT period must be followed for 
resolution to determine if the event qualifies as a DLT as specified in the DLT criteria above.
Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to designation 
as a DLT. 
6.4
Toxicity management guidelines 
6.4.1
Durvalumab 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab are provided in the durvalumab Toxicity 
Management Guidelines (TMGs). Please see APPENDIX 1.
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 should be permanently 
discontinued (see section Error! Reference source not found. of this protocol and the Dosing 
Modification and Toxicity Management Guidelines in Error! Reference source not found.).
Following the first dose of IP, subsequent administration of durvalumab can be modified based on 
toxicities observed as described in the Dosing Modification and Toxicity Management Guidelines 
in Error! Reference source not found.. 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 by the reporting 
investigator.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 64 of 129
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Company.
All toxicities will be graded according to NCI CTCAE, Version5.0. 
6.4.2
Sirolimus
Table 2 Criteria for interruption and re-initiation of Sirolimus
Stomatitis
Description
Management/Next Dose for Sirolimus
Grade 1
Minimal symptoms, 
normal diet
No modifications necessary.
Manage with non-alcoholic or salt water (0.9%) 
mouth wash several times a day 
Grade 2
Symptomatic but can 
eat and swallow 
modified diet
Manage with topical analgesic mouth 
treatments (e.g. benzocaine, menthol or phenol) 
with or without topical corticosteroids (i.e. 
triamcinolone oral paste) 
Grade 3
Symptomatic and 
unable to adequately 
aliment or hydrate 
orally 
Temporary dose interruption until recovery to 
grade ≤1.
Manage with topical analgesic mouth 
treatments (e.g. benzocaine, menthol or phenol) 
with or without topical corticosteroids (i.e. 
triamcinolone oral paste) 
Grade 4
Symptoms associated 
with 
life-threatening 
consequences 
Discontinue Sirolimus and treat with 
appropriate medical therapy. 
*Patients requiring a delay of >2 weeks should go off protocol therapy.
Other Non-
hematologic 
toxicities
Management/Next Dose for Sirolimus
≤ Grade 1
If toxicity is tolerable, no dose adjustment required. Initiate appropriate 
medical therapy and monitor.
Grade 2
If toxicity is tolerable, no dose adjustment required. Initiate appropriate 
medical therapy and monitor. 
If toxicity becomes intolerable, temporary dose interruption until 
recovery to grade ≤1. Re-initiate sirolimus at the same dose.
If toxicity recurs at grade 2, interrupt sirolimus until recovery to grade 
≤1. Re-initiate sirolimus at the same dose.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 65 of 129
Other Non-
hematologic 
toxicities
Management/Next Dose for Sirolimus
Grade 3
Temporary dose interruption until recovery to grade ≤1. Initiate 
appropriate medical therapy and monitor. 
Consider re-initiating sirolimus. If toxicity recurs at grade 3, consider 
discontinuation. 
Grade 4
Discontinue sirolimus and treat with appropriate medical therapy. 
*Patients requiring a delay of >2 weeks should go off protocol therapy.
Hematologic 
Toxicities (anemia, 
neutropenia, 
thrombocytopenia)
Management/Next Dose for Sirolimus
≤ Grade 1
No change in dose
Grade 2
Hold until ≤ Grade 1.  Resume at same dose.
Grade 3
Hold until < Grade 2.  Resume at same dose. *
Grade 4
Off protocol therapy
* Patients who develop grade 3 neutropenia associated with temperature higher than 38.3 C 
should go off protocol therapy.  Patients requiring a delay of >2 weeks should go off protocol 
therapy
6.4.3
Potential Overlapping Toxicites
Based on the pharmacological properties of a large monoclonal antibody and oral small molecule 
inhibitor, there are not anticipated overlapping toxicities. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 66 of 129
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 3) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period (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 (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 3).  
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: 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 67 of 129

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 ≥50 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.
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, less 
than 1% per year) when used consistently and correctly are described in Table 3.  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 3. 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-
releasing transdermal system: e.g. 
Ortho Evra® 

Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only 
highly effective progesterone-based 
a
This is also considered a hormonal method


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 68 of 129
Blood donation
Patients should not donate blood while participating in this study, or for at least 90 days following 
the last infusion of durvalumab.
7.2
Concomitant treatment(s)
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 days 
prior to initiation of study drug to the study completion/ discontinuation visit. Because there is a 
potential for interaction of sirolimus with other concomitantly administered drugs through the 
cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, 
over-the-counter medications, or alternative therapies.  The Principal Investigator should be alerted 
if the patient is taking any agent known to affect or with the potential to affect selected CYP450 
isoenzymes.  Appendix 4 presents guidelines for identifying medications/substances that could 
potentially interact with the study agent(s).
7.2.1
Permitted concomitant medications
Table 4. Permitted 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
Inhaled steroids for COPD, mineralocorticoids (eg 
fludrocortisone for adrenocortical insufficiency), 
and prednisone < 10mg daily
Permitted


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 69 of 129
Standard-of-Care Chemotherapy (with or without Radiation) after Surgical Resection 
After surgical resection of their tumor, patients may receive SOC chemotherapy (with or without 
radiation) after surgical resection of their tumor. Choice of SOC adjuvant therapy will be at the 
discretion of the treating physician, depending on the stage of their disease, as deemed clinically 
appropriate.
7.2.2
Excluded concomitant medications
Table 5. 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. 
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.).


Clinical Study Protocol
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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 70 of 129
Prohibited medication/class of drug:
Usage:
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
Seville orange, star fruit, grapefruit and their 
juices 
Should not be used concomitantly as they affect P450 
and P glycoprotein (P-gp) activity.
Strong inhibitors of CYP3A4 or P-GP 
Should not be given concomitantly, see table 5
Strong inducers of CYP3A4
Should not be given concomitantly, see table 5
Moderate CYP3A4 inhibtors
Should be used with caution, see table 5
Table 6. List of CYP3A4 strong and moderate inhibitors and inducers
Strong CYP3A4,5,7 
inhibitors
Moderate CYP3A4,5,7 
inhibitors
CYP3A4 inducers
clarithromycin
aprepitant
Barbiturates
Conivaptan
atazanavir
Carbamazepine
grapefruit juice
cimetidine
Efavirenz
Indinavir
ciprofloxacin
Modafenil
Itraconazole
darunavir
Nevirapine
Ketoconazole
diltiazem
Oxcarbazepine
Lopinavir
erythromycin
Phenobarbital
Mibefradil
fluconazole
Phenytoin
Nefazodone
tofisopam
pioglitazone 
Nelfinavir
verapamil
Rifabutin
Posaconazole
amprenavir
Rifampin
Ritonavir
fosamprenavir
St. John's wort
Saquinavir
Topiramate


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 71 of 129
Strong CYP3A4,5,7 
inhibitors
Moderate CYP3A4,5,7 
inhibitors
CYP3A4 inducers
Telithromycin
troglitazone 
Troleandomycin
Voriconazole
This database of CYP inhibitors was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table and from the University of Washington’s Drug 
Interaction Database based on in vitro studies. Strong inhibitors are predicted to increase 
BKM120 AUC > 5-fold, and moderate inhibitors are predicted to increase BKM120 AUC ≥ 2-
fold but < 5-fold. 
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” 
Table; and from (Pursche et al. 2008).


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 72 of 129
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.

Tumor efficacy (RECIST) assessment dates are not affected by dose delays and 
remain as originally scheduled, as they are based on the date of surgery.

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.

Patients may delay durvalumab 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
8.1.1
Screening phase
Screening procedures will be performed up to 35 days before Day -7, unless otherwise specified. 
All patients must first read, understand, and sign the IRB 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. 
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 


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 73 of 129

12-lead ECG (in triplicate [2-5 minutes apart])

Tumor biopsy for fresh tissue if not already obtained

Review of prior/concomitant medications 

Imaging by CT/MRI 

Clinical laboratory tests for:
o
Hematology (see Table 7)
o
Clinical chemistry (see Table 8)
o
TSH
o
Coagulation (PT, PTT, INR)
o
Creatinine Clearance
o
Serum pregnancy test (for women of childbearing potential only)
o
Hepatitis serologies
o
Urinalysis (see Table 9)
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 do not need to 
be repeated on cycle 1 day 1.
1. Sirolimus dosing: will be given 6mg po once on day 1, followed by 2mg po daily on days 
2-21. Steady state trough levels will be collected on day 23 and stored for batch analysis.
2. Heavy water dosing: first dose to be taken in clinic on day 23 and a 6 week supply for 
self- administration will be dispensed in labeled conical tubes. The patients will also be 
shown how to collect salivate samples. 
3. Durvalumab dosing: starting on Day 22 q 3 weeks for 2 doses
4. Restaging imaging prior to surgery
5. Standard of care surgical resection
6. Peripheral blood research tube collection per study calendar
8.1.3
End of treatment
End of treatment is defined as the 30 day post hospital discharge/surgery follow-up. All required 
procedures may be completed within  ±7 days of the end of treatment visit. See Appendix 2.  


Clinical Study Protocol
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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 74 of 129
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
Biological sampling procedures
8.2.1
Biomarker/pharmacodynamic sampling and evaluation methods
Assessment of secondary and exploratory biomarker objectives on tumor tissue, lymph node 
tissue, and whole blood that may include, but is not limited to, immunohistochemistry, 
immunofluorescence microscopy, RNA sequencing, DNA sequencing, flow cytometry, and mass 
spectrometry. Additionally, blood samples will be banked for future analyses related to NSCLC, 
sirolimus followed by durvalumab’s mode of action, and/or understanding of response and may 
include, but is not limited to, DNA sequencing.
PD-L1 testing
To ensure comparability of data across all studies of durvalumab 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. Following completion 
of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical utility. In other 
cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, ovarian, 
esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, small cell 
lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only limited clinical 
performance data. 
Sample collection for PD-L1 testing

The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy. Samples taken at 
this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant. 


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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
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 months old was not available, patients 
were asked to undergo a new biopsy if considered clinically appropriate by their treating 
physician. 

Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy. Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e., >100 tumor cells) to allow 
for adequate 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 (e-code or unique identifier)

Specimen identifier (written on the specimen)

Site identifier

Specimen collection date

Type of specimen submitted

Quantity of specimen

Date of sectioning

Archival of fresh tumor

Tumor type

Primary tumor location

Metastatic tumor location (if applicable)

Fixative
The following fields of data should be collected from PD-L1 testing laboratory:

Are the negative and positive controls stained correctly

Is the H&E material acceptable


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 76 of 129

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
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 Bio-Bank storage location. 
These blocks should undergo quality review, prior to evaluation or shipment. Where it is 
not possible or indicated to ship the block to a testing laboratory, unstained slides should 
be prepared from the paraffin-embedded tumor sample block (described below) prior to 
evaluation or shipment. 
Preparing newly acquired samples for 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. 
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. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 77 of 129
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-micron 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

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.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 78 of 129

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.
Next Generation Sequencing of the tumor Either an internal or external validated platform to 
test for a wide panel of genes including those known to have prognostic or predictive impact on 
lung cancer outcomes will be tested as per standard institutional protocol. 
8.2.2
Blood-based Studies for immunologic analysis
Collection:
Approximately 12-16 ml of blood will be collected into two, 8 ml Cell Preparation Tubes (CPT) 
at study specified time points. The CPT tubes will be labeled and logged at Emory's Winship 
Cancer Institute by a skilled nurse or phlebotomist. 
Handling: 
They will be maintained at room temperature until they are transported to an Emory immunology 
laboratory for processing for flow cytometry, cytokine, DNA, and RNA analysis. Plasma and 
PBMC may be used fresh or will be frozen and banked for future batch analyses. All blood-based 
samples will be handled in biosafety hoods with the handling personnel wearing protective safely 
gear (lab coat, gloves, and safety glasses when required).  
Storage:
Frozen PBMC and plasma samples will be stored at minus 80 degrees Celsius or on liquid nitrogen 
per standard laboratory protocols.  
Flow Cytometry
Detailed phenotypic analysis will be performed on peripheral blood mononuclear cells using 
standard flow cytometry methods. Fluorescent antibody stains may be used to assess various T cell 
markers including: CD3, CD4, CD8, CD45RA, CCR7, CD28, PD1, FoxP3, and Tbet.  Additional 
phenotypic B cell analysis may include CD19, IgD, CD38, and CD27 markers. Other markers may 
be added based on the mechanism of action of the immunologically active agent and growing 
cancer immunology research findings.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 79 of 129
Cytokine Analyses
Cytokine levels will be assessed using commercially available multiplex kits (such as the Luminex 
and Legendplex platforms). Cytokines of interest may include, but not limited to TNF-alpha, IFN-
gamma, IL1-beta, IL-2, IL-6, IL-10, IL17a, and others.
HLA Typing
Patient peripheral blood sample will be used for HLA typing. 
DNA and RNA Analyses
Investigational germline and tumor genetic analysis may include RNA isolation and sequencing, 
DNA extraction and sequencing (including but not limited to whole exome sequencing), and 
assessment of tumor mutation burden. 
Deuterium Label Analysis
Deuterium enrichment in the body water can be determined by collection of saliva, urine or blood 
samples. CD8 T cells, CD4 T cells and regulatory T cell populations will be sorted from the blood 
and post-surgical tissues at the Emory flow cytometry core, cell pellets frozen and sent to 
Dr.Hellerstein’s laboratory for DNA extraction and analysis of 2H enrichment. Specifically, we 
will analyze how much deuterium incorporation has occurred in various sorted subsets to measure 
the level of proliferation in the cell types in the window of deuterium incorporation.
Sample Prioritization
Pre- and Post-Treatment FFPE Biopsy Samples 
1. Pathology analyses 
2. PD-L1 IHC analysis 
3. Multiplex IF analysis 
4. Banking for additional non-protocol-specified exploratory analyses 
Pre-Treatment Fresh Frozen Biopsy Samples 
1. RNA isolation and sequencing 
2. Back-up for RNA and banking for additional non-protocol-specified exploratory analyses 
Post-Treatment Fresh Frozen Biopsy Samples 
1. RNA sequencing 
2. DNA extraction and WES
8.2.3 Sirolimus Level Collection
Sirolimus levels should be collected as troughs to facilitate intra-patient comparison. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 80 of 129
Step 1: The level is scheduled to be drawn on day 22, which is C1D1 Durvalumab and the last 
dose is on day 21. Therefore this timing should be appropriate for trough level. If there are 
anticipate delays in durvalumab, then appotintment should be made for this lab draw. The 
coordinator should call the patient 1-2 days before the appointment to remind them about trough 
level and for patient to bring that am dose to clinic. 
Step 2: Collection Tube details: 
Whole Blood (EDTA): One 5 mL lavender (EDTA) tube. Minimum volume needed 250 µL whole 
blood (EDTA), single test, with no repeat.
Step 3: Specimen Preparation: Whole blood. Do not spin. Samples obtained from Winship (either 
at Emory University or other site such as Emory St. Joseph’s Hospital) should be submitted the 
same day to special chemistry lab. Samples obtained at Grady should be be couriered over to 
Winship at Clifton road for analysis ( along with the CPT tube for immunologic analysis). 

Unacceptable conditions include serum or plasma collection or clotted specimens 
and will be discarded. Patient should be scheduled for repeat lab

Storage/Transport Temperature
Stable at room temperature, 15-30oC for up to 7 days. Stable refrigerated at 2-8oC 
for up to 14 days.

Performed only on day shift. Must be in Special Chemistry lab by 13:00 pm M-F 
and 11:00 am on weekends and holidays for same day results.
8.2.3
Estimate of volume of blood to be collected
The total volume of blood that will be drawn from each patient in this study is as follows: See 
Table 10. Additional blood may need to be drawn for follow-up of sirolimus trough levels. 
Table 10. Volume of Blood to be Drawn From Each Patient
Assessment
Sample volume 
(mL)
No. of samples
Total volume 
(mL)
Safety
Clinical chemistry
12
6
72
Hematology
4
6
24
                                      Sirolimus Level
4
1
4
                                     Fasting Lipid Panel
4
1
4
Research Cell Preparation Tubes
16
9
144
Total
248


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 81 of 129
8.2.4
Archival tumor samples and fresh tumor biopsies use beyond PD-L1
8.2.5
Archival tumor samples
Core biopsy blocks may be requested for immunofluorescent staining of 2-4 unstained slides if 
sufficient tissue is available. This is not a required analysis. 
8.2.5.1
Fresh tumor biopsies
If patients have lesions amenable to core biopsy, then they will be asked to consent to an additional 
research biopsy to obtain 2-3 image guided fresh core samples prior to any study treatment for 
baseline immune analysis. These will be kept in a patient labelled sterile container at room 
temperature and transported to the Ahmed laboratory by courier during the same business day. 
Once in the lab, the samples will be processed for analysis by flow cytometry, and may include 
RNA and DNA analysis.            
8.2.6
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. As collection of the biological samples is an integral 
part of the study, then the patient is withdrawn from further study participation.
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.
9.
DISEASE EVALUATION AND METHODS
9.1.1
Pathologic Response Assessment
A detailed pathological evaluation will be performed on the surgically resected samples to obtain 
data described below. 
1. Tumor size (3 measurements) 
2. Tumor diagnosis using the 2015 World Health Organization (WHO) classification 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 82 of 129
3. Predominant differentiation of the tumor (well, moderately, or poorly differentiated), and for 
adenocarcinoma histology, the histology subtypes present 
4. Lowest degree of tumor differentiation 
5. Angiolymphatic invasion 
6. Neural invasion 
7. Margin status in mm 
8. Degree of response International Union Against Cancer (UICC) pathological T and N stage 
9. Total percentage of areas of necrosis 
10. Total percentage of areas of fibrosis 
11. Total percentage of viable tumor tissue 
12. Total percentage of viable malignant cells 
13. Evidence of field effect.
9.1.2
Radiographic Response Assessment of Anti-tumor effect
For the purposes of this study, patients should be re-evaluated for response prior to surgical 
resection.  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)46. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with sirolimus. 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of Durvalumab, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 83 of 129
Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT 
scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 84 of 129
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 6 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 85 of 129
scanning techniques, if possible.
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it is 
not routinely or serially performed.  
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.
Tumor markers Tumor markers will not be used in this study to assess response.
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease.
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 


Clinical Study Protocol
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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 86 of 129
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 87 of 129
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator).
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 88 of 129
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 89 of 129
10.
ASSESSMENT OF SAFETY
10.1.1
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 the 
SoAs). Samples will be run at the clinic/hospital site utilized by each patient. Laboratory values 
outside reference ranges will be reviewed by a study investigator. 
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. 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 7 (hematology), Table 8 
(chemistry), and Table 9 (urinalysis).
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 7. Hematology Laboratory Tests
Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Hematocrit
Neutrophils
Hemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular hemoglobin
Total white cell count
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.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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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 8. Clinical Chemistry (Serum or Plasma) Laboratory Tests
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate
Sodium
Calcium 
Total bilirubina
Chloride
Total protein
Creatinine
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyltransferase
Uric acid
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If total 
bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin.
b
It 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
gamma glutamyltransferase, and magnesium testing are to be performed at baseline, on Day 0 (unless all 
screening laboratory clinical chemistry 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
Table 9. Urinalysis Testsa
Bilirubin
pH
Blood
Protein
Glucose
Specific gravity
Ketones
Colour and appearance
a Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red 
blood cells


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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If a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to Error! 
Reference source not found. for further instructions on cases of increases in liver biochemistry 
and evaluation of Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet 
the criteria for a Hy’s law case or if any of the individual liver test parameters fulfill any of the 
SAE criteria. 
All patients should have further chemistry profiles performed at the post-surgery, end of treatment 
visit.
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 10.5.
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.
10.1.2
Physical examinations
Physical examinations will be performed according to the assessment schedules (see the SoAs). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the 
respiratory, 
cardiovascular, 
GI, 
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 10.5. 
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 (eg, 30 minutes) to confirm the finding.  
Situations in which ECG results should be reported as AEs are described in Section 10.5
At Screening, a single ECG will be obtained on which QTcF must be <470 ms. 
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 
12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. 
Situations in which ECG results should be reported as AEs are described in Section 10. 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 92 of 129
10.1.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs.
First infusion
On the first infusion day, patients 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. 
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. 
10.1.4
Early patient review for safety
Patients will be seen in close interval follow-up (Cycle 1 Day 8, Cycle 2 Day 8, and during surgical 
window to ensure early identification and management of toxicities. 
10.1.5
WHO/ECOG performance status
ECOG performance status will be assessed at the times specified in the assessment schedules (see 
the SoAs) based on the following:
0.
Fully active; able to carry out all usual activities without restrictions
1.
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (e.g., light housework or office work)


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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2.
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours.
3.
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
4.
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair
5.
Dead 
Any significant change from baseline or screening must be reported as an AE.
10.1.6
Other safety assessments
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD 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. 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar 
with the content of this section.
10.2
Safety parameters
10.2.1.1
Definition of adverse events
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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An AE includes but is not limited to any clinically significant worsening of a patient’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or 
intervention by the investigator, or a finding judged by the investigator to represent a change 
beyond the range of normal physiologic fluctuation, should be reported as an AE.
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational 
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the patient has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
patient being enrolled into the study) for a documented pre-existing condition, that did not worsen 
from baseline, is not considered an AE (serious or nonserious). An untoward medical event 
occurring during the prescheduled elective procedure or routinely scheduled treatment should be 
recorded as an AE or SAE.
The term AE is used to include both serious and non-serious AEs.
10.2.2
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.

Medical or scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in this situation. 
Examples of medically important events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or 
development of drug dependency or drug abuse.


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca.
10.2.3
Definition of adverse events of special interest (AESI)
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious. 
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 include:

Diarrhea / Colitis and intestinal perforation

Pneumonitis / ILD

hepatitis / transaminase increases

Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus)

Rash / Dermatitis

Nephritis / Blood creatinine increases

Pancreatitis / serum lipase and amylase increases  

Myocarditis

Myositis / Polymyositis
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 skin of the eyes, haematological and rheumatological events, 
vasculitis, non-infectious meningitis and non-infectious encephalitis.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs.


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator’s Brochure. 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.
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 Error! Reference source not 
found.) 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 <<specify where this information will be recorded e.g. eCRF, CRF, etc.)>>
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:


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 97 of 129
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: Particular tumor markers which are related to disease 
progression. 
Additional Clinical chemistry: CRP, LDH
10.2.4
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Appendix 1). All data post the final DCO and database closure will 
be recorded in the patient notes but, with the exception of SAEs, will not otherwise be reported for 
the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure must be 
reported as detailed in Section 10.5


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 98 of 129
10.3
Assessment of safety parameters
10.3.1
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.
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 10.1.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
non-serious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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10.4
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). <<teams to 
include required follow up period for the comparator agent>>).  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 patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF.
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:

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


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Edition Number: 4
Date:  11 February 2022
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
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 10.4.2

Description of the SAE
The grading scales found in the 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 5.0can be downloaded from the Cancer Therapy Evaluation 
Program website (http://ctep.cancer.gov).
10.4.1
Study recording period and follow-up for adverse events and serious adverse 
events
If a patient discontinues from treatment and 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.
10.4.2
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?”


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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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 Error! Reference source not 
found..
10.4.3
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 
patient’s 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 patient’s medical record.
10.4.4
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 CRF.
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.
10.4.5
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 fulfill any of the SAE criteria 
or are the reason for discontinuation of treatment with the IPs.


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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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.
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.
10.4.6
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Error! Reference source not found. for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s law.
10.4.7
Disease progression
Disease progression can be considered as a worsening of a patient’s 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.
10.4.8
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 
patient’s inclusion in this study.
10.4.9
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 CRF in 
the Statement of Death page. It should not be reported as an SAE.


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
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the Study Monitor/Physician as an SAE within 
24 hours. It should also be documented in the Statement of Death page in the CRF.

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 CRF. 

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.
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.
AstraZeneca/MedImmune 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.
10.4.10
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF.
AstraZeneca/MedImmune 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.
10.4.11
Post-study events
After the patient has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study patients 
after the 90-day safety follow-up period for patients treated with durvalumab. However, if an 
investigator learns of any SAEs, including death, at any time after the patient has been permanently 
withdrawn from study, and he/she considers there is a reasonable possibility that the event is 
related to study treatment, the investigator should notify the study sponsor and 
AstraZeneca/MedImmune Patient Safety.


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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10.5
Reporting of serious adverse events
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last dose of 
durvalumab or until the initiation of alternative anticancer therapy. The investigator and/or 
Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of 
the SAE as per local requirements.
All serious, related and unexpected adverse events must be reported to AstraZeneca regardless of 
the country where the study is conducted.
For those events requiring expedited reporting to the regulatory authorities, the investigator and/or 
sponsor must inform all applicable regulatory authorities (e.g. FDA), via a MedWatch/AdEERs or 
applicable required regulatory form (e.g. CIOMS), of any serious, related and unexpected adverse 
events in accordance with reporting obligations (e.g. FDA21 CFR 312.32) and will concurrently 
forward all such reports to AstraZeneca in English. A copy of the MedWatch/AdEERs report must 
be emailed to AstraZeneca at the time the event is reported to the regulatory authorities (e.g. FDA). 
It is the responsibility of the sponsor to compile all necessary information and ensure that the 
regulatory authorities receive a report according with the applicable reporting requirement 
timelines and to ensure that these reports are also submitted to AstraZeneca at the same time.
* A cover page should accompany the MedWatch/AdEERs form indicating the following:

“Notification from an Investigator Sponsored Study”

The investigator IND number assigned by the FDA

The investigator’s name and address

The trial name/title and AstraZeneca ISS reference number (ESR-19-20015)
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined 
by the principal investigator.
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA.


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 105 of 129
Serious adverse events that do not require expedited reporting to the regulatory authories still need 
to be reported to AstraZeneca using the MedDRA coding language for serious adverse events. This 
information should be reported on a monthly basis and under no circumstance less frequently than 
quarterly. 
10.5.1
Reporting of deaths to AstraZeneca
All deaths must be recorded and reported as outlined in Section 10.5.  In addition, all SAEs 
resulting in death or death of unknown cause must be reported to AstraZeneca via 
AEMailboxClinicalTrialTCS@astrazeneca.com within 7 calendar days of awareness or sooner 
when required (See Section 10.5).
10.5.2
Other events requiring reporting
10.5.3
Overdose
An overdose is defined as a patient receiving a dose of durvalumab in excess of that specified in 
the Investigator’s Brochure, unless otherwise specified in this protocol.
Any overdose of a study patient with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor. The sponsor 
must report these to AstraZeneca/MedImmune Patient Safety or designee using the designated 
Safety e-mailbox (see Section 10.5 for contact information) within 7 calendar days or sooner when 
required (see Section 10.5). If the overdose results in an AE, the AE must also be recorded as an 
AE (see Section 10.5). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is serious 
and must be recorded and reported as an SAE (see Section 10.5). There is currently no specific 
treatment in the event of an overdose of durvalumab. 
An overdose of sirolimus is required to be reported within 24 hours of knowledge of the event to 
the sponsor. 
The investigator will use clinical judgment to treat any overdose.
10.5.4
Hepatic function abnormality
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in 
a study patient, with or without associated clinical manifestations, is required to be reported as 
“hepatic function abnormal” within 24 hours of knowledge of the event to the sponsor. The 
Sponsor must report these events to AstraZeneca Patient Safety using the designated Safety e-
mailbox (see Section 10.5 for contact information) within 7 calendar days or sooner when required, 
unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 106 of 129
obstruction) that is unrelated to investigational product has been confirmed. The criteria for a 
potential Hy’s Law case is Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) 
≥3x Upper Limit of Normal (ULN) together with Total Bilirubin (TBL) ≥2xULN at any point 
during the study following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP).

If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study patient will be based on the 
clinical judgment of the investigator.

If no definitive underlying diagnosis for the abnormality is established, dosing of the study patient 
must be interrupted immediately. Follow-up investigations and inquiries must be initiated by the 
investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune. 
10.5.5
Pregnancy
10.5.6
Maternal exposure
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or 
birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from the 
study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he 
or she becomes aware of it. 
The sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days.  The Sponsor must report to AstraZeneca Patient Safety using the 
designated Safety e-mailbox (see Section 10.5 for contact information) within 7 calendar days or 
sooner when required (see Section 10.5), for pregnancies with SAEs and within 30 days for all 
other pregnancies. 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 107 of 129
The same timelines apply when outcome information is available. 
10.5.7
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 + any drug combination therapy or 90 days after the 
last dose of durvalumab monotherapy, whichever is the longer time period. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 180 days after the last dose 
of durvalumab + any drug 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 patient’s partner. Therefore, the local study team should 
adopt the generic ICF template in line with local procedures and submit it to the relevant Ethics 
Committees (ECs)/Institutional Review Boards (IRBs) prior to use. 
10.6
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 recognized that could have led to an error
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


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 108 of 129

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 that 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 Sponsor within 1 day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
The Sponsor works with the Investigator to ensure that all relevant information is completed within 
1 or 5 calendar days. The Sponsor must report to AstraZeneca Patient Safety using the designated 
Safety e-mailbox (see Section 10.5 for contact information) within 7 calendar days or sooner when 
required (see Section 10.5) if there is an SAE associated with the medication error and within 30 
days for all other medication errors.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 109 of 129
11.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
11.1
Description of analysis sets
11.1.1
Safety analysis set
All enrolled patients will be evaluable for safety analyses from the time of their first treatment with 
sirolimus and/or durvalumab.
11.1.2
Efficacy analysis set
The primary and secondary efficacy analyses will include all enrolled patients who have received 
at least one dose of durvalumab, underwent resection and who do not have EGFR mutant tumors 
(efficacy population).
11.2
Methods of statistical analyses
The number of patients who enroll, discontinue, or complete the study will be summarized. 
Reasons for premature study withdrawal will be listed and summarized. Enrollment and major 
protocol deviations will be listed and evaluated for their potential effects on the interpretation of 
study results. Demographic information such as age and race will be tabulated. Descriptive 
statistics, including means, standard deviations, and ranges for continuous parameters, as well as 
percentages and frequencies for categorical parameters, will be presented. Adverse events, Grade 
3/4 adverse events, and serious adverse events will be tabulated.
11.2.1
Safety analyses
After study complete, DLTs will be summarized and tabulated by type and grade. DLT rate will 
be calculated as proportion (Patients with DLT/Total patients) along with 95% confidence 
intervals using the Clopper-Pearson method. Chi-square test or Fisher’s exact test will be used to 
compare the probability of DLT between the different other factors, such as PD-L1 status, , etc. 
respectively.
Other adverse events (toxicity) will be listed and summarized.Adverse events will also be listed 
by severity, seriousness, and by system organ class. The number and percentage of subjects who 
experience AEs will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate. AEs will be presented with and without regard to causality based on the 
investigator’s judgment. The frequency of overall toxicity, categorized by toxicity grades 1 
through 5, will be described. Additional summaries will be provided for AEs that are observed 
with higher frequency.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 110 of 129
11.2.2
Efficacy analyses
Primary Efficacy Endpoint
The effectiveness of sirolimus followed by durvalumab will be assessed by complete pathologic 
response rate in the efficacy population. If the null hypothesis is rejected then this is evidence that 
the response rate exceeds 10% when sirolimus followed by durvalumab is given before resection. 
The one-sided 95% confidence interval (CI) for complete pathologic response will be reported. 
Exact binomial test will be used to compare the estimated complete pathologic response rate to the 
historical reference. 
Secondary Efficacy Endpoints
The complete pathologic response rates for PDL-1 negative and PDL-1 positive patients in the 
efficacy population will be presented separately. 
A comparison of both the complete pathologic response and investigator assessed response rates 
per RECIST v1.1 rates between the PD-L1 positive and PD-L1 negative groups will be performed 
by calculating the lower bound of a one-sided 80% CI for the difference, complete pathologic 
response for PDL-1 positive patients − complete pathologic response for PDL-1 negative 
patients. Chi-square test or Fisher’s exact test will be used to compare the efficacy in term of 
response rate between the different groups stratified by other factors, respectively. Logistics 
regression model will be further employed to test the adjusted effect of each other factor on the 
response rate after adjusting for other clinical factors and demographic factors, respectively. 
Correlation of response will be performed for tumor mutation burden using spearman correlation 
coefficient and tested with Wald’s test.
11.2.3
Exploratory analyses
Exploratory biomarker analyses will be performed to explore the relationship between the clinical 
outcomes and the immunological, pathological and genomic characteristics of the cancers. 
Biomarker analyses may include, but may not be limited to, the analyses described below. 
• A detailed pathological evaluation will be performed on the surgically resected samples.
•  Immunologic analyses by IHC, IF, and flow cytometry 
•  Genomic analaysis may include DNA sequencing (NGS or WES) and RNA sequencing from 
tumor tissue and normal blood/tissue, to identify mutations, mutation burden, gene expression 
profiles and associations with treatment response.
11.2.4
Interim analyses
There will be a safety assessment following the completion of surgery for the first six patients on 
the protocol. Both the DLT assessment and Enrollment will continue during this time. There will 
be an analysis of the pCR rate of the 16 patients included in the first stage of the design. 


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 111 of 129
11.3
Determination of sample size
Pathologic complete response is rare following neoadjuvant chemotherapy but was reported in 0-
8% of cases39.  The current study is designed to test improved rate of pathologic complete response 
from 10% to 25% treatment with sirolimus followed by durvalumab. Using a MinMax 2-stage 
design, a total of 31 patients will be enrolled in 2 stages. At the end of stage I, at least 2 of 16 
patients must achieve complete pathologic complete response in order for the study to enroll 15 
additional patients. The regimen of sirolimus followed by durvalumab will be considered to have 
sufficient efficacy to warrant further testing in this patient population if 6 or more of the 31 patients 
achieve a pathologic CR at the end of stage II. The study has 80% power at a 1-sided alpha of 0.1 
to show a compelling 25% pCR compared to a less compelling rate of 10%. Because this is a signal 
finding study, an alpha of 0.1 is considered reasonable since any promising signal will be 
confirmed in a larger follow-up study.
Planned total number of patients is 31 over 2 years, with an estimated accrual rate of approximately 
1-2 patients/month. Racial, ethnic, and gender accrual estimates below are based on 2010 Atlanta 
Census demographic information.
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
1
+
1
=
2
Not Hispanic or Latino
14
+
14
=
28
Ethnic Category: Total of all 
subjects
15
(A1) +
15
(B1)=
30
(C1)
Racial Category
American Indian or Alaskan 
Native
0
+
0
=
0
Asian
1
+
1
=
2
Black or African American
    6
+
6
=
12


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 112 of 129
Native Hawaiian or other Pacific 
Islander
1
+
1
=
2
White
7
+
7
=
14
Racial Category: Total of all 
subjects
15
(A2) +
15
(B2)=
30
(C2)
(A1 = A2)
(B1 = B2)
(C1 = C2)
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
This protocol, the Informed Consent Forms, any information to be given to the patient, and relevant 
supporting information must be submitted to the Emory IRB by the Principal Investigator and 
reviewed and approved by the Emory IRB before the study is initiated. 
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB. Investigators are also responsible for promptly informing the 
IRB of any protocol amendments.
In addition to the requirements for reporting all adverse events to the Sponsor, investigators must 
comply with requirements for reporting serious adverse events to the local health authority and 
IRB. Investigators may receive written IND safety reports or other safety-related communications 
from the Sponsor.
12.3
Informed consent and confidentiality
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the Informed Consent Form (or separate authorization for use and 


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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 113 of 129
disclosure of personal health information) signed by the patient, unless permitted or required by 
law.
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names are 
not included in data sets that are transmitted to any Sponsor location.
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to study investigators or patients unless 
required by law. The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication
12.4
Changes to the protocol and informed consent form
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by the sponsor and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB at Emory.  A copy of the 
written approval of the IRB must be provided to AstraZenica. Examples of amendments requiring 
such approval are:
1. increases in drug dose or duration of exposure of subjects,
2. significant changes in the study design (e.g. addition or deletion of a control group),
3. increases in the number of invasive procedures,
4. addition or deletions of a test procedure required for monitoring of safety.
These requirements for approval should in no way prevent any immediate action from being taken 
by the investigator or by AstraZeneca in the interests of preserving the safety of all patients 
included in the trial. If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons AstraZeneca must be notified and the IRB at 
the center must be informed immediately. Amendments affecting only administrative aspects of 
the study do not require formal protocol amendments or IRB approval but the IRB must be kept 
informed of such administrative changes. Examples of administrative changes not requiring formal 
protocol amendments and IRB approval include:
1.
changes 
in 
the 
staff 
used 
to 
monitor 
trials 
2.
minor changes in the packaging or labeling of study drug.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 114 of 129
12.5
Audits and inspections
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide 
oversight for the conduct of this study.  The DSMC functions independently within Winship 
Cancer Institute to conduct internal monitoring functions to ensure that research being conducted 
by Winship Cancer Institute Investigators produces high-quality scientific data in a manner 
consistent with good clinical practice (GCP) and appropriate regulations that govern clinical 
research.    Depending on the risk level of the protocol, the DSMC review may occur every 6 
months or annually.  For studies deemed High Risk, initial study monitoring will occur within 6 
months from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  For 
studies deemed Moderate Risk, initial study monitoring will occur within 1 year from the date of 
the first subject accrued, with 2 of the first 5 subjects being reviewed.  Subsequent monitoring will 
occur in routine intervals per the Winship Data and Safety Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with the 
protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal 
Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and 
availability of source documents, AEs/SAEs, and essential regulatory documents.  Following the 
monitoring review, monitors will provide a preliminary report of monitoring findings to the PI and 
other pertinent individuals involved in the conduct of the study.  The PI is required to address and 
respond to all the deficiencies noted in the preliminary report.  Prior to the completion of the final 
summary report, monitors will discuss the preliminary report responses with the PI and other team 
members (when appropriate).  A final monitoring summary report will then be prepared by the 
monitor.  Final DSMC review will include the final monitoring summary report with 
corresponding PI response, submitted CAPA (when applicable), PI Summary statement, and 
available aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI is 
responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB.  
Continuing Review submissions will include the DSMC recommendation letter.  Should any 
revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the PI will 
be responsible for notifying the DSMC of such changes.  The Committee reserves the right to 
conduct additional audits if necessary.


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 115 of 129
13.
STUDY MANAGEMENT
13.1
Training of study site personnel
Each of the Emory University Affiliated Study sites will undergo training sessions for the sub-
investigators and the clinical study staff, utilizing a standardized PowerPoint presentation that 
will highlight pertinent details of the protocol. 
13.2
Monitoring of the study
13.2.1
Source data
Source data will be logged onto Oncore per Winship Standard procedures. 
13.3
Study timetable and end of study
The end of this study is defined as Last Patient Last Visit, which is expected to when the last 
patient completes the survival follow-up (which may occur in person or by phone).  This is 
expected to occur approximately 2 years after the last patient receives the last dose of neoadjuvant 
durvalumab. The treatment period of this study will end when the last data point required for 
primary efficacy analysis (i.e., pathology evaluation at time of surgery) is obtained. This is 
expected to occur approximately 30 days after the last patient’s surgery. 
After completing treatment with sirolimus + durvalumab, patients will be followed for survival for 
up to 2 years after the last patient receives the last dose of durvalumab (by phone or in person). 
Patients removed from study for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event. The recruitment period is expected to last 1.5 to 2 years. The 
total length of the study, from screening of the first patient to the end of the study, is expected to 
be approximately 4 years.
14.
DATA MANAGEMENT
Data will be collected using an institutional electronic data recording system, Oncore. Electronic 
case report forms and study calendar will be generated prior to study activation. Investigator 
responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the US 
Code of Federal Regulations. The Investigator will permit study-related audits by AstraZenica or 
its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA), providing 
direct access to the facilities where the study took place, to source documents, to CRFs, and to all 
other study documents.


Clinical Study Protocol
Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 116 of 129
The Investigator, or a designated member of the Investigator‟s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the subject‟s 
records (e.g., medical records, office charts, hospital charts, and study related charts) for source 
data verification. The data collection must be completed prior to each visit and be made available 
so that the accuracy and completeness may be checked. 
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the protocol therapy, that is copies of CRFs and source documents (original 
documents, data, and records [e.g., hospital records; clinical and office charts; laboratory notes; 
memoranda; subject‟s diaries or evaluation checklists; SAE reports, pharmacy dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives, microfilm, or magnetic media; x-rays; 
subject files; and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study; documents regarding subject treatment and drug 
accountability; original signed informed consents, etc.]) be retained by the Investigator for as long 
as needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).
15.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
15.1
Identity of investigational product(s)
Table 11. List of Investigational Products for This Study
Investigational product
Dosage form and strength
Manufacturer
Durvalumab
50 mg/mL solution for infusion 
after dilution at flat dose 
1500mg
MedImmune/AstraZeneca
Sirolimus
2 mg oral tablet by mouth
Pfizer


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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 117 of 129
16.
LIST OF REFERENCES
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3. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with 
completely resected non-small-cell lung cancer. N Engl J Med. 2004;350: 351-360.
4. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-
small-cell lung cancer. N Engl J Med. 2005;352: 2589-2597.
5. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by 
the LACE Collaborative Group. J Clin Oncol. 2008;26: 3552-3559.
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observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group 
B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin 
Oncol. 2008;26: 5043-5051.
7. Chuang JC, Liang Y, Wakelee HA. Neoadjuvant and Adjuvant Therapy for Non-Small Cell Lung 
Cancer. Hematol Oncol Clin North Am. 2017;31: 31-44.
8. Song WA, Zhou NK, Wang W, et al. Survival benefit of neoadjuvant chemotherapy in non-small cell 
lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol. 2010;5: 510-516.
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10. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N 
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12. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-
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Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373: 123-135.
14. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-
positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 
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15. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with 
previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised 
controlled trial. Lancet. 2017;389: 255-265.
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Investigational Drug Substance: MEDI4736 Sirolimus (Rapamune)
Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
Page 118 of 129
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Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther. 2017;16: 2598-2608.
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Study Number 19-20015
Edition Number: 4
Date:  11 February 2022
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Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 120 of 129


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 121 of 129
Day      (+/-7)
Every 3 Months 
(±4 weeks)
Appendix 2: 
End of Study and Follow-up Evaluations
30
3
6
Chart follow-up
Full Physical examination
X
Vital signs (temperature, respiratory rate, blood pressure, pulse)
X
Weight
X
Urine hCG or serum βhCG
AE/SAE assessment
X
Concomitant medications
X
Post-operative chemotherapy and/or  radiotherapy as clinically indicated
ECOG performance status
X
X
X
Subsequent anticancer therapy
X
X
Survival status: phone contact with patients who agree to be contacted and chart review
X
X
X (every 6 months)
Hematology
X
Serum chemistry 
X
Research blood collection 
X
X
X
Tumor assessment (CT or MRI) per standard of care


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 122 of 129
Appendix 3: American Joint Committee on Cancer Non-small cell Lung 
Cancer Staging, 8th Edition


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 123 of 129


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 124 of 129
Appendix 4: Information on Possible Drug Interactions
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team
The patient ____________________________ is enrolled on a clinical trial using the 
investigational agents sirolimus followed by durvalumab. This clinical trial is supported by 
AstraZenica.  This form is addressed to the patient, but includes important information for others 
who care for this patient. 
Sirolimus interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-
counter remedy), or herbal supplements such as St. John’s wort. 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These 
are the things that you and they need to know: 
Sirolimus interacts with (a) certain specific enzyme(s) in your liver. 
The enzyme(s) in question is/are CYP3A4 isoenzyme 
Sirolimus must be used very carefully with other medicines that need these liver enzymes 
to be effective or to be cleared from your system.  
Other medicines may also affect the activity of the enzyme.  
o
Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects.
You and healthcare providers who prescribe drugs for you must be careful about adding 
or removing any drug in this category. 
Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4 isoenzyme.
Your 
prescribers 
should 
look 
at 
this 
web 
site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to 
see if any medicine they want to prescribe is on a list of drugs to avoid.  
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small 


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 125 of 129
and located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.  
Be careful: 
o
If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold.
o
If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over. 
o
If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking Sirolimus
Other medicines can be a problem with your study drugs. 

You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 

Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctors can be contacted at:
Emory University Winship Cancer Center 404-778-1900
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to:
Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine.
Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial.
Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines 
that interact with this enzyme. 
Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP______.”
Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.  
Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________. 


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 126 of 129
Appendix 5: Memory Aid for Heavy Water
Patient Initials:
Take all doses of heavy water  
Patient ID#
at least 4 hours apart
 
Day of 
Heavy
Water
Date
Heavy 
Water
Intake
Salivette
Time Dose 1 
taken
(am)
Time extra 
dose taken
(midday)
Time dose 2 
taken
(pm)
1
50 ml x 
3
2
50 ml x 
3
3
50 ml x 
3
4
50 ml x 
3
5
50 ml x 
3
6
50 ml x 
2
7
50 ml x 
2
Chew 2 hours 
after HW
8
50 ml x 
2
9
50 ml x 
2
10
50 ml x 
2
11
50 ml x 
2
12
50 ml x 
2
13
50 ml x 
2


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 127 of 129
14
50 ml x 
2
Chew 2 hours 
after HW
15
50 ml x 
2
16
50 ml x 
2
17
50 ml x 
2
18
50 ml x 
2
19
50 ml x 
2
20
50 ml x 
2
21
50 ml x 
2
22
50 ml x 
2
23
50 ml x 
2
24
50 ml x 
2
25
50 ml x 
2
26
50 ml x 
2
27
50 ml x 
2
28
50 ml x 
2
29
50 ml x 
2
30
50 ml x 
2


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 128 of 129
31
50 ml x 
2
32
50 ml x 
2
33
50 ml x 
2
34
50 ml x 
2
35
50 ml x 
2
36
50 ml x 
2
37
50 ml x 
2
38
50 ml x 
2
39
50 ml x 
2
40
50 ml x 
2
41
50 ml x 
2
42
50 ml x 
2


Clinical Study Protocol
Drug Substance Sirolimus (Rapamune)
Study Number 19-20015
Edition Number 4
Date 11 February 2022
Page 129 of 129
Appendix 6: Trial outline patient handouts
Please usepertinent flow sheet for patient pending D2O and use full sized copies loaded into 
oncore/Complion.