Clinical trial NCT03164772
Conditions: Metastatic Non-small Cell Lung Cancer NSCLC
Keywords: mRNA Vaccine durvalumab MEDI4736 anti-PD-L1 tremelimumab anti-CTLA-4 BI 1361849 PharmaJet Tropis® device
Sponsor: Ludwig Institute for Cancer Research
Start date: 2017-12-20; Completion date: 2021-10-29
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, multicenter, 2-arm study to evaluate the safety and preliminary efficacy of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors for NSCLC.

Arm A: messenger ribonucleic acid (mRNA) Vaccine \[BI 1361849 (formerly CV9202)\] + anti-programmed death ligand 1 (PD-L1) antibody \[durvalumab\]

Arm B: messenger ribonucleic acid (mRNA) Vaccine \[BI 1361849\] + anti-programmed death ligand 1 (PD-L1) \[durvalumab\] + anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody \[tremelimumab\]

The run-in evaluation phase is followed by an expansion phase in which the cohort is expanded to 20 subjects (inclusive of subjects from the run-in).

Detailed description:
This was a Phase 1/2, open-label, multicenter, 2-arm study to evaluate the safety and preliminary efficacy of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors in subjects with NSCLC.

Up to 56 subjects were planned for enrollment from up to 8 clinical sites in 2 arms:

Arm A: mRNA Vaccine \[BI 1361849 (formerly CV9202)\] + anti-PD-L1 antibody \[durvalumab\]

Arm B: mRNA Vaccine \[BI 1361849\] + anti-PD-L1 \[durvalumab\] + anti-CTLA-4 antibody \[tremelimumab\]

Subjects must have had histologically confirmed metastatic NSCLC. For subjects with known EGFR or ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine kinase inhibitor or ALK/ROS-1 inhibitor, respectively. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy and must not have had progression at or before 12 weeks after start of the prior anti-PD-1/PD-L1 treatment.

Arms: arm 1: The BI 1361849 mRNA vaccine comprises 6 drug product components (F2408 coding for MUC1, F2409 coding for survivin, F2410 coding for NY-ESO-1, F2624 coding for 5T4, F2625 coding for MAGE-C2, and F2626 coding for MAGE-C1), which were provided and administered separately; each component was administered twice, thus there were 12 intradermal administrations of 100 µL (80 µg) each for each dose. The PharmaJet Tropis® device was used for the administration of the BI 1361849 components.

Durvalumab 1500 mg was to be administered as an intravenous (IV) infusion every 4 weeks for 12 cycles; BI 1361849 was to be administered as 14 doses over the 12 cycles. arm 2: The BI 1361849 mRNA vaccine comprises 6 drug product components (F2408 coding for MUC1, F2409 coding for survivin, F2410 coding for NY-ESO-1, F2624 coding for 5T4, F2625 coding for MAGE-C2, and F2626 coding for MAGE-C1), which were provided and administered separately; each component was administered twice, thus there were 12 intradermal administrations of 100 µL (80 µg) each for each dose. The PharmaJet Tropis® device was used for the administration of the BI 1361849 components.

Durvalumab 1500 mg was to be administered as an intravenous (IV) infusion every 4 weeks for 12 cycles; tremelimumab 75 mg was to be administered as an intravenous (IV) infusion every 4 weeks for the first 4 cycles (Arm B only); BI 1361849 was to be administered as 14 doses over the 12 cycles.
Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab intervention 3: BI 1361849 intervention 4: PharmaJet Tropis® device
Intervention descriptions: intervention 1: anti-PD-L1 intervention 2: anti-CTLA-4 intervention 3: mRNA Vaccine intervention 4: The PharmaJet Tropis® device was used for the intradermal administration of the BI 1361849 vaccine components.

Protocol documents:
Prot_000.pdf: 
 
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Study Protocol LUD2014-012-VAC 
NCT03164772 
US-IND# 17480 
Amendment 10.0 
Final 
30-JUL-2021 
 
Protocol Title 
A Phase 1/2 Study of Combination Immunotherapy and mRNA Vaccine in Subjects with Non-
small Cell Lung Cancer (NSCLC) 
 
Objectives and Synopsis 
This is an open-label multicenter 2-arm study to evaluate the safety and preliminary efficacy 
of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors for NSCLC: 
Arm A: 
mRNA Vaccine [BI 1361849 (formerly CV9202)] + anti-PD-L1 [durvalumab] 
Arm B: 
mRNA Vaccine [BI 1361849] + anti-PD-L1 [durvalumab] + anti-CTLA-4 
[tremelimumab]. 
For each arm of the study, there is a dose evaluation phase in which the Recommended 
Combination Dose (RCD) is determined according to a standard 3 + 3 design. For Arm A, the 
RCD of BI 1361849 + durvalumab is determined. The starting dose of durvalumab is 1500 mg 
with possible de-escalation to 750 mg; the dose for BI 1361849 remains constant. For Arm B, 
the RCD of BI 1361849 + durvalumab from Arm A with the addition of tremelimumab 75 mg is 
evaluated. There is no dose escalation/de-escalation for Arm B; if there is unacceptable 
toxicity in Arm B, the arm will be discontinued.  The dose evaluation phase is followed by an 
expansion phase, in which the cohort at the RCD for each arm is expanded to 20 subjects 
(inclusive of the subjects from the dose evaluation cohort).  
Dose Level Table for Evaluation Phase 
Dose 
Level 
Arm A 
Dose 
Level 
Arm B* 
BI 1361849 
Durvalumab 
BI 1361849 
Durvalumab 
Tremelimumab 
-1 
12 x 
80 µg** 
750 mg 
 
 
 
 
Starting 
12 x 
80 µg** 
1500 mg 
Starting 
12 x 
80 µg** 
Arm A RCD 
75 mg 
*If there is unacceptable toxicity in Arm B, dosing will continue at RCD from Arm A, without tremelimumab.   
**See Note 2 below. 
NOTE 1: See Section 3.1.7.1 for durvalumab and tremelimumab doses for instances when a subject’s body weight 
drops to ≤ 30 kg while on the study. 
NOTE 2: The BI 1361849 drug product is a vaccine comprising six drug product components (F2408, F2409, F2410, 
F2624, F2625, and F2626), which are provided and administered separately; each component is administered 
twice, thus there are 12 administrations of 100 µL (80 µg) each. 


 
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Primary Objective 
[Endpoints] 
Dose Evaluation Phase:  
Safety and Tolerability [CTCAE 4.03, including DLTs and RCD] 
Expansion Phase:  
Safety and Tolerability [CTCAE 4.03] 
Secondary Objectives 
[Endpoints] 
Dose Evaluation and Expansion Phases (all subjects): 
Clinical Efficacy by irRECIST and RECIST 1.1 [PFS rate and ORR at 
8 and 24 weeks, best overall response, DCR, DoR, OS] 
Exploratory Objectives 
[Endpoints] 
Dose Evaluation and Expansion Phases (all subjects): 
Biologic Activity [Effects on Tumor Microenvironment, Immune 
Response] 
DLT=Dose-limiting Toxicity; RCD=Recommended Combination Dose; ORR=Objective Response Rate; 
DCR=Disease Control Rate; DoR=Duration of Response; PFS=Progression-free Survival; OS=Overall Survival; 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST = Response 
Evaluation Criteria in Solid Tumors; irRECIST=immune-related RECIST. 
 
Sponsor:  
Ludwig Institute for Cancer Research, New York, 
NY 
 
 
 
 
 
 
 
 
Sponsor Representative Signature and Date 
 
 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and 
provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s). The information cannot be used or divulged to any third party or published without the written consent of the 
Ludwig Institute for Cancer Research, except to the extent necessary to obtain informed consent from those persons to whom 
study medication may be administered. Any misappropriation of this information is prohibited by law. 
 


 
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Table of Contents 
1 
Background ............................................................................................................................. 7 
1.1 
Checkpoint Inhibitors in the Treatment of Non-Small Cell Lung Cancer ......................... 7 
1.2 
Study Drugs ...................................................................................................................... 8 
1.2.1 
Durvalumab (MEDI4736) - PD-L1 Antibody ............................................................. 8 
1.2.2 
Tremelimumab - CTLA-4 Antibody .......................................................................... 9 
1.2.3 
BI 1361849 ............................................................................................................. 11 
2 
Study Rationale ..................................................................................................................... 15 
2.1 
BI 1361849 Dose ............................................................................................................ 15 
2.2 
Durvalumab and Tremelimumab Dose.......................................................................... 16 
3 
Experimental Plan ................................................................................................................. 18 
3.1 
Study Design .................................................................................................................. 18 
3.1.1 
Study Phase ........................................................................................................... 18 
3.1.2 
Enrollment/Randomization ................................................................................... 18 
3.1.3 
Blinding/Unblinding ............................................................................................... 19 
3.1.4 
Subject Population................................................................................................. 19 
3.1.5 
Number of Sites/Subjects ...................................................................................... 19 
3.1.6 
Sample Size Considerations ................................................................................... 19 
3.1.7 
Treatment Arms and Treatment Schema .............................................................. 20 
 
Dose Evaluation Phase................................................................................... 20 
 
Dose Expansion Phase ................................................................................... 22 
3.1.8 
Dosing Adjustments, Delays, and Discontinuations .............................................. 22 
3.1.9 
DLT and MTD/RCD for the Combination Therapy ................................................. 22 
3.1.10 
Subject Withdrawal from Treatment or from Study ............................................. 24 
 
Treatment beyond Progression ..................................................................... 25 
3.1.11 
Subject Evaluability and Subject Replacements .................................................... 25 
3.1.12 
Optional Study Treatment Extension .................................................................... 25 
3.1.13 
Interim Analysis ..................................................................................................... 25 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 25 
3.1.15 
Duration of Study .................................................................................................. 26 
3.1.16 
On Study and Post Study Follow-up ...................................................................... 26 
 
End of Study Visit ........................................................................................... 27 
3.2 
Study Flowchart ............................................................................................................. 28 
3.3 
Additional Instructions for Blood Draws for PBMC Collection ...................................... 30 
4 
Study Objectives and Endpoints ........................................................................................... 31 
4.1 
Safety and Tolerability ................................................................................................... 31 
4.1.1 
Endpoints and Assessment Methods .................................................................... 31 
4.1.2 
Subject Evaluation and Statistics ........................................................................... 31 
4.2 
Clinical Efficacy .............................................................................................................. 32 
4.2.1 
Endpoints and Assessment Methods .................................................................... 32 
 
Objective Response Rate (ORR) ..................................................................... 32 


 
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Disease Control Rate (DCR) ........................................................................... 33 
 
Duration of Response (DoR) .......................................................................... 33 
 
Progression-free Survival (PFS) ...................................................................... 33 
 
Overall Survival (OS) ...................................................................................... 33 
4.2.2 
Subject Evaluation and Statistics ........................................................................... 33 
4.3 
Biological Activity........................................................................................................... 34 
4.3.1 
Endpoints and Assessment Methods .................................................................... 34 
 
Tumor Microenvironment ............................................................................. 34 
 
Biological Activity in Blood Samples .............................................................. 36 
4.3.2 
Subject Evaluation and Statistics ........................................................................... 37 
5 
Subject Eligibility ................................................................................................................... 39 
5.1 
Inclusion Criteria ............................................................................................................ 39 
5.2 
Exclusion Criteria ........................................................................................................... 40 
5.3 
Restrictions on Concomitant Therapies ........................................................................ 44 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 44 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 45 
6 
Study Drug Preparation and Administration ........................................................................ 46 
6.1 
Durvalumab (MEDI 4736) .............................................................................................. 46 
6.1.1 
Study Drug Information ......................................................................................... 46 
6.1.2 
Durvalumab Investigational Product Inspection ................................................... 46 
6.1.3 
Durvalumab Preparation ....................................................................................... 46 
6.1.4 
Durvalumab Administration .................................................................................. 47 
6.2 
Tremelimumab .............................................................................................................. 49 
6.2.1 
Study Drug Information ......................................................................................... 49 
6.2.2 
Tremelimumab Investigational Product Inspection .............................................. 49 
6.2.3 
Tremelimumab Preparation .................................................................................. 49 
6.2.4 
Tremelimumab Administration ............................................................................. 50 
6.3 
BI 1361849 ..................................................................................................................... 51 
6.3.1 
Study Drug Information ......................................................................................... 51 
6.3.2 
Preparation of Components of BI 1361849 ........................................................... 52 
6.3.3 
BI 1361849 Administration .................................................................................... 53 
6.4 
Estimated Study Requirements ..................................................................................... 54 
6.5 
Monitoring of Tremelimumab, Durvalumab, and BI 1361849 Dose Administration .... 54 
6.5.1 
Monitoring for Tremelimumab and Durvalumab Administration ......................... 54 
6.5.2 
Monitoring for BI 1361849 Administration ........................................................... 55 
6.6 
Drug Overdose Management ........................................................................................ 55 
7 
Administrative, Legal and Ethical Requirements .................................................................. 56 
7.1 
Documentation and Reporting of Adverse Events ........................................................ 56 
7.1.1 
Definitions ............................................................................................................. 56 
7.1.2 
Additional Expedited Reporting Requirements for this Study .............................. 57 
 
Pregnancy ...................................................................................................... 57 
 
Overdose ....................................................................................................... 58 
 
Hepatic Function Abnormality ....................................................................... 58 
 
New Cancers .................................................................................................. 58 


 
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Deaths ............................................................................................................ 58 
7.1.3 
Severity of an Adverse Event ................................................................................. 59 
7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 59 
7.1.5 
General Reporting Requirements .......................................................................... 60 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 60 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 61 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................ 61 
7.2 
Administrative Sponsor Requirements ......................................................................... 64 
7.2.1 
Trial Master Files ................................................................................................... 64 
7.2.2 
Case Report Form Data Collection ........................................................................ 64 
7.2.3 
Language ................................................................................................................ 64 
7.2.4 
Monitoring ............................................................................................................. 65 
7.2.5 
Protocol Amendments ........................................................................................... 65 
7.2.6 
Premature Subject Withdrawal from Treatment or from Study ........................... 65 
7.2.7 
Early Trial Termination .......................................................................................... 66 
7.2.8 
Study Drug Shipments and Accountability ............................................................ 66 
7.3 
Regulatory, Legal and Ethical Requirements ................................................................. 66 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 66 
7.3.2 
Informed Consent .................................................................................................. 66 
7.3.3 
Institutional Review Board .................................................................................... 67 
7.3.4 
Subject Confidentiality .......................................................................................... 67 
8 
Appendices ........................................................................................................................... 68 
8.1 
Protocol Version History ................................................................................................ 68 
8.2 
Participating Study Sites, Investigators and Staff, Laboratories, and Sponsor 
Information ............................................................................................................................... 92 
8.3 
Dose Adjustments and Delays for Durvalumab and Tremelimumab ............................ 93 
8.3.1 
Durvalumab and Tremelimumab Dose Modification Due to Toxicity ................... 93 
8.3.2 
Durvalumab and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities ................................................................................................................... 95 
8.4 
BI 1361849 Toxicity Management and Dose Modification ........................................... 97 
8.5 
RECIST 1.1 and irRECIST Guidelines ............................................................................... 99 
8.6 
Exploratory Assessment of Correlative Immunologic Research .................................. 107 
8.7 
ECOG Performance Status ........................................................................................... 108 
8.8 
List of Abbreviations .................................................................................................... 109 
9 
References .......................................................................................................................... 111 
 


 
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Figures 
Figure 1. Enrollment Schema for Arms A and B ............................................................................ 18 
Figure 2. Dose Escalation and De-Escalation Schema ................................................................... 22 
 


 
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1 Background 
1.1 Checkpoint Inhibitors in the Treatment of Non-Small Cell Lung 
Cancer 
Lung cancer is responsible for nearly 1 in 5 cancer-related deaths, or an estimated 1.6 million 
people, worldwide. In the U.S., lung cancer is the leading cause of cancer-related death among 
both men and women.(1)  For patients who are diagnosed with advanced disease, conventional 
treatment options including surgery, chemotherapy, and radiation are unlikely to result in cure.  
Lung cancer has also emerged as an exciting target of immune-based therapies, specifically 
checkpoint inhibitors.(2) In non-small cell lung cancer (NSCLC), marked single-agent activity has 
been observed with inhibition of programmed death receptor 1 (PD-1) on immune cells or 
inhibition of programmed death receptor ligand 1 (PD-L1).(3-5)  Notably, PD-L1 appears to be 
expressed in 25% to 50% of NSCLC tumors, with expression both on tumor cells and within the 
tumor microenvironment (TME) on tumor-associated macrophages.(6)  While the relationship of 
expression to therapeutic response is still being defined, early studies indicate there may be 
some activity of such inhibitors in NSCLC.(7-9)  
Checkpoint inhibitors, particularly PD-1/PD-L1 antibodies, have been shown to be effective in 
the treatment of NSCLC(10-12), and in 2015, nivolumab and pembrolizumab were approved by 
FDA for the treatment of lung cancer after progression on or after platinum-based 
chemotherapy.  
In March 2015, FDA approved the PD-1 checkpoint inhibitor nivolumab for the treatment of 
advanced squamous NSCLC that has stopped responding to chemotherapy. This approval was 
based on results of a Phase 3 trial in which subjects receiving nivolumab had median overall 
survival of 9.2 months versus 6.0 months with docetaxel.(11)  In October 2015, FDA expanded 
its approval of nivolumab to include non-squamous NSCLC that has stopped responding to 
chemotherapy. This approval was based on the results of a Phase 3 trial that showed that 
subjects who received nivolumab had a median overall survival of 12.2 months compared to 9.4 
months for those receiving docetaxel.(10)  
Also in October 2015, pembrolizumab, a PD-1 checkpoint inhibitor was approved for patients 
with NSCLC (both squamous and non-squamous) with tumors that test positive for PD-L1. In a 
Phase 1 clinical trial, PD-L1 expression level of 50% was associated with the likelihood of clinical 
benefit. Among subjects with a proportion score of at least 50%, the response rate was 
45.2%.(12)  
For both of these immunotherapies, it is recommended that patients with epidermal growth 
factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should 
have disease progression on FDA-approved therapy prior to receiving nivolumab or 
pembrolizumab. 
Both nivolumab and pembrolizumab are being studied in multiple indications in randomized 
Phase 3 trials compared to standard of care chemotherapy as first-line treatment, and several 
other PD-1/PD-L1 checkpoint inhibitors are also in late stage clinical testing.  


 
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An alternate checkpoint inhibitor strategy, inhibition of cytotoxic T lymphocyte-associated 
antigen 4 (CTLA-4) on regulatory T-cells (Tregs) which are often increased in the TME, has also 
demonstrated single-agent activity in certain tumor types.  Although single-agent anti-CTLA-4 
antibodies have not shown responses in NSCLC or improvement in overall survival, there has 
been prolongation of progression-free survival observed with phased ipilimumab in a 
randomized Phase 2 trial.(13)  Furthermore, there is significant synergy seen with combining 
anti-CTLA-4 antibodies with anti-PD-1 antibodies in melanoma, as the two immunotherapies 
target complementary checkpoints in immune activation.(14)  In EGFR-driven models of lung 
adenocarcinoma, PD-1 inhibition did not alter the numbers of Tregs expressing high levels of 
CTLA-4, and EGFR signaling itself results in increased Treg infiltration, which may provide 
synergistic efficacy with anti-CTLA-4 in NSCLC as well.(15) 
1.2 Study Drugs 
This study will evaluate the safety and efficacy of the addition of a vaccine therapy (BI 1361849, 
previously known as CV9202) to 1 or 2 checkpoint inhibitors (durvalumab and tremelimumab) 
for NSCLC. 
1.2.1 Durvalumab (MEDI4736) - PD-L1 Antibody 
Durvalumab is briefly described in the section below using excerpts that have been extracted 
from the Investigator’s Brochure (IB). Please refer to the current IB for complete and current 
information. 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1.  Durvalumab is selective for recombinant PD-L1 and 
blocks the binding of recombinant PD-L1 to the PD-1 and cluster of differentiation (CD) 80 
receptors.  
As of the data cutoff dates in the IB (15Apr2015 to 18Sep2015), a total of 1,910 subjects have 
been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored and 
10 collaborative studies. Of the 1,910 subjects, 1,279 received durvalumab monotherapy, 454 
received durvalumab in combination with tremelimumab or other anticancer agents, 14 
received other agents (1 gefitinib, 13 MEDI6383), and 163 have been treated with blinded 
investigational product. No studies have been completed or terminated prematurely due to 
toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique adverse events (AEs). 
Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, have 
been observed with durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, 
neuropathy / neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, 
pancreatitis is an important potential risk particularly with durvalumab and tremelimumab 
combination therapy. These events are manageable by available/established treatment 
guidelines as described in Section 8.3.  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 


 
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Clinical activity has been observed across the 4 studies, and two of the studies have data for 
NSCLC as detailed below. 
Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg 
Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, measurable disease 
at baseline, and ≥ 1 follow-up scan, or discontinued due to disease progression or death without 
any follow-up scan). In PD-L1 unselected subjects, the objective response rate (ORR), based on 
investigator assessment per RECIST v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% 
in bladder cancer (n = 15), and disease control rate at 24 weeks ranged from 4.2% in triple-
negative breast cancer (n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 
status was known for 383 of the 456 response evaluable subjects. Across the PD-L1 positive 
tumors, ORR was highest for bladder cancer, advanced cutaneous melanoma, hepatocellular 
carcinoma (HCC) (n = 3 each, 33.3% each), NSCLC (n = 86; 26.7%), and squamous cell carcinoma 
of the head and neck squamous cell carcinoma of the head and neck (SCCHN) (n = 22; 18.2%). In 
the PD-L1 positive subset, disease control rate at 24 weeks was highest in advanced cutaneous 
melanoma (n = 3; 66.7%), NSCLC (n = 86; 36.0%), HCC and bladder cancer (n = 3 each; 33.3% 
each), and SCCHN (n = 22; 18.2%). 
Study D4190C00006: Of the 102 subjects with advanced NSCLC treated with durvalumab in 
combination with tremelimumab, 63 subjects with at least 16 weeks of follow-up were 
evaluable for response (defined as measurable disease at baseline and at least 1 follow-up scan; 
this included discontinuations due to disease progression or death without follow-up scan). Of 
the 63 evaluable subjects, 17 (27%) had a best overall response of partial response (PR), 14 
(22%) had stable disease (SD), 22 (35%) had progressive disease (PD), and 10 (16%) were not 
evaluable. The ORR (confirmed and unconfirmed complete response (CR) or PR) was 27% and 
the disease control rate ([DCR], CR, PR, or SD) was 49% as assessed by RECIST v1.1. 
Durvalumab, like other drugs in the anti PD-L1 class, has shown early evidence of activity against 
solid tumors as a single agent and is currently being evaluated in combination with 
tremelimumab and other therapies in NSCLC.(16, 17) 
1.2.2 Tremelimumab - CTLA-4 Antibody 
Tremelimumab is briefly described in the section below using excerpts that have been extracted 
from the Investigator’s Brochure (IB). Please refer to the current IB for complete and current 
information. 
Tremelimumab (formerly CP-675,206) is a human immunoglobulin G2 (IgG2) mAb being 
investigated as a cancer immunotherapeutic agent.  Tremelimumab is specific for human CTLA-
4, with no cross-reactivity to related human proteins.   
As of the data cutoff dates (1 November 2015 for monotherapy studies and 15 April 2015 to 12 
July 2015 for combination therapy studies), 34 sponsored clinical studies have been conducted 
as part of the tremelimumab clinical development program. Of these, 13 studies have 
completed and 21 are ongoing. Eight tremelimumab monotherapy studies have been completed 
and 3 are ongoing. As of the data cutoff date of 1 November 2015, 973 subjects received 
tremelimumab in completed monotherapy studies and the ongoing Study D4881C00024 and 
569 subjects have been treated in the ongoing blinded Phase 2b monotherapy Study 
D4880C00003 [DETERMINE]). In the third ongoing monotherapy study (D4884C00001), no 
subjects have been treated as of the data cutoff. In addition, approximately 59 subjects have 


 
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been treated with tremelimumab in monotherapy arms of combination studies. Five studies of 
tremelimumab in combination with other anticancer agents have been completed and 18 are 
ongoing. In total, 250 subjects with a variety of tumor types have received tremelimumab in 
combination with other anticancer agents in these studies. 
In clinical patients, tremelimumab exhibits linear (dose-proportional) PK following IV infusion. 
The estimate of clearance (CL), volume of distribution at steady state (Vss), and terminal-phase 
half-life is 0.132 mL/h/kg, 81.2 mL/kg and 22.1 days, respectively. These values are consistent 
with those of natural IgG2. 
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged 
that is similar to that of the related anti-CTLA-4 antibody, ipilimumab. Response rates to anti-
CTLA-4 antibodies are generally low, approximately 10%. However, in patients who respond, the 
responses are generally durable, lasting several months even in patients with aggressive tumors 
such as refractory metastatic melanoma. Some patients may have what is perceived to be 
progression of their disease in advance of developing disease stabilization or a tumor response. 
Overall, the impact on conventionally-defined progression-free survival (PFS) can be small; 
however, the durable response or stable disease seen in a proportion of patients can lead to 
significant prolongation of overall survival (OS). For example, ipilimumab was shown to 
significantly improve OS in both first- and second-line treatment of patients with metastatic 
melanoma. The melanoma data with ipilimumab clearly demonstrate that a small proportion of 
patients with an objective response and a small impact on PFS rates can lead to significant 
prolongation of OS. In a large, single-arm Phase II tremelimumab study (A3671008) in subjects 
with advanced refractory and/or relapsed melanoma, objective responses (primary endpoint) 
following tremelimumab 15 mg/kg administered once every 90 days (Q90D) were observed in 
7% of subjects. In each case, the response was durable (present at ≥6 months from enrolment). 
A Phase III, open-label, randomized study (A3671009) comparing tremelimumab 15 mg/kg Q90D 
(Arm A) to either dacarbazine (DTIC) or temozolomide (Arm B) in subjects with advanced 
melanoma was terminated following a pre-specified interim futility analysis. Based on the final 
analysis, the median OS (primary endpoint) was 12.6 months in Arm A and 10.7 months in Arm 
B.(18)  Although Phase II and Phase III studies (A3671002, A3671008, and A3671009) of 
tremelimumab in metastatic melanoma did not meet the primary endpoints of response rate 
and OS, respectively, the data suggest activity of tremelimumab in melanoma.(18, 19)  
Preliminary activity of single-agent tremelimumab observed in studies of malignant 
mesothelioma (20, 21) provided a sound scientific rationale for further investigation of single-
agent tremelimumab in this patient population. 
Clinical studies of tremelimumab are ongoing in several solid tumor types, including malignant 
mesothelioma, and have been completed in solid tumor types including melanoma, 
adenocarcinoma of the colon or rectum, non-small cell lung cancer (NSCLC), prostate cancer, 
breast cancer, pancreatic cancer, and renal cell carcinoma.  In a Phase II maintenance study in 
NSCLC, PFS at 3 months was 22.7% in the tremelimumab arm compared with 11.9% in the best 
supportive care arm (Study A3671015). 
The profile of adverse events (AEs) and the spectrum of event severity have remained stable 
across the tremelimumab clinical program and are consistent with the pharmacology of the 
target. To date, no tumor type or stage appears to be associated with unique AEs (except for 
vitiligo that appears to be confined to patients with melanoma). 


 
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1.2.3 BI 1361849 
BI 1361849 (previously known as CV9202) is briefly described in this section below using 
excerpts that have been extracted from the Investigator’s Brochure (IB). Please refer to the 
current IB for complete and current information. 
Vaccination with mRNA molecules represents a novel approach in cancer immunotherapy. 
RNActive® cancer vaccines are based on a proprietary technology platform (CureVac), aiming to 
enhance stability and efficiency of in vivo translation for RNA encoding for selected tumor-
associated antigens (TAA).BI 1361849 comprises 6 different mRNAs, encoding for the TAAs 
MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1. The vaccine is intended for the 
treatment of patients with histologically or cytologically confirmed NSCLC. 
RNActive® vaccines, and in particular the antigen components of BI 1361849, have been shown 
to be effectively translated into the encoded proteins. Systemic effects of RNActive® vaccination 
occur via priming of immune effectors via dendritic cells that have locally taken up the RNA-
based vaccine and present the encoded antigens to the immune system in the lymph nodes 
draining the injection site, and via systemic recirculation of these effectors (immune cells, 
antibodies). Dendritic cell migration, increased activation of lymph node immune cells and 
increased proliferation of antigen-specific lymphocytes have been shown to occur after 
RNActive® vaccination. RNActive® vaccination induces a balanced systemic antigen-specific 
immune response, comprising humoral and cellular responses, including multifunctional 
cytotoxic CD8+ T lymphocytes. 
Anti-tumor efficacy has been shown in a syngeneic murine animal model, using tumor cells 
stably expressing the well accepted model antigen ovalbumin as a surrogate tumor-associated 
antigen. In this model, vaccination with ovalbumin-encoding RNActive® vaccine led to effective 
reduction of tumor growth, which was dependent to a large extent on the presence of CD8+ 
T-cells. Intra-tumoral changes of gene expression reflecting increased cytotoxicity were 
demonstrated. Also, synergy between radiotherapy and the added vaccine could be shown, and 
similarly for checkpoint inhibition and the added vaccine. Pre-clinical studies were not 
suggestive of relevant toxicities aside from commonly mild alterations at the site of injection. 
The RNActive® was degraded locally with an average half-life of 2 days. There was no detectable 
systemic exposure to the administered RNA. Systemic effects of the vaccine are based on the 
systemically recirculating immune effectors rather than systemic exposure to the RNA. 
For each of the individual RNActive® cancer vaccines, data from one trial are currently available. 
The trials for CV9201 (Trial CV-9201-003) and CV9103 (Trial CV-9103-001) have been completed, 
the respective trials for BI 1361849 (Trial CV-9202-006) and CV9104 (Trial CV-9104-004) are 
currently ongoing. 
As of March 2017, an estimated >250 subjects have to date been exposed to four RNActive® 
cancer vaccines. The majority of the subjects were enrolled in a placebo-controlled, double-
blind ongoing trial of the hexavalent prostate cancer vaccine CV9104. CV9104 shares one of its 
six constituents with BI 1361849, namely the RNActive® vaccine encoding for MUC1.  Forty-six 
subjects have been treated with vaccine CV9201 (comprising 5 of the six antigen constituents of 
BI 1361849 lacking the MUC1 constituent).  
Data from all RNActive® cancer vaccines are considered of interest for the development of 
BI 1361849, as many general aspects, in particular regarding feasibility and safety of multiple 


 
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and reiterated intradermal RNActive® administrations, are shared by the vaccines. The 
pertinence of data especially from the development of the pentavalent vaccine CV9201 for 
BI 1361849, sharing five of the six antigen constituents comprised in BI 1361849, is ascertained 
by the confirmed comparability of the shared antigen components between the two vaccines. 
To date, 26 subjects have been exposed to BI 1361849 (see details for Study CV-9202-006 
below). 
Based on the initial dose escalation trials and preliminary Phase 2 data, RNActive® vaccines 
appear well tolerated and safe, with all 4 clinical vaccines sharing a very similar safety profile.  
Adverse events frequently reported as vaccine related were very similar for all RNActive® cancer 
vaccines tested in clinical trials and consisted of mild injection site reactions as well as flu-like 
symptoms such as pyrexia and occasionally chills. Grade 3 transient pyrexia was reported for 
one subject of 26 for BI 1361849; none was reported in trial CV9201-003. No signs or symptoms 
of a clinically manifest autoimmune disorder were observed for any of the RNActive® cancer 
vaccines. Also, no anaphylactic or hypersensitivity reactions to the vaccines have been reported, 
except for one AE of non-serious asthma that occurred in a subject with known chronic 
obstructive pulmonary disease, and was considered probably related to study treatment with 
CV9201 by the investigator. 
The recommended dose for each constituent of RNActive® vaccines, encoding for a specific 
tumor antigen, is identical across all RNActive® cancer vaccines. All individual antigen 
constituents of a multivalent RNActive® cancer vaccine are to be administered individually and 
in duplicate, based on data showing enhanced efficiency of vaccination. The recommended dose 
per antigen constituent is 320 μg, split into two administrations of 160 μg each, and the two 
administrations are to occur in two different defined regions (upper arm, thigh) drained by 
separate lymph nodes. In particular, the recommended dose of BI 1361849, based on trial CV-
9201-003 and trial CV-9202-006, has been confirmed as 320 μg/antigen component and 
administration time point, which is identical to the dose of the antigen components of the other 
RNActive® cancer vaccines.  
The BI 1361849 components may also be administered by a needle-free device, the PharmaJet 
Tropis® device. Due to the fill volume of 100 μL, the device allows for administration of half the 
previously established doses. Instead of 320 μg per antigen, 160 μg per antigen is dosed when 
using the same manner of administration of two inoculations per antigen and vaccination time 
point. Preclinical data, demonstrating a more even intradermal distribution of the applied 
volume, increased protein production even at reduced doses (e.g. 25% of dose), and clinical data 
(trial CV-9104-007 of RNActive® vaccine CV9104), showing at least similar immunogenicity, 
support the use of this device. Device-related AEs were qualitatively and quantitatively similar to 
conventional needle administration.   
Summary for Trial CV-9202-006 (See IB for details) 
The Phase 1b trial with BI 1361849, CV-9202-006, was an exploratory, open label study of 
BI 1361849 combined with local radiation as consolidation/maintenance treatment in subjects 
with stage IV NSCLC and a response or stable disease after standard first-line therapy. Radiation 
was to be started one week after the first vaccination. The population was stratified by 
histological subtype (non-squamous cell carcinoma [non-EGFR mutated], squamous cell 
carcinoma, non-squamous carcinoma with activating EGFR mutations) and subjects were to 


 
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receive indicated standard maintenance treatments in combination with BI 1363849.  All 
subjects were to receive 1920 μg per administration time point, and treatment was to continue 
until disease progression requiring subsequent anticancer therapy. All subjects were to receive 
also 20 Gy of radiotherapy, fractionated in daily doses of 5 Gy over a course of 4 days, to be 
administered in week two of vaccine treatment.  
The trial, which was closed in July 2016, confirmed feasibility and tolerability of the 
recommended dosing (320 μg per antigen constituent and administration time point) and for 
long-term therapy up to 806 days (>2 years). In total, about 225 vaccinations (on average ~8.6 
vaccinations per subject) were administered.  Exploratory efficacy results showed a median PFS 
of about 2.9 months after initiation of study treatment, i.e. maintenance therapy, and a median 
OS of about 14 months. One subject in stratum 1, who was treated with BI 1361849, 
pemetrexed and experimental low-dose radiotherapy, achieved a partial response; otherwise, 
best response was SD or PD. Two subjects in stratum 1 achieved long-term disease control (20 
months and 27 months, respectively); one subject in stratum 3, treated with BI 1361849 added 
to erlotinib therapy received vaccination therapy for >25 months despite having experienced a 
new pulmonary lesion after 14 months (treatment beyond progression was allowed per protocol 
if clinical benefit was maintained).   
Many of the subjects showed a pre-existing immune response to target antigens at baseline 
(baseline immune response to the respective TAA).  Overall, 21 (84%) of 25 evaluable subjects 
fulfilled the criteria for humoral and / or cellular immune responders. Ten (40%) subjects 
fulfilled criteria for cellular immune responders to any of the CV9202 encoded antigens at any 
post-baseline assessments based on either IFN-γ ELISpot or flow cytometry-based intracellular 
cytokine staining (ICS). The frequency of CD4 (measured by ICS) immune responders to any 
CV9202 encoded antigen was slightly higher compared to that of CD8 responders (measured by 
ICS) at any post-baseline assessment time-point (28.0% / 7 subjects vs. 16.0% / 4 subjects, 
respectively).  All 25 subjects in the evaluable population were positive for IgM and IgG against 
any of the CV9202 encoded antigens at baseline. Twenty (80%) subjects had a humoral immune 
response post-baseline (i.e. IgG or IgM against any of the CV9202 encoded antigens at any post-
baseline time point) and were rated as humoral immune responder after applying responder 
criteria. The majority of subjects (19 [76.0%]) were responders for IgG at any post-baseline time 
point, whereas only few subjects (7 [28.0%]) were positive for IgM at post-baseline time points. 
A total of 13 (52%) subjects were multiple responders, i.e. 9 subjects in stratum 1 and 4 subjects 
in stratum 2.  Overall, only a limited number of the performed post-baseline cellular 
immunomonitoring assays fulfilled “immune responder” criteria for the individual assay 
outcome, and among those, persistence over both post-baseline time points was not common. 
The tolerability profile of BI 1361849 appeared very similar to that of other RNActive® vaccines. 
All subjects reported at least one AE and 25 (96.2%) subjects reported BI 1361849 related AEs. 
Eleven (42.3%) subjects reported serious adverse events (SAEs), none of which were considered 
BI 1361849 related. Treatment-emergent AEs by maximum CTCAE grade were Grade 1 (4 
[15.4%] subjects), Grade 2 (7 [26.8%] subjects), Grade 3 (13 [50.0%] subjects), and Grade 4 (2 
[7.7%] subjects). The two Grade 4 events, neutrophil count decreased, were not considered 
related to BI 1361849.  With very few exceptions, BI 1361849-related AEs were of Grade 1 and 
Grade 2. Three of the Grade 3 AEs (one subject with pyrexia and 2 subjects with fatigue) were 
considered related to BI 1361849.  No drug-related SAE has been reported in the trial.  A low 
number of subjects experienced nausea/emesis considered related to BI 1361849 in the trial. 


 
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The most frequent AEs reported were erythema at the injection site and pyrexia, mostly being 
reported as vaccine-related but of grade 1 only. Flu-like symptoms potentially represent a 
pharmacodynamic effect (mimicking of a viral infection, stimulation of the innate immune 
system via TLRs 7 and 8 due to the RNA-related properties). None of the findings, including e.g. 
cardiorespiratory or vascular AEs, suggest the occurrence of an uncontrolled release of 
cytokines or the emergence of autoimmune disorders. This is in line with experience with other 
vaccines directed against BI 1361849 encoded antigens, which suggests that autoimmune 
disorders are not commonly observed with such treatment.  
 
 


 
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2 Study Rationale 
As described in Section 1.1, checkpoint inhibitors, particularly PD-1/PD-L1 antibodies, have been 
shown to be effective in the treatment of NSCLC.  Checkpoint inhibitors are also associated with 
minimal toxicities compared with chemotherapy or targeted therapies and function quite 
distinctly from other therapies. Therefore, the potential for effective and safe combination with 
existing therapies is significant.  
Vaccine therapies stimulate the immune system to attack cancer cells (“active 
immunotherapy”), as opposed to blocking immune inhibition in the TME by checkpoint 
inhibitors (“passive immunotherapy”).  Randomized vaccine studies in NSCLC have shown 
benefit in some subgroups.  Tecemotide (Stimuvax®) demonstrated overall survival (OS) benefit 
over placebo in a subgroup of stage III subjects who received concurrent chemotherapy and 
radiation prior to vaccine, and belagenpumatucel-L (Lucanix®) demonstrated OS benefit in 
squamous cell carcinoma subjects who were randomized within 12 weeks of completion of prior 
treatment and in those who had received prior radiation.(22, 23)  However, checkpoint 
mechanisms limit the effectiveness of vaccines at the TME, which may explain why more global 
long-term benefit from vaccines has not been realized.  Therefore, combining “passive 
immunotherapy” with “active immunotherapy” may overcome some of limitations of vaccine 
therapy alone. In an animal model of RNActive® vaccination using ovalbumin (OVA) as model 
cancer antigen stably transfected into E.G7 tumor cells, the combination of the vaccine and a 
PD-1 inhibitor was more effective than either medication alone. Similar results were also 
obtained for the combination of the RNActive® vaccine and a CTLA-4 inhibitor.  Combination of 
the PD-1 inhibitor and OVA-RNActive® resulted in complete tumor responses in a part of the 
treated mice, who were also protected against subsequent rechallenge with the OVA-negative 
parent tumor cell line.(24) 
2.1 BI 1361849 Dose  
The BI 1361849 drug product is a vaccine comprising six drug product components (F2408, 
F2409, F2410, F2624, F2625, and F2626), which are provided and administered separately.  The 
recommended dose per antigen constituent is 320 μg (160 μg x 2), for a total of 1920 μg (320 μg 
x 6 constituents). 
BI 1361849 may also be administered by a needle-free device, the PharmaJet Tropis® device. 
See Section 1.2.3 for additional details.  
Due to the filling volume of 100 μL, the device allows for administration of half the previously 
established doses, i.e., 160 μg instead of 320 μg per antigen when using the same manner of 
administration of two inoculations per antigen and vaccination time point. Advantages include 
improved patient convenience, handling safety, ease, and reliability of intradermal 
administration. Preclinical data showed that using a needle-free device such as the PharmaJet 
Tropis® device, the efficiency of delivery increases and protein production is higher even at half 
or a quarter of the administered dose, hence lower doses can be used. Clinical data from a 
Phase 2 trial, CV-9104-007, suggests that administration of half the dose by the PharmaJet 
Tropis® device results in at least similar immunogenicity compared to needle administration of 
the full dose. 


 
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For this study, the Pharmajet Tropis® device will be used for the administration of the 
BI 1361849 components.  Allowing for a filling volume of 100 μL (80 μg) and 2 administrations 
per component, the recommended dose per each of the 6 antigen components will be 160 μg (2 
x 80 µg), for a total of 960 μg (12 administrations). 
2.2 Durvalumab and Tremelimumab Dose 
Currently, fixed dosing is recommended for durvalumab and tremelimumab with the dose and 
schedule of 1500 mg durvalumab Q4W and 75 mg tremelimumab Q4W for subjects > 30 kg. 
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (Study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors).(25)  
Population PK analysis indicated only minor impact of body weight on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body weight-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 weight of approximately 75 kg). A 
total of 1000 patients were simulated using body weight distribution of 40–120 kg. Simulation 
results demonstrate that body weight-based and fixed dosing regimens yield similar median 
steady state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen.   
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma).(26) 
Population PK model indicated minor impact of body weight on PK of tremelimumab (coefficient 
of ≤ 0.5). The weight-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on median 
body weight of approximately 75 kg) regimens were compared using predicted PK 
concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1000 patients with body weight distribution of 40 to 120 kg. Similar to 
durvalumab, simulations indicated that both body weight-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between-
subject variability with fixed dosing regimen.  
Similar findings have been reported by others.(27-30)  Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies. In addition, Zhang et al. investigated 18 
therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 18 
in terms of reducing the between-subject variability in pharmacokinetic/pharmacodynamics 
parameters.(29)  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectations of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body weight of 
75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) and a fixed dose 
of 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) are included in the current study.  
The 1500 mg Q4W dosing of durvalumab is recommended only for subjects with > 30kg body 
weight in order to limit endotoxin exposure.  Subjects with a body weight ≤ 30 kg are not eligible 
for enrollment in the current study.  See Section 3.1.7.1 for additional details regarding the dose 


 
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de-escalation cohort for durvalumab and for durvalumab and tremelimumab dose requirements 
for instances when a subject’s body weight drops to ≤ 30 kg while on the study. 


 
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3 Experimental Plan 
3.1 Study Design 
This is an open-label multicenter Phase 1/2 study to evaluate the safety and preliminary efficacy 
of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors for NSCLC: 
• 
Arm A: mRNA Vaccine [BI 1361849] + anti-PD-L1 [durvalumab] 
• 
Arm B: mRNA Vaccine [BI 1361849] + anti-PD-L1 [durvalumab] + anti-CTLA-4 
[tremelimumab] 
For each arm of the study, there is a dose evaluation phase in which the Recommended 
Combination Dose (RCD) is determined according to a standard 3 + 3 design. The dose 
evaluation phase is followed by an expansion phase, in which the cohort at the RCD for each 
arm is expanded to 20 subjects (inclusive of the subjects from the dose evaluation cohort). 
NOTE: The BI 1361849 drug product is a vaccine comprising six drug product components 
(F2408, F2409, F2410, F2624, F2625, and F2626), which are provided and administered 
separately. See Section 6.3 for additional details. 
3.1.1 Study Phase 
Phase 1/2 
3.1.2 Enrollment/Randomization 
Enrollment will start in the Arm A dose evaluation cohorts in a sequential fashion.  After the RCD 
is determined for Arm A, enrollment will start for the dose evaluation of Arm B (see Section 
3.1.7.1) and for the Arm A Expansion Cohort (see Figure 1), whereby no randomizations will be 
performed.  Any new subject will be assigned to the Arm B dose evaluation cohort, unless no 
slot is available, in which case the subject will be assigned to the Arm A Expansion Cohort.  After 
the dose evaluation and safety review for Arm B is complete, enrollment into the Arm B 
Expansion Cohort will be prioritized over Arm A (see Figure 1). 
Arm A 
Dose Evaluation
Arm A 
Expansion Cohort*
Arm B
Dose Evaluation
Arm B
Expansion Cohort 
priority
secondary
Prioritized*
 
Figure 1. Enrollment Schema for Arms A and B 
* After the dose evaluation and safety review for Arm B is complete, enrollment into the Arm B Expansion 
Cohort will be prioritized over Arm A.  


 
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3.1.3 Blinding/Unblinding 
This is an open-label study. 
3.1.4 Subject Population 
Subjects with histologically confirmed metastatic NSCLC.  For subjects with known EGFR or 
ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine kinase inhibitor or 
ALK/ROS-1 inhibitor, respectively. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy 
and must not have had progression at or before 12 weeks after start of treatment. Details on 
subject eligibility are found in Section 5. 
3.1.5 Number of Sites/Subjects 
Up to 8 sites in the US, with a total of up to 56 subjects. 
3.1.6 Sample Size Considerations 
The dose evaluation phase will utilize a standard 3 + 3 design for Arms A and B, which will result 
in the enrollment of 6 to 18 subjects. 
In the expansion phase, 20 subjects per arm are thought to provide sufficient data to adequately 
identify essential safety and preliminary efficacy signals.  Therefore, up to 14 additional subjects 
will be added to the 6 subjects treated at the RCD in each arm (A and B).  
The sample size n=20 for the expansion phase is deemed to provide sufficient precision for the 
estimation of incidence of adverse events.  The Clopper Pearson confidence intervals (CI) for 
incidence of adverse events based on a sample size of 20 subjects are provided below: 
Number of Subjects 
with Event 
Incidence 
95% Confidence Interval 
(Clopper Pearson) 
1/20 
0.05 
(0.00127, 0.24873) 
2/20 
0.10 
(0.01235, 0.31698) 
3/20 
0.15 
(0.03207, 0.37893) 
4/20 
0.20 
(0.05733, 0.43661) 
5/20 
0.25 
(0.08657, 0.49105) 
6/20 
0.30 
(0.11893, 0.54279) 
7/20 
0.35 
(0.15391, 0.59219) 
8/20 
0.40 
(0.19119, 0.63946) 
9/20 
0.45 
(0.23058, 0.68472) 
10/20 
0.50 
(0.27196, 0.72804) 
11/20 
0.55 
(0.31528, 0.76942) 
12/20 
0.60 
(0.36054, 0.80881) 
13/20 
0.65 
(0.40781, 0.84609) 
14/20 
0.70 
(0.45721, 0.88107) 
15/20 
0.75 
(0.50895, 0.91343) 
16/20 
0.80 
(0.56339, 0.94267) 
17/20 
0.85 
(0.62107, 0.96793) 
18/20 
0.90 
(0.68302, 0.98765) 


 
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Number of Subjects 
with Event 
Incidence 
95% Confidence Interval 
(Clopper Pearson) 
19/20 
0.95 
(0.75127, 0.99873) 
 
3.1.7 Treatment Arms and Treatment Schema 
Study drug will be administered over 12 cycles with a cycle length of 28 days.  The study drugs 
used in this study will be administered per cycle as shown below: 
Note: the dosing intervals for BI 1361849 intervals increase over time 
Cycle 
(28d) 
Cycle 
Day 
Arm A Dosing Schedule 
Arm B Dosing Schedule 
BI 1361849 
(12 x i.d. each) 
Durvalumab 
(i.v.) 
BI 1361849 
(12 x i.d. each) 
Durvalumab 
(i.v.) 
Tremelimumab* 
(i.v.) 
1 
1 
X 
X 
X 
X 
X 
8 
X 
 
X 
 
 
15 
X 
 
X 
 
 
2 
1 
X 
X 
X 
X 
X 
15 
X 
 
X 
 
 
3 
1 
X 
X 
X 
X 
X 
15 
X 
 
X 
 
 
4 
1 
X 
X 
X 
X 
X 
5 
1 
X 
X 
X 
X 
 
6 
1 
X 
X 
X 
X 
 
7 
1 
 
X 
 
X 
 
15 
X 
 
X 
 
 
8 
1 
 
X 
 
X 
 
9 
1 
X 
X 
X 
X 
 
10 
1 
 
X 
 
X 
 
15 
X 
 
X 
 
 
11 
1 
 
X 
 
X 
 
12 
1 
X 
X 
X 
X 
 
i.d. = intradermal; i.v. = intravenous 
 
 Dose Evaluation Phase 
Each subject enrolled in the dose evaluation cohorts of the study will be evaluated for dose-
limiting toxicities (DLTs), as defined in Section 3.1.9.  Dose de-escalation and evaluation of RCD 
will be performed based on the available dose levels (see table below) and the respective rules 
for a standard 3 + 3 study design (see Schema below). 
For Arm A, the RCD of BI 1361849 + durvalumab is determined. The starting dose of durvalumab 
is 1500 mg with possible de-escalation to 750 mg; the dose for BI 1361849 remains constant. For 
Arm B, the RCD of BI 1361849 + durvalumab from Arm A with the addition of tremelimumab 75 
mg is evaluated. There is no dose escalation/de-escalation for Arm B; if there is unacceptable 
toxicity in Arm B, the arm will be discontinued. 


 
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Dose Level Table for Evaluation Phase 
Dose 
Level 
Arm A 
Dose 
Level 
Arm B* 
BI 1361849 
Durvalumab 
BI 1361849 
Durvalumab 
Tremelimumab 
-1 
12 x 
80 µg** 
750 mg 
 
 
 
 
Starting 
12 x 
80 µg** 
1500 mg 
Starting 
12 x 
80 µg** 
RCD from Arm A 
75 mg 
*If there is unacceptable toxicity in Arm B, dosing will continue at RCD from Arm A, without tremelimumab. 
**BI 1361849 is a vaccine comprising six drug product components (F2408, F2409, F2410, F2624, F2625, and F2626), 
which are provided and administered separately; each component is administered twice, thus there are 12 
administrations of 100 µL (80 µg) each. 
NOTE 1: The Pharmajet Tropis® device will be used for the administration of the BI 1361849 
components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per 
component, the recommended dose per each of the 6 antigen components will be 160 μg (2 x 
80 μg), for a total of 960 μg (12 administrations). See Section 6.3.3 for details on the 
administration of BI 1361849.  
NOTE 2:  
• 
The durvalumab dose of 1500 mg Q4W is for subjects > 30 kg. If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing equivalent 
to 20 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject 
would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  When the 
weight improves to >30 kg, the subject may return to fixed dosing of durvalumab 1500 mg. 
• 
When tremelimumab 75 mg Q4W (x4) is given with durvalumab 1500 mg Q4W, if a 
subject’s body weight drops to ≤ 30 kg while on the study, the subject will receive weight-
based dosing for both drugs. For durvalumab, the weight-based dosing is described above; 
for tremelimumab, weight-based dosing equivalent to 1 mg/kg tremelimumab will be given 
as long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject would receive a 30 mg 
dose; a 25 kg subject would receive a 25 mg dose; etc.).  When the weight improves to >30 
kg, the subject may return to fixed dosing of tremelimumab 75 mg and durvalumab 1500 
mg. 
 


 
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Dose Escalation and De-Escalation Schema (3 + 3 Design)
1
0
 ≤1   
>1
 >1 
Treat 3 
Subjects 
@ DL and 
assess 
DLTs
Expand 
to 6 
Subjects 
@ DL and 
assess 
DLTs
DL is unsafe
DL is safe
Is DL + 1 available
and not
previously declared unsafe?
Escalation
DL = DL + 1
Yes
No
DL = Starting 
Dose Level
Is DL + 1 available
and not
previously declared unsafe?
Yes
DL is RCD
No
Is DL - 1 
available?
No
RCD cannot be 
determined
Was DL - 1 
previously declared 
safe?
No
3 subjects already 
treated @ DL?
Yes
Yes
No
Yes
De-Escalation
DL = DL - 1
DL - 1 is RCD
DL = Dose Level (per DL Table)         DLT = (Subjects with) Dose Limiting Toxicities         RCD = Recommended Combination Dose (per DL Table)
 
Figure 2. Dose Escalation and De-Escalation Schema 
Per Figure 2, the RCD for Arm A and Arm B is defined as the highest dose level at which no more 
than 1 of 6 subjects (i.e., < 33%) experience DLTs.  The RCD cannot be determined if none of the 
predefined dose level cohorts fulfill that criterion.  In such case, the arm will be discontinued 
without an expansion phase.   
 Dose Expansion Phase 
In each arm for which an RCD is declared in the dose evaluation phase, the RCD dose level 
cohort will be expanded to 20 subjects (i.e., 14 subjects will be added to the 6 treated at the 
RCD in the dose evaluation phase for each arm (A and B).   
3.1.8 Dosing Adjustments, Delays, and Discontinuations 
Individual subject dosing adjustments due to toxicity will be allowed/may be required in 
accordance with the “Dose Adjustment and Management Guidelines” for toxicity related to 
durvalumab / tremelimumab and BI 1361849, outlined in Section 8.3 and Section 8.4, 
respectively.   
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
3.1.9 DLT and MTD/RCD for the Combination Therapy 
MTDs will not be determined in this study.  Instead, RCDs will be determined in the context of 
the predefined dose levels used during the dose evaluation phase as per Section 3.1.7.1. 


 
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DLTs will be observed over a period of the first 2 cycles of the combination therapy, including 
the pre-dose assessment for Cycle 3, defined as the DLT Evaluation Period.  The decisions for 
dose evaluations, de-escalations and RCD, as described in Section 3.1.7.1 will primarily be based 
on the number of subjects with DLTs occurring during the DLT Evaluation Period.  DLTs occurring 
outside the DLT Evaluation Period will also be evaluated and may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of durvalumab, tremelimumab, or BI 1361849 components, and fulfill any of the 
following criteria: 
1. Any Grade ≥ 3 colitis, pneumonitis, neurological event or uveitis. 
2. Any Grade 2 pneumonitis, neurological event or uveitis, with the following exception: 
• 
Grade 2 pneumonitis, neurological event or uveitis that downgrade to Grade ≤ 1 
within 3 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade 3 irAEs that downgrade to Grade ≤ 2 within 3 days, or to Grade ≤ 1 or 
baseline within 14 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Liver transaminase elevation ≤ 8 times ULN that downgrades to Grade ≤ 2 (≤ 5 times 
ULN) within 7 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 
days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, (2) 
does not require medical intervention, and (3) improves to Grade 2 within 7 days. 
• 
Grade 3 and 4 lymphopenia. 
• 
Grade 3 thrombocytopenia that (1) is not associated with clinically significant 
bleeding, (2) does not require medical intervention, and (3) improves to Grade 2 
within 7 days. 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days. 
• 
Any pre-existing laboratory abnormality that deteriorates to Grade 3/4, but where 
the increment of deterioration is considered not clinically significant by both 
investigator and sponsor. 
• 
Grade 3 or 4 asymptomatic increases in amylase or lipase levels for which 
appropriate evaluation shows no clinical evidence of pancreatitis. 


 
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Immune-related AEs (irAEs) are defined as AEs of immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a DLT. 
While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or listed as exempt 
above may also be defined as DLT after consultation with the sponsor and Investigators, based 
on the emerging safety profiles of durvalumab, tremelimumab, and BI 1361849.  Likewise, 
subjects who become not evaluable for DLT, because they discontinued or interrupted 
treatment due to toxicities other than DLTs, may be counted as DLT subjects, if the toxicities 
cannot be managed in accordance with the dosing modifications described in Section 3.1.8. 
Subjects who experience a DLT will be discontinued from study treatment and will enter the On 
Study and Post Study Follow-up (see Section 3.1.16).  However, if it is in the best interest of the 
subject, the Investigator, subject and Sponsor may agree to continue treatment with 
BI 1361849. 
3.1.10 Subject Withdrawal from Treatment or from Study 
A subject will be withdrawn from study treatment for any of the following reasons: 
1. Withdrawal of consent for further treatment 
2. Pregnancy or intent to become pregnant 
3. DLT at any time (see Section 3.1.9) 
4. Progressive disease requiring alternative systemic treatment 
5. Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal 
6. Development of intercurrent, non-cancer-related illnesses or complications that prevent 
either continuation of therapy or regular follow-up 
7. Best medical interest of the subject (at the discretion of the Investigator) 
 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study.  If applicable, subjects who are withdrawn from study treatment should undergo 
the planned On Study Follow-up procedures (see Study Flowchart, Section 3.2), followed by the 
Post Study follow-up period (see Section 3.1.16). 
 
A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator  
2. Initiation of alternative anticancer therapy (marketed or investigational) 
3. Withdrawal of consent for all follow-up 
4. Lost to follow-up 
5. Death 
Section 7.2.6 provides additional details regarding documentation for early subject withdrawal 
from study treatment and early withdrawal from study.  
See also Sections 8.3 and 8.4 for subject withdrawal from treatment due to necessary dosing 
interruptions or discontinuations. 


 
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 Treatment beyond Progression 
Subjects meeting criteria for progression by irRECIST (Section 8.5) will be allowed to continue on 
therapy until confirmation of progression by irRECIST if the subject agrees and signs an 
appropriate informed consent form regarding continuation of treatment and as long as the 
following criteria are met at the discretion of the Investigator: 
a. Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
b. No significant decline in ECOG performance status; 
c. Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
See Section 8.5 for additional information regarding RECIST 1.1 and irRECIST. 
3.1.11 Subject Evaluability and Subject Replacements 
In the dose evaluation phase, subjects are fully evaluable for DLT if they fulfill the criteria for the 
Per-Protocol Population for DLT Assessment (as defined in Section 4.1.2). 
Subjects who are not fully evaluable for DLT per Section 4.1.2 will be replaced. 
Subjects are fully evaluable for secondary endpoints of PFS rate and ORR, if they fulfill the 
criteria for the Per-Protocol Population for Clinical Efficacy (as defined in Section 4.2.2). 
Subjects who are not fully evaluable for PFS rate and ORR may be replaced. 
3.1.12 Optional Study Treatment Extension 
Treatment extension beyond 12 cycles is not planned at this time. 
3.1.13 Interim Analysis 
Interim Safety Reviews will be performed to assess DLTs in the dose evaluation cohorts for 
determination of RCD (see Section 3.1.7.1). Interim analyses may be performed to analyze the 8- 
and 24-week endpoints. 
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal, and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and co-investigators as needed), the Sponsor’s Medical 
Monitor/Clinical Advisor, and drug safety personnel from Medimmune/AstraZeneca and 
CureVac/Boehringer Ingelheim, providers of the study drugs.  Additional investigators and staff, 
or additional Sponsor personnel and consultants, shall participate in reviews, if indicated.  The 
safety monitoring panel will communicate by phone and/or email on a regular basis, and in 
particular, to review the safety of individual cohorts for the purpose of dose evaluation or de-
escalation as per Section 3.1.7.1. 
An Independent Data Monitoring Board will not be utilized for this open-label study. 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 
1. A death that is unexpected and at least probably related to any of the study drugs. 


 
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2. Severe anaphylactic reaction (i.e., with respiratory and cardiovascular failure) to any of 
the study drugs. 
3. Any events that, in the judgment of the Medical Monitor, are deemed serious enough to 
warrant immediate review by the internal data safety monitoring panel.  This may 
include any symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, 
colitis, dermatitis, or hepatitis or any symptomatic treatment-related Grade ≥ 3 
neurological toxicity or uveitis.  
4. Any other safety finding assessed as related to study drug that, in the opinion of the 
internal data safety monitoring panel, contraindicates further dosing of study subjects. 
5. Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest 
that the study treatment has no clinical benefit for the subjects. 
Study stopping rules may be applied to individual study arms, if the internal data safety 
monitoring panel concludes that the identified risk to one study arm does not carry over to 
another. 
General criteria for premature trial termination are outlined in Section 7.2.7. 
3.1.15 Duration of Study 
Length of Study per subject: 
Up to 15 months; 12 months for treatment and 3 months 
for On Study Follow-up.  
Enrollment Period: 
24 months 
Length of Study: 
39 months 
Length of Survival Post Study 
Follow-up 
5 years from initiation of treatment 
NOTE: Per Amendment 10.0, all post study follow-up will 
be discontinued as of 31 October 2021 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue treatment, or 
prematurely withdraw from the study as per Section 3.1.10, will be followed as per institutional 
guidelines in accordance with the usual standard of care principles.   
Subjects who complete study treatment or discontinue treatment prematurely will enter an On 
Study Follow up, which will be conducted for 90 days (over 3 visits) after the last administration 
of study drug according to the flowchart in Section 3.2.  Refer to Section 7.1.5 for information on 
recording AEs during the On Study Follow-up.  
If the determination is made to remove a subject from treatment at a visit that coincides with 
the first visit of the On Study Follow-up Period, any assessments required in the first On Study 
Follow-up visit that are not covered as part of the last on-treatment visit (usually correlative 
labs) should be done as soon as possible.  If these assessments cannot be done on the same day, 
the subject should be brought back in at the earliest opportunity.  Any assessments or 
correlative samples required by both the last on-treatment visit and the first On Study Follow-up 
visit should not be repeated. 
In addition to the On Study Follow-up, there will be a Post Study Follow-up, during which clinical 
outcomes data (dates of progression/relapse and survival) will be collected at least every 6 
months for 5 years from initiation of treatment.  If after 5 years there are a significant number 
of subjects who are still alive, there will be an option to extend this period.  


 
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The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 90 days since the last administration of study drug. 
NOTE: Per Amendment 10.0, all post study follow-up will be discontinued as of 31 October 2021. 
For subjects who do not continue Post Study Follow-up at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 
Investigator, will obtain this data through review of outside records or communication with the 
subject or his/her physician. 
 End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End 
of Study visit must be conducted at the time of withdrawal. For subjects not yet in On Study 
Follow-up, this End of Study visit will be the first planned visit of the On Study Follow-up. For 
subjects already in On Study Follow-up, this End of Study visit will be the next planned visit of 
the On Study Follow-up. However, any procedures/assessments that were done within 7 days of 
the End of Study visit need not be repeated. All subjects of childbearing potential who withdraw 
from study must have a serum pregnancy test done at the End of Study visit, unless it was done 
within 7 days prior to the End of Study Visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described 
above, unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up). 
 


 
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3.2 Study Flowchart 
 
Cycle 5 Cycle 6
Cycle Day 
1
8 (±2) 15 (±2) 1 (±2)
8 (±2) 15 (±2) 1 (±2) 15 (±2) 1 (±2)
8 (±2)
1 (±3)
1 (±3)
Cumulative Study  Day
Up to 1 month 
before Tx start
1
8
15
29
36
43
57
71
85
92
113
141
Treatment
Durvalumab (Arms A and B)
X
X
X
X
X
X
Tremelimumab (Arm B)
X
X
X
X
BI 1361849 - 6 components (Arms A and B)
X
X
X
X
X
X
X
X
X
X
Disease Staging (date/stage at 1st diagnosis and at 
study entry)
X
Disease Assessment  by  irRECIST/RECISTa
X
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)h
X
Demographics (incl. DoB; sex; height; race; ethnicity) 
X
Medical history
X
Physical Exam (incl. weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
Vital Signs (T, HR, BP, RR)e
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication(s)/ Procedure(s) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)f 
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca,  Mg, 
protein, albumin, Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa,c
X
X
X
X
X
X
X
Coagulation parametersa,d
X
Serum pregnancy test (Urine test  only on Day 1)a
Up to 1 week  
before Tx start 
X
X
X
Specimens for Other Peripheral Blood AssaysL
Blood for exosomal profiling a
X
X
Blood for PaxGene RNA and DNAa,k
Note: Discontinued per Amendment 9.1
X
XJ
XJ
Blood (PBMC and plasma) for flow cytometry and 
biological assaysa,i,k
Note: Discontinued per Amendment 9.1
X
XJ
XJ
Blood for humoral responses and other biomarkersa,k
Note: Discontinued per Amendment 9.1
X
XJ
XJ
Biopsy or FFPE slides for tumor microenvironmentg
X
Overall Survival
Progression Free Survival
Specimens for Routine Laboratory Procedures
5
Study Week
1
11
X
(one week after 3rd or 5th 
BI 1361849 injection) 
Cycle 4
14J
Tumor and Disease Assessments
21
17
13
Treatment (each cycle = 4 weeks)
Long Term Follow-upL
Tumor BiopsyL
LUD2014-012-VAC 
Study Flowchart
Screening / 
Baseline
Cycle 2
Cycle 3
2
3
7
Cycle 1
6J
9


 
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Cycle 8 Cycle 9
Cycle 
11
Cycle Day 
1 (±3) 15 (±3) 22(±2)
1 (±3)
1 (±3)
1 (±3) 15 (±3) 1 (±3)
1 (±3)
8 (±2)
Cumulative Study  Day
169
183
190
197
225
253
267
281
309
316
Treatment
Durvalumab (Arms A and B)
X
X
X
X
X
X
Tremelimumab (Arm B)
BI 1361849 - 6 components (Arms A and B)
X
X
X
X
Disease Staging (date/stage at 1st diagnosis and at 
study entry)
Disease Assessment  by  irRECIST/RECISTa
X
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)h
Demographics (incl. DoB; sex; height; race; ethnicity) 
Medical history
Physical Exam (incl. weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
Vital Signs (T, HR, BP, RR)e
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication(s)/ Procedure(s) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)f 
X
X
X
X
X
X
X
X
X
X
X
X
X
Specimens for Routine Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca,  Mg, 
protein, albumin, Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa,c
X
X
X
X
X
X
X
Coagulation parametersa,d
X
Serum pregnancy test (Urine test  only on Day 1)a
X
X
X
X
X
Specimens for Other Peripheral Blood AssaysL
Blood for exosomal profiling a
X
X
Blood for PaxGene RNA and DNAa,k
Note: Discontinued per Amendment 9.1
XJ
XJ
X
Blood (PBMC and plasma) for flow cytometry and 
biological assaysa,i,k
Note: Discontinued per Amendment 9.1
Blood for humoral responses and other biomarkersa,k
Note: Discontinued per Amendment 9.1
XJ
XJ
X
Biopsy or FFPE slides for tumor microenvironmentg
optional
post-
treatment 
Overall Survival
Progression Free Survival
LUD2014-012-VAC 
Study Flowchart (cont.)
X
X
Treatment (each cycle = 4 weeks)
Cycle 12
Long Term Follow-upL
Tumor BiopsyL
Every 6 months 
until 5 years post 
initiation of 
treatment
33
37
39
41
 Last Study 
Drug Dose + 
91
( ±7) days  
End of  Study
45
Cycle 7
28J
Tumor and Disease Assessments
46
Last Study 
Drug Dose 
+42  
(±4) days
Last Study 
Drug Dose 
+28
( ±4) days
29
27
Post Study  
Follow-upL
On Study Follow-upf,K
Cycle 10
Q8W starting 8 weeks after
 last disease assessment
25
Study Week


 
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3.3 Additional Instructions for Blood Draws for PBMC Collection  
NOTE: Per Amendment 9.1, this section will no longer be applicable. See Note in Section 4.3.1.2 regarding discontinuation of 
blood sample collection for immune monitoring. 
Blood for PBMC collection (for correlative testing) is drawn on Cycle 1/Day 1, Cycle 2/Day 8, and Cycle 4/Day 8. Please refer to 
the Laboratory Manual for details regarding the higher volume (a maximum of 130 mL for PBMCs only) of blood that is 
required for these blood draws. 
For subjects who weigh ≤ 55 kg at any of the above mentioned visits, please refer to the Laboratory Manual for specific details 
regarding the lower limits for the allowable volume of blood to be drawn. 
 
 
 
Flowchart Footnotes
a - pre-dose, when applicable. Note: Review of results for hematology, chemistry and pregnancy test (when applicable) is required prior to dosing.
b - Full physical examination at baseline; targeted physical examination at other time points
c - Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated.
d - Coagulation tests: prothrombin time, APTT and INR – only performed at Screening, first On Study Follow-up,  and as clinically indicated.
e - See Section 6.5 for assessment of vital signs on drug admin days. Note: when durvalumab vital assessments do not precede the BI 1361849 dose, 
      pre-dose vital assessments must be done for BI 1361849.
f - See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration
g - Biopsy Samples:
      1. A fresh core pre-treatment  biopsy (minimum 3 cores from lung tissue or 4 cores from another site) obtained within 60 days of study start will 
      be requested prior to study entry; archival sample may be used if a pre-treatment fresh biopsy is not feasible.  
     NOTE: Per Amendment 9.1, biopsies should not be taken from a target lesion unless that is the only suitable lesion, in which case it should be of 
      reasonable size (refer to Section 4.3.1.1).
      2. If a fresh core pre-treatment biopsy was obtained, an on-treatment biopsy will be collected 1 week after the 3rd or 5th BI 1361849 treatment, if feasible; 
       this on-treatment biopsy should only be collected if a pre-treatment fresh biopsy was obtained (so that paired biopsies may be examined).
      3. Optional post-treatment core biopsies (minimum 3 cores from lung or 4 cores from another site) will be obtained at the time of tumor progression 
      or at the completion of treatment from subjects who consent to this procedure, and if clinically feasible. See Section 4.3.1.1 for details
      4. If possible and as determined by Investigator, a minimum of 8 subjects in each arm will have fresh tissue sampling from which fine needle aspiration  
      (FNA) can be also obtained for immune profiling
h - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
i -  See Section 3.3 for instructions for blood draws for PBMC collection. Note: PBMC collection is discontinued per Amendment 9.1.
J - Sampling at 7(±2) days after preceding vaccine administration. If vaccine administration time points are delayed, the PBMC & biological specimen collection
     time points should also be delayed to maintain the 5-9 day time frame after preceding vaccination. If the vaccination is omitted, blood sampling  
     should occur after the next subsequent vaccine administration. 
     Sample for WBC (hematology) must be available for the day of the blood samples for immunomonitoring.
    Note: Sample collection for PaxGene, PBMC, and humoral response is discontinued per Amendment 9.1 (See Section 4.3.1.2)
    Visits 6, 14, and 28 are no longer required per Amendment 9.1.
k - If treatment is discontinued after <14 weeks of treatment, samples for PBMC, PaxGene and humoral response should be collected within 5-9 days after the 
     last preceding vaccination or as close as possible to this time frame if the 5-9 day window is not feasible. 
     Note: Sample collection for PaxGene, PBMC, and humoral response is discontinued per Amendment 9.1 (See Section 4.3.1.2)
L- Per Amendment 10, Post Study Follow-up will be discontinued as of 31 October 2021; and all correlative testing will be discontinued, with the possible 
   exception of PD-L1 expression and whole exome sequencing.


 
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4 Study Objectives and Endpoints 
Primary Objective 
[Endpoints] 
Dose Evaluation Phase: 
Safety and Tolerability [CTCAE 4.03, including DLTs and RCD] 
Expansion Phase: 
Safety and Tolerability [CTCAE 4.03] 
Secondary Objectives 
[Endpoints] 
Dose Evaluation and Expansion Phases (all subjects): 
Clinical Efficacy by irRECIST and RECIST 1.1 [PFS rate and ORR at 8 and 
24 weeks, best overall response, DCR, DoR, OS] 
Exploratory Objectives 
[Endpoints] 
Dose Evaluation and Expansion Phases (all subjects): 
Biologic Activity [Effects on Tumor Microenvironment, Immune 
Responses] 
DLT=Dose-limiting Toxicity; RCD=Recommended Combination Dose; ORR=Objective Response Rate; DCR=Disease 
Control Rate; DoR=Duration of Response; PFS=Progression-free Survival; OS=Overall Survival; CTCAE=National Cancer 
Institute Common Terminology Criteria for Adverse Events; RECIST = Response Evaluation Criteria in Solid Tumors; 
irRECIST=immune-related RECIST 
4.1 Safety and Tolerability 
Assessment of safety and tolerability will be performed by the internal data safety monitoring 
panel on an ongoing basis, based on data review and regular conference calls.   
4.1.1 Endpoints and Assessment Methods 
Clinical laboratory tests, vital signs and weight measurements, physical exams, ECG, ECOG 
performance status evaluation, imaging scans and any other medically indicated assessments, 
including subject interviews, will be performed (as detailed in Section 3.2) to detect new 
abnormalities and deteriorations of any pre-existing conditions.  The investigator will evaluate 
any laboratory abnormalities for clinical significance, and clinically significant abnormalities will 
be recorded as adverse events.  All treatment-emergent clinically significant abnormalities and 
deteriorations from time of signing the informed consent to the end of study visit will be 
recorded in the Case Report Forms as adverse events and graded according to the CTCAE 
Version 4.03.  See further adverse event documentation and reporting requirements in Section 
7.1. 
For the dose evaluation phase, DLTs and RCDs will be assessed as per Sections 3.1.9 and 3.1.7.1, 
respectively. 
4.1.2 Subject Evaluation and Statistics 
The Per-Protocol (PP) Population for DLT Assessment includes: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) 
• 
All subjects with no DLT who receive at least 75% of the scheduled doses of durvalumab 
and tremelimumab and at least 4 of the 5 BI 1361849 vaccinations as well as respective 
safety assessments without major protocol violations during the DLT Evaluation Period 
(as defined in Section 3.1.9)  
 
Refer to Section 3.1.11 for subject replacement. 


 
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The Safety Population is defined as all subjects who receive at least one dose of any of the study 
drugs. 
In the dose evaluation phase, for the primary endpoint of determining DLTs and the RCD, the 
analysis of safety and tolerability will be based on the PP Population for DLT Assessment. 
In both phases (evaluation and expansion), the overall analysis of safety and tolerability will be 
based on the Safety Population. 
Appropriate summaries of AEs, SAEs, laboratory data and vital signs data will be presented for 
the Safety Population overall and by cohort.  Adverse events will be coded using the MedDRA 
dictionary.  Incidences of treatment-emergent adverse events (TEAE, those events that started 
after dosing or worsened in severity after dosing) will be presented overall and by maximum 
severity and relationship to study drugs. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Frequencies and percentages will be presented for the 
shifts in these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to 
each post-treatment assessment time point. Additionally, for each continuous hematology and 
chemistry parameter, descriptive statistics will be presented for the changes from baseline to 
each post-treatment assessment time point. Descriptive statistics will be presented for the 
changes in vital signs from baseline to each post-treatment assessment time point.  
4.2 Clinical Efficacy 
4.2.1 Endpoints and Assessment Methods 
Clinical efficacy will be assessed by irRECIST and RECIST 1.1 (see Section 8.5), measuring 
progression free survival (PFS) rate and objective response rate (ORR) at 8 and 24 weeks based 
on disease assessments at the scheduled Weeks 9 and 25 visits, as well as best overall response, 
disease control rate (DCR), duration of response (DoR), and overall survival (OS). Tumor disease 
assessments will be made at a minimum of every 8 weeks on study. See the sections below for 
additional details. 
For the primary analysis, all efficacy endpoints will be assessed at the completion of the On 
Study Follow-up or completion of 12 cycles of therapy for the last subject. 
PFS and OS will be updated at yearly intervals during the Post Study Follow-up and can be 
provided as addendums to the final report.  
NOTE: Per Amendment 10.0, all post study follow-up will be discontinued as of 31 October 2021. 
 Objective Response Rate (ORR) 
ORR is defined as the percentage of subjects meeting criteria of Complete Response (CR) or 
Partial Response (PR) over a period of at least 4 weeks.  Subjects who drop out prior to meeting 
the responder criteria for ORR will be considered as non-responders. 


 
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 Disease Control Rate (DCR) 
DCR is defined as the percentage of subjects meeting criteria of Stable Disease (SD), PR, or CR 
over a period of at least 4 weeks. Subjects who drop out prior to meeting the responder criteria 
for DCR will be considered as non-responders. 
 Duration of Response (DoR) 
DoR is defined as the interval between the date of earliest determination of CR or PR to the date 
of earliest determination of PD, or to the date of death, if PD does not occur. 
 Progression-free Survival (PFS) 
PFS is defined as the interval between the date of first dose to the date of earliest determination 
of Progressive Disease (PD), or to the date of death, if PD does not occur.  Subjects without 
documentation of progression at the time of the analysis will be censored at the date of last 
response assessment. Subjects with no tumor response assessment will be censored at the start 
date of the treatment. Subjects who discontinued treatment or withdrew from the study for 
reasons other than documented PD or death will be censored at the date of last response 
assessment prior to discontinuation or withdrawal. 
 Overall Survival (OS) 
OS is defined as the interval between the date of first dose until the date of death or the date of 
last follow-up.  Subjects who are still alive will be censored on the date of last follow-up.  Every 
effort will be made to follow subjects for OS after they discontinue the study. 
4.2.2 Subject Evaluation and Statistics 
The Intent-To-Treat (ITT) Population is defined as all subjects who receive at least one dose of 
any of the study drugs.  
The Per-Protocol (PP) Population for Clinical Efficacy is defined as all subjects who received at 
least 75% of the scheduled doses of durvalumab and tremelimumab and at least 4 of the 5 
BI 1361849 vaccinations over the first 2 cycles, as well as, respective disease assessments, 
without major protocol violations.   
All efficacy analyses will be based on both ITT and PP populations for each cohort. 
Tumor Response will be summarized and analyzed descriptively for each arm and analysis 
population.  A 95% Confidence Interval based on binomial distribution will be constructed for 
the estimated PFS rate and ORR at 8 and 24 weeks and DCR. 
The number and percentage of subjects who died or had a confirmed progression, who survived 
without a confirmed progression, and who were lost to follow up (unknown survival and/or 
progression status) will be summarized.   
PFS rate at 8 and 24 weeks and the corresponding 95% CIs will be calculated based on Kaplan-
Meier product limit estimates and will be displayed along with the corresponding number of 
subjects at risk. 


 
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PFS and OS will be summarized using the 25th percentile, Median, and 75th percentile as well as 
the minimum and maximum survival time, calculated by Kaplan-Meier method, and will be 
displayed graphically. 
4.3 Biological Activity 
4.3.1 Endpoints and Assessment Methods 
Samples for exploratory assessment of correlative immunologic response will be collected 
according to the Study Flowchart in Section 3.2.  Correlative data will be obtained to assess the 
effects of the regimen on the tumor microenvironment and biological activity in blood.  The 
exploratory assessments will help to determine whether protein expression, mutational burden, 
gene expression, soluble PD-L1 or immune cell profiling can be associated with clinical benefit or 
resistance to combination therapy.  
For BI 1361849, cellular and humoral immune response to vaccine target antigens and 
additional antigens can be assessed to detect signs of antigen spreading (e.g. based on a panel 
of selected additional NSCLC antigens). NOTE: Per Amendment 9.1, some assessments will no 
longer be applicable. See Note in Section 4.3.1.2 regarding discontinuation of blood sample 
collection for immune monitoring. 
NOTE: Per Amendment 10.0, all correlative testing will be discontinued, with the possible 
exception of PD-L1 expression and whole exome sequencing. 
 Tumor Microenvironment 
Samples: 
1. A fresh core pre-treatment biopsy (minimum 3 cores from lung tissue or 4 cores from 
another site) obtained within 60 days of study start will be requested prior to study entry; 
archival sample may be used if a pre-treatment fresh biopsy is not feasible.  
NOTE: Per Amendment 9.1, biopsies should not be taken from a target lesion unless that is 
the only suitable lesion, in which case it should be of reasonable size (refer to Section 5.1, 
#2).  
2. If a fresh core pre-treatment biopsy was obtained, an on-treatment biopsy will be collected 
1 week after the 3rd or 5th BI 1361849 treatment, if feasible. This on-treatment biopsy 
should only be collected if a pre-treatment fresh biopsy was obtained so that paired 
biopsies may be examined. 
3. Optional post-treatment core biopsies (minimum 3 cores from lung tissue or 4 cores from 
another site) will be obtained at the time of tumor progression or at the completion of 
treatment from subjects who consent to this procedure and if clinically feasible.   
4. If possible and as determined by the Investigator, a minimum of 8 subjects in each arm will 
have fresh tissue sampling from which fine needle aspiration (FNA) can be also obtained for 
immune profiling.  
A minimum of 25 slides (5 µm formalin-fixed, paraffin embedded (FFPE)) will be requested from 
the biopsy specimens to evaluate PD-L1 expression as assessed by immunohistochemistry, 
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of these evaluations with clinical response as well as changes in profiling associated with 
resistance.  Analyses may include the following: 
• 
Mutational burden, gene expression profiling, and immune profiling from before 
therapy 
• 
Immune markers of response and resistance. 
Remaining core biopsies will be formalin-fixed and paraffin-embedded as per institutional 
standards for further evaluation with immunohistochemistry (IHC) or tumor DNA/RNA 
extraction for microarrays sequencing or nanostring. 
4.3.1.1.1 Immunohistochemistry 
Quantitative immunofluorescence will be used to evaluate multiple immune biomarkers 
simultaneously in FFPE archival tissue or in biopsy samples, as available. 
PD-L1 has been examined in studies of PD-1/PD-L1 inhibitors with mixed results in terms of 
prevalence and impact on clinical benefit from anti-PD-1/PD-L1 therapy, although this has been 
attributed to variability in different assays and in different definitions of positivity.  It is unknown 
how the introduction of the vaccine may alter PD-L1 expression and the immune 
microenvironment and whether that may influence outcomes to combination therapy.   
In this study, a pre-treatment biopsy will allow the evaluation of PD-L1 and other immune 
biomarkers to determine correlation with response to combination therapy.  In addition to PD-
L1 immunohistochemistry, CD3, CD4 and CD8 immunostaining will be performed to evaluate the 
degree of immune infiltrate in tumor specimens, as available.  Finally, other markers of immune 
suppression (FoxP3 to stain T regulatory cells, TIM-3, Lag-3 and others) will be evaluated, as 
feasible. 
4.3.1.1.2 DNA sequencing 
Whole-exome sequencing (WES) targeted next-gen sequencing will be performed, as feasible. 
The targeted sequencing (Oncopanel) is a cancer genomic assay, which is used to detect somatic 
mutations, copy number variations, and structural variants in tumor DNA that surveys exonic 
DNA sequences of 275 cancer genes and 91 introns across 30 genes for rearrangement 
detection. 
4.3.1.1.3 Gene expression 
Inflammatory or immune-related gene expression signatures may serve as predictors of clinical 
benefit and will be evaluated in biopsy samples, as available. 
4.3.1.1.4 Immune profiling 
Immune profiling in tumor biopsies will be done to evaluate correlates of response and 
resistance.  FNA samples will also be used, if available. 
4.3.1.1.5 Cytokines & Chemokines  
Cytokine and chemokine environment will be determined on protein level in biopsy samples, as 
available.  


 
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 Biological Activity in Blood Samples 
Blood samples will be collected according to Section 3.2 and may be used for the evaluation of 
PBMC profile by flow cytometry, cytokine profile, soluble PD-L1 analysis, and exosomal profiling. 
NOTE: Per Amendment 9.1, the following sample collections will be discontinued: 
1. Blood for PaxGene RNA and DNA 
2. Blood (PBMC and plasma) for flow cytometry and biological assays 
3. Blood for humoral responses and other biomarkers 
Blood collection for exosomal profiling will continue as indicated in Section 3.2. Refer to Section 
8.1, Amendment 9.1, for rationale.  
4.3.1.2.1 Immune Monitoring for Responses to BI 1361849 Vaccine 
NOTE: Per Amendment 9.1, these assessments will no longer be applicable. See Note in Section 
4.3.1.2 regarding discontinuation of blood sample collection for immune monitoring. 
There is a great potential for mutual benefits by combining passive and active cancer vaccine 
strategies to improve clinical efficiency.   
Assays for antigen-specific immune responses encompass, for example, intracellular cytokine 
staining (ICS) and ELISpot for detection of antigen-specific T-cells by their functional capacity to 
produce various effector cytokines in response to the vaccine (NY-ESO-1, MageC1, MageC2, 5T4, 
Survivin, Muc-1) and/or non-vaccine tumor antigens (e.g. MAGE-A3).  Humoral responses 
against vaccine antigens are routinely analyzed by immunoassay techniques such as ELISA and 
can easily be extended to non-vaccine antigens (antigen arrays).  If possible, the immune 
analyses will also include a detailed phenotypic characterization of, e.g., circulating T-cell 
subsets, activation and differentiation states of immune cells, and checkpoint marker 
expression.  Furthermore, B cells, NK cells, DCs, monocytes and the peripheral immune-
suppressive environment mediated by myeloid derived suppressor cells (MDSCs) and regulatory 
T-cells are evaluated.  Measurements of systemic lymphoid repertoire, e.g., T-cell receptor 
sequencing and immune-related transcriptional changes, cytokine and chemokine profiling are 
additional approaches of interest suitable to identify potential blood-derived biomarkers.   
Blood samples will be collected according to Section 3.2 for the assessment of humoral and 
cellular immune responses and additional biomarker screenings.  A sample for white blood cell 
(WBC) count must also be available for the day of the blood samples for immunomonitoring.  
Immunomonitoring blood sampling is scheduled at 7 ± 2 days after preceding vaccine 
administration.  In the event that, prior to a planned blood sampling time point, the immediately 
preceding vaccination has to be delayed or omitted, the blood sampling has to be delayed in the 
same fashion to ensure that the blood sample has been obtained within 7 ± 2 days (5-9 day time 
frame) after the immediately preceding vaccination.  In the event that the vaccination had to be 
omitted, blood sampling should occur after the next subsequent vaccine administration.  
See Section 8.4 for maximum allowable delays for vaccine administrations. 


 
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The primary aim of these specific immunomonitoring assessments is to trace the immunological 
effects of the vaccine in regard to antigen-specific immune responses, which may be more 
pronounced under conditions of simultaneous checkpoint inhibition. 
Specifically, the aims are:  
• 
to compare vaccine-induced antigen-specific responses, under conditions of simultaneous 
checkpoint inhibition, with immune-reactivity under checkpoint-blockade alone (cellular 
and humoral immune responses against vaccine encoded antigens may increase to some 
extent in context of a general, non-specific immune activation by checkpoint inhibition).  
• 
to generate hypotheses with regards to combination therapy-related biomarker 
candidates based on comparative immune analysis within a comprehensive data set. 
4.3.2 Subject Evaluation and Statistics 
NOTE: Per Amendment 9.1, some assessments will no longer be applicable. See Note in Section 
4.3.1.2 regarding discontinuation of blood sample collection for immune monitoring. 
NOTE: Per Amendment 10.0, all correlative testing will be discontinued, with the possible 
exception of PD-L1 expression and whole exome sequencing. 
For each arm of the study, only subjects who receive at least 1 dose of the respective drugs and 
who provide the baseline and at least 1 on-treatment sample (if applicable) will be evaluated.  
As these analyses represent exploratory evaluations of potential biomarkers of response or 
resistance to therapy, descriptive statistics will be used to describe findings and potential 
relationships to outcomes to therapy.  Criteria for assay positivity (changes compared to 
baseline) of individual assays will be described in the statistical analysis plan (SAP). 
The exploratory pharmacodynamic assessment of the immunologic changes in the tumor 
microenvironment will include the correlation between clinical activity and the expression level 
of PD-L1 and tumor-infiltrating lymphocyte (TILs) changes in biopsy samples, as available. The 
association between response and PD-L1 expression within each arm will be assessed 
descriptively. Confidence intervals for the overall odds ratio and the odds ratio within each arm 
will be presented. The association between response and TILs changes (increase, decrease, or 
no change) will be evaluated similarly.  
Subjects are considered fully evaluable for immune response if the following criteria are met: 
• 
Subjects have received at least 4 treatments with BI 1361849 including all vaccine antigens 
according to protocol 
• 
Samples from baseline and both post-baseline sample 7 days (±2 days) after treatment are 
available 
• 
Subjects have not received any prohibited concomitant treatments (see Section 5.3.1) 
within 21 days before on-treatment blood sampling. Immunosuppressive medication that 
has been taken by subjects 2 to 3 weeks prior to randomization will be documented so 
that any potential influence on baseline values may be evaluated. 
• 
Sufficient amount and quality of blood sample and isolated PBMCs is available to fully 
perform and analyze, in accordance with respective assay SOPs, at least the ICS assay, as a 
measure for antigen-specific cellular immune response   


 
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• 
The analysis of antigen-specific cell-mediated immune response by ICS is required to 
include all BI 1361849 antigens including baseline values to be fully evaluable. 
All other exploratory results will be summarized descriptively. 


 
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5 Subject Eligibility 
NOTE: Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1. 
Histologic confirmation of metastatic NSCLC.   
For subjects with known EGFR or ALK/ROS-1 mutations, prior therapy must have 
included an EGFR tyrosine kinase inhibitor or ALK/ROS-1 inhibitor, respectively.  
Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy. Subjects who received 
prior anti-PD-1/PD-L1 therapy must have progressed during or after treatment, but not 
prior to Week 12 of treatment. 
2. 
Measurable disease according to RECIST 1.1, defined as ≥ 1 lesion that can be 
accurately measured in at least 1 dimension (longest diameter to be recorded for non-
lymph node lesions, shortest diameter to be recorded for lymph node lesions).  Each 
lesion must be ≥ 10 mm when measured by CT, MRI, or caliper measurement by clinical 
examination or ≥ 20 mm when measured by chest x-ray. 
NOTE: Per Amendment 9.1, biopsies should not be taken from a target lesion unless 
that is the only suitable lesion, in which case it should be of reasonable size (refer to 
Section 4.3.1.1). 
3. 
Willing to undergo a pre-treatment biopsy, or if not feasible, availability of archival 
(diagnostic) specimens. 
4. 
Subjects with treated brain metastases must have been treated with surgery and/or 
radiation therapy ≥ 21 days pre-study and must be clinically stable with no requirement 
for steroids. 
5. 
Laboratory parameters for vital functions should be in the normal range.  Laboratory 
abnormalities that are not clinically significant are generally permitted, except for the 
following laboratory parameters, which must be within the ranges specified, regardless 
of clinical significance: 
Hemoglobin 
≥ 9 g/dL 
Neutrophil count 
≥ 1.5 x 109/L 
Lymphocyte count 
≥ 400 cells/µL. (See Section 3.3 for instructions for 
blood draws for PBMC collection.) 
Platelet count 
≥ 100,000/mm3 
Serum creatinine, or 
Creatinine Clearance 
≤ 1.5x Institutional Upper Limit of Normal (ULN), or 
> 40 mL/min (by Cockcroft-Gault formula) 
Serum bilirubin 
≤ 1.5 × ULN (except for subjects with Gilbert’s 
syndrome who will be allowed after consultation 
with their physician)   
AST/ALT 
≤ 2.5 x ULN 
Alkaline phosphatase 
≤ 2.5 x ULN 
6. 
ECOG Performance Status ≤ 2. 


 
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7. 
Age ≥ 18 years. 
8. 
Able and willing to provide valid written informed consent. 
9. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up. 
10. 
Body weight > 30 kg. 
5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Treatment with an investigational agent within 4 weeks of starting treatment, and any 
prior drug-related toxicity (except alopecia) should have recovered to Grade 1 or less.  
2. 
Prior treatment with anti-CTLA-4 therapy. 
3. 
Active, suspected or prior documented autoimmune disease or inflammatory disorders 
(including but not restricted to inflammatory bowel disease [e.g., colitis or Crohn's 
disease], celiac disease, diverticulitis [with the exception of diverticulosis], Sarcoidosis 
syndrome, Wegner’s granulomatosis with polyangiitis, Hashimoto’s thyroiditis, 
rheumatoid arthritis, systemic lupus, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, scleroderma and its variants, multiple sclerosis, myasthenia gravis, 
etc. ).  Vitiligo, alopecia, residual hypothyroidism (e.g., following Hashimoto syndrome) 
due to autoimmune condition only requiring hormone replacement, psoriasis or any 
chronic skin condition not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger are permitted. Subjects without active 
disease in the last 5 years may be included but only after consultation with the study 
physician. Subjects with celiac disease controlled by diet alone may also be included. 
4. 
Subjects with clinically significant cardiovascular disease, including: 
a. New York Heart Association (NYHA) Class II or higher congestive heart failure. 
b. Myocardial infarction, unstable angina, cerebrovascular accident or transient 
ischemic attack within 6 months of Day 1. 
c. Clinically significant supraventricular or ventricular arrhythmia. 
d. QTcF ≥ 450 ms (male) or QTcF ≥ 470 ms (female). 
e. Clinically uncontrolled hypertension. 
5. 
History of pneumonitis or interstitial lung disease, or any unresolved immune-related 
adverse events following prior therapy. 
6. 
Major surgery within 4 weeks of starting treatment (or scheduled for surgery during the 
projected course of the study). 
7. 
Women of child bearing potential who are pregnant as evidenced by positive serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) or nursing.  
8. 
Female subjects of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from the time of screening and must agree to continue using such precautions 
for 90 days after the last dose of durvalumab or for 6 months after the last dose of 
tremelimumab (whichever is longer).  Non-sterilized male partners of a female subject 


 
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must use male condoms plus spermicide throughout this period. Cessation of birth 
control after this point should be discussed with a responsible physician. Not engaging 
in sexual activity for the total duration of the drug treatment and the drug washout 
period is an acceptable practice; however, periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of contraception. 
Female subjects should refrain from breastfeeding throughout the period described 
above. 
Females of childbearing potential are defined as those who are not surgically sterile 
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. 
Females will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause.  The following age-specific requirements 
apply:  
• 
Females <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).  
• 
Females ≥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.  
 
Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condoms plus spermicide from screening through 
90 days after last dose of durvalumab or through 6 months after the last dose of 
tremelimumab (whichever is longer).  Female partners of childbearing potential of a 
male subject must use a highly effective method of contraception (see table below) 
throughout this period. Cessation of birth control after this point should be discussed 
with a responsible physician.  Not engaging in sexual activity for the total duration of 
the trial and the drug washout period is an acceptable practice; however, periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. 
Male subjects should refrain from sperm donation throughout the period described 
above. 
Highly effective methods of contraception are described in the table below. A highly 
effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Note that some 
contraception methods are 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 


 
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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). 
 
Acceptable highly effective methods of contraception are described in the following 
table: 
Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)b 
• “Implants”: Etonogestrel-releasing 
implants: e.g., Implanon® or Norplan®  
• “Intravaginal Devices”: 
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: e.g., 
Cerazette® 
a - Highly effective (i.e. failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill. 
9. 
Subjects who are immunosuppressed, including those with known 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 and/ or HBV 
DNA), hepatitis C (defined as presence of HCV RNA), or human immunodeficiency virus 
(positive HIV 1/2 antibodies) and/or known HIV carrier.  Subjects with a past or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and 
absence of HBsAg) are eligible.  Subjects positive for hepatitis C (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA. 
11. 
History of severe allergic reactions to any unknown allergens or components of the 
study drugs (see specific exclusions for BI 1361849 below). 
12. 
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, bleeding disorders, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or 
serious chronic gastrointestinal conditions associated with diarrhea.  
13. 
Mental impairment or social situations that may compromise compliance with the 
requirements of the study or compromise the ability of the subject to give written 
informed consent. 
14. 
Lack of availability for immunological and clinical follow-up assessment. 
15. 
• 
Allergy to any components of BI 1361849 protamine sulfate (e.g. allergy to 
protamine-containing insulins), or fish allergy, or prior vasectomy (as it may 


 
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increase the risk of protamine allergy), or known Type I allergy to beta-lactam 
antibiotics. 
• 
Skin disease (e.g., psoriasis) that may prevent intradermal administration of the 
vaccine into the target areas. 
• 
Prior cancer vaccine treatment or allogeneic bone marrow transplantation. 
• 
Any previous vaccination or immunotherapy (including any treatments that have 
immunostimulatory properties such as mistletoe extract) within 2 weeks prior to 
Day 1 
• 
History of splenectomy. 
• 
Requirement for chronic immunosuppressive treatment including daily systemic 
steroid doses of ≥ 10 mg prednisone equivalent per day. 
• 
Any severe systemic infection which continued until 2 weeks prior to Day 1. 
16. 
Any condition that, in the clinical judgment of the treating physician, is likely to 
interfere with the interpretability of the data or prevent the subject from complying 
with any aspect of the protocol or that may put the subject at unacceptable risk. 
17. 
Subjects must not donate blood while on study and for at least 90 days following the 
last durvalumab treatment or for 6 months after the last dose of tremelimumab 
(whichever is longer). 
18. 
History of allogeneic organ transplant. 
19. 
History of leptomeningeal carcinomatosis. 
20. 
Active or prior malignancy except for history of other prior malignancy treated with 
curative intent which, in the opinion of the treating investigator and the Sponsor, has 
minimal risk of interfering with safety or efficacy endpoints of the study.  
 
 
 


 
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5.3 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with corticosteroids (greater than Prednisone 10 mg daily or 
equivalent) or other immunosuppressive treatments (e.g., methotrexate, chloroquine, 
azathioprine).  See Section 5.3.2 for exceptions.  [Wash-out period: 2 weeks prior to Day 
1.] 
2. 
Other cancer therapy (e.g., drug, non-palliative radiation, or immunotherapy). 
[Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1 (6 weeks 
for nitrosoureas)]. 
3. 
Live/attenuated vaccines 1 month prior to Day 1 and for at least 6 months after the last 
dose of treatment. 
4. 
Sunitinib within 3 months after the last dose of tremelimumab. 
5. 
Drugs with laxative properties and herbal or natural remedies for constipation should 
generally be avoided through 90 days post last dose of tremelimumab because of the 
potential for exacerbation of diarrhea, but, for example, opiate-induced constipation 
may be treated with laxatives at the Investigator’s discretion. 
6. 
• 
Systemic immunosuppressive drugs including systemic steroid doses of ≥ 10 mg 
prednisone equivalent per day are prohibited. In case immunosuppressive therapy, 
or treatment with steroids ≥ 10 mg prednisone equivalent per day >3 days, is 
clinically mandated due to an intercurrent illness, it should be agreed upon with the 
Sponsor whether continuation of BI 1361849 can be allowed, and the possible risks 
to continue the vaccine treatment during the intercurrent illness should be 
judiciously weighed against the potential benefit of continued treatment.  
• 
Any treatments that have immunostimulatory properties including mistletoe extract 
are prohibited and should be discontinued at least 2 weeks prior to Day 1.  
• 
No local anesthetics for the vaccination procedure are allowed. 
The wash-out period prior to Day 1 of the study for all non-permitted drugs should be at least 
1 week, unless stated otherwise above. 
 


 
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5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
Inhaled or oral steroids for treating mild to moderate asthma or allergies, or topical 
steroids for localized (< 5% of body surface area) dermatitis, not to exceed 10 mg/day 
prednisone or bioequivalent corticosteroid. 
2. 
Physiologic replacement of glucocorticoids as maintenance therapy for adrenal 
insufficiency.  Standard doses of hydrocortisone for maintenance therapy are up to 10–
20 mg/m2/day divided 2–4 times per day.  For a subject with a body surface area (BSA) 
of 1.73 m2, this translates to a total dose of up to 34.6 mg of hydrocortisone per day. 
The equivalent dose of dexamethasone is up to 1.2 mg per day.  Some subjects may 
additionally receive mineralocorticoid-replacement maintenance therapy with 
fludrocortisone.  The maintenance dose of fludrocortisone for this indication is 0.05–0.1 
mg/day. 
3. 
NSAIDs, acetylsalicylic acid, and specific COX-2 inhibitors. 
4. 
Antihistamines and other non-steroidal anti-allergy medication. 
5. 
Hormone or hormone-related anti-cancer therapy. 
6. 
At the discretion of the Investigator, any drug or non-drug therapy necessary to treat 
any condition arising during the study, including high-dose corticosteroids to treat 
immune-mediated adverse reactions.  Subjects should receive full supportive care, 
including transfusions of blood and blood products, and treatment with antibiotics, 
anti-emetics, anti-diarrheal, and analgesics, and other care as deemed appropriate, and 
in accordance with their institutional guidelines.  Use of anticoagulants such as warfarin 
is permitted; however, caution should be exercised and additional international 
normalized ratio (INR) monitoring is recommended. 
All prescription and nonprescription drugs and herbal supplements must be recorded in the 
concomitant medications section of the case report form, listing generic (preferably) or brand 
name, indication, dose, route, and dates of administration.  All non-drug therapies must be 
recorded in the respective sections of the case report form. 


 
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6 Study Drug Preparation and Administration 
All study drugs are supplied by the Sponsor (see Section 7.2.8). Commercially available 0.9% 
(w/v) saline or 5% (w/v) dextrose will be supplied by each site. BI 1361849 requires 
reconstitution with Ringer’s lactate solution (see Section 6.3.2).   
On the days when both tremelimumab and durvalumab are to be administered, the durvalumab 
infusion will start at least 60 minutes after the end of the tremelimumab infusion.  The BI 
1361849 injections will start at least 60 minutes after the end of the durvalumab infusion is 
completed when injections and infusions occur on the same day.   
See Section 6.5 for monitoring of subjects during tremelimumab, durvalumab and BI 1361849 
dose administrations. 
6.1 Durvalumab (MEDI 4736) 
6.1.1 Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented in the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container 
Description 
Type: 
Single use vial  
Material: 
clear glass 
Size: 
10 mL 
Formulation 
Liquid solution containing 500 mg durvalumab per vial.  
The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% 
(weight/volume [w/v]) polysorbate 80, at pH 6.0. 
Active Ingredient 
Content 
Mass/Weight: 
500 mg 
Volume: 
10mL 
Concentration: 
50 mg/mL 
Storage Conditions 
2°C to 8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, and storage conditions 
6.1.2 Durvalumab Investigational Product Inspection 
Each vial of durvalumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. See Section 7.2.8 for additional details. 
6.1.3 Durvalumab Preparation 
The dose of durvalumab for administration must be prepared by the IP manager or designated 
personnel using aseptic technique.  No incompatibilities between durvalumab and 
polyvinylchloride or polyolefin copolymers have been observed. 


 
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Dose Calculation: 
Subjects will receive a fixed dose of durvalumab:  
• 
Starting dose:1500 mg Q4W  
NOTE: the durvalumab dose of 1500 mg Q4W is for subjects > 30 kg.  If a subject’s body 
weight drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 
equivalent to 20 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg (e.g., a 30 
kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  
When the weight improves to >30 kg, the subject may return to fixed dosing of durvalumab 
1500 mg. 
• 
Dose de-escalation: 750 mg Q4W  
The volume of durvalumab (in mL) to be added to the IV bag is calculated as follows: 
Volume of 
Durvalumab 
(mL) 
= 
Dose level (mg) 
÷ 
Durvalumab 
Concentration 
(nominal 50 mg/mL) 
 
Dose Preparation: 
Durvalumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter.  The 
final durvalumab concentration after dilution in the bag must be 1 mg/mL to 15 mg/mL.  The 
calculated volume of durvalumab is added to the IV bag, and the bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag. 
Example: For a 1500 mg dose (for subjects > 30 kg in weight), 30 mL of durvalumab may be 
diluted in a 250 mL IV bag, and the bag is mixed by gentle inversion. 
Durvalumab does not contain preservatives; any unused portion must be discarded.  
6.1.4 Durvalumab Administration 
Following preparation of the dose, durvalumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational products. Fully functional 
resuscitation facilities should be available.  
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
Durvalumab must not be administered via IV push or bolus, but as an IV infusion. 
• 
Durvalumab solution should not be infused with other solutions or medications. 
• 
Durvalumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 (± 5) minutes (a 0.2- or 0.22-μm in-line filter is required).  An infusion 
of less than 55 minutes is considered a deviation. 


 
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• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time between needle puncture of the durvalumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 
8°C (36°F to 46°F). Standard infusion time is 60 ± 5 minutes (an infusion of less than 55 
minutes is considered a deviation). However, if there are interruptions during infusion, 
the total allowed infusion time should not exceed 8 hours.  In the event that either 
preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. 
• 
The date, start time, interruption, and completion time of durvalumab administration 
must be recorded in the source documents.   
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.5. 
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 


 
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6.2 Tremelimumab 
6.2.1 Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented in the QA Disposition 
of IMP Report. 
Container Description 
Type: 
Single use vial  
Material: 
Clear glass 
Size: 
20 mL 
Formulation 
Liquid solution containing 400 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 
0.27 mM disodium edetate dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 5.5. 
Active Ingredient Content 
Mass/Weight: 
400 mg 
Volume: 
20 mL 
Concentration: 
20 mg/mL 
Storage Conditions 
2°C to 8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, and storage conditions 
Tremelimumab is also available in a 25 mg/vial format; the concentration remains 20 mg/mL. 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented on the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: Single-use vial 
Material: Clear glass 
Size: 2 mL 
Formulation 
Liquid solution containing 25 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.27 
mM disodium edetate dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 5.5. 
Active Ingredient 
Content 
Mass/Weight: 
25 mg/vial 
Volume: 
1.25 mL/vial 
Concentration: 
20 mg/mL 
Storage Conditions 
+2°C to +8°C (36°F to 46°F). Do not freeze. 
Labeling 
Product name, lot number, and storage conditions 
 
6.2.2 Tremelimumab Investigational Product Inspection 
Each vial of tremelimumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. See Section 7.2.8 for additional details. 
6.2.3 Tremelimumab Preparation  
The dose of tremelimumab for administration must be prepared by the IP manager or 
designated personnel using aseptic technique. No incompatibilities between tremelimumab and 
polyvinylchloride or polyolefin have been observed. 


 
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Dose Calculation: 
Subjects will receive a fixed dose of tremelimumab: 75 mg Q4W (x4). When tremelimumab is 
given with durvalumab 1500 mg Q4W, if a subject’s body weight drops to ≤ 30 kg while on the 
study, the subject will receive weight-based dosing for both drugs. For durvalumab, the weight-
based dosing is described in Section 6.1.3; for tremelimumab, weight-based dosing equivalent to 
1 mg/kg tremelimumab will be given as long as the body weight remains ≤ 30 kg (e.g., a 30 kg 
subject would receive a 30 mg dose; a 25 kg subject would receive a 25 mg dose; etc.).  When 
the weight improves to >30 kg, the subject may return to fixed dosing of tremelimumab 75 mg 
and durvalumab 1500 mg.  
The volume of tremelimumab (in mL) to be added to the IV bag is calculated as follows: 
Tremelimumab 
Dose (mL) 
= 
dose level (mg) 
÷ 
Tremelimumab 
concentration  
(20 mg/mL) 
 
Dose Preparation: 
Tremelimumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter.  The 
final concentration of tremelimumab after dilution in the bag must be between 0.10 mg/mL and 
10 mg/mL. The calculated volume of tremelimumab is added to the IV bag, and the bag is mixed 
by gentle inversion to ensure homogeneity of the dose in the bag. 
Example: The volume of tremelimumab required for 75 mg dose is 3.75 mL and may be 
administered using a 250 ml bag.  
The corresponding volume of investigational product should be rounded according to 
institutional practice. For example, (for a 75 mg dose of tremelimumab), if the institutional 
practice is to round the volume to the nearest tenth mL, 3.75 mL would be rounded to 3.8 mL, 
which would be the volume of tremelimumab added to the bag; the bag is then mixed by gentle 
inversion. 
Tremelimumab does not contain preservatives; any unused portion must be discarded.  
6.2.4 Tremelimumab Administration 
Following preparation of the dose, tremelimumab will be administered according to the 
following guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
Tremelimumab must not be administered via IV push or bolus, but as an IV infusion. 
• 
Tremelimumab solution should not be infused with other solutions or medications. 


 
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• 
Tremelimumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line.   
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 (± 5) minutes (a 0.2- or 0.22-μm in-line filter is required).   
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time from needle puncture of the tremelimumab vial to the start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C 
(36°F to 46°F). Standard infusion time is 60 ± 5 minutes (an infusion of less than 55 
minutes is considered a deviation). However, if there are interruptions during infusion, 
the total allowed infusion time should not exceed 8 hours.  In the event that either 
preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. 
• 
The date, start time, interruption, and completion time of tremelimumab administration 
must be recorded in the source documents. 
• 
Subjects’ vital signs will be monitored before, during and after infusion as indicated in 
Section 6.5.  
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 
6.3 BI 1361849 
6.3.1 Study Drug Information 
The BI 1361849 drug product is a vaccine comprising six drug product components. The drug 
products are derived from drug substances which are antigen-encoding mRNAs (R1857, R1861, 
R1863, R1859, R1855, R2312). The drug substance components are formulated individually to 
produce the drug product components of BI 1361849 (F2408, F2409, F2410, F2624, F2625, 
F2626). These are subsequently lyophilized for the purpose of storage and prior to intradermal 
injection reconstituted in a specific Ringer’s Lactate injection solution (see note in Section 6.3.2). 
Throughout the process, individual components are kept separate. The various names and 
abbreviations used to refer to the BI 1361849 components are summarized in the table below. 
 


 
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Names and abbreviations of the six drug product components comprising BI 1361849 
Drug 
Product 
Component 
Drug 
Substance 
Component 
mRNA 
Sequence 
Length 
Name 
Official 
abbre- 
viation 
Common 
abbre- 
viation 
F2408 
R2312 
1885 bases 
Mucin 1, cell 
surface 
associated 
MUC1 
MUC1 
F2409 
R1859 
646 bases 
BIRC5 
baculoviral 
IAP repeat- 
containing 5 
BIRC5 
survivin 
F2410 
R1857 
760 bases 
Cancer/testis 
antigen 1B 
CTAG1B 
NY-ESO-1 
F2624 
R1855 
1480 bases 
Trophoblast 
glycoprotein 
TPBG 
5T4 
F2625 
R1861 
1339 bases 
Melanoma antigen 
family C, 2 
MAGEC2 
MAGE-C2 
F2626 
R1863 
1813 bases 
Melanoma antigen 
family C, 1 
MAGEC1 
MAGE-C1 
 
6.3.2 Preparation of Components of BI 1361849 
BI 1361849 comprises 6 drug product components. Each box of BI 1361849 contains one vial of 
each of the components, which are formulated as a sterile lyophilizate in a 2 mL glass vial with 
rubber stopper closure. Each vial will be reconstituted with 600 µL (0.6 mL) of Ringer’s Lactate 
solution to provide a solution containing the drug substance at a concentration of 0.8 g/L 
(equivalent to 0.48 mg per vial and 0.16 mg (80 μg) per injection of 100 μL).  
NOTE: The Ringer’s Lactate solution (from Fresenius Kabi) used for reconstitution will be 
provided to the sites; the solution contains the following ingredients in the respective 
concentrations: Sodium Chloride 103 mM, Potassium Chloride 5.5 mM, Calcium Chloride 
dehydrate 1.8 mM, Sodium lactate 28 mM.  Other Ringer’s Lactate solutions may contain Mg, 
which may seriously impair the vaccine, according to CureVac. 
Based on results of stability studies of drug product components F2408, F2409, F2410, F2624, 
F2625, and F2626, the product is stable at room temperature for the shelf life indicated on the 
product labeling. 


 
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The drug product should be administered as soon as possible after reconstitution. Based on in-
house data and for reasons of sterility it is recommended to use reconstituted product within 4 
hours. 
NOTE (per Amendment 7):  
The first lot for this study (Lot E142087-008L002) expired at the end of May 2019. During 
testing of the replacement lots, one of the components (F2409) precipitated at 3 hours after 
reconstitution in Ringer Lactate Solution (the precipitate was identified as protamine and 
RNA). Therefore, F2409 must be used within 2 hours of reconstitution. It is recommended 
that all of the components should be administered within the 2-hour timeframe, if possible. 
If this is not feasible, the 4-hour in use period is still applicable to the other 5 components. 
6.3.3 BI 1361849 Administration 
The Pharmajet Tropis® device will be used for the administration of the BI 1361849 components. 
Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per component, the 
recommended dose per each of the 6 antigen components will be 160 μg (2 x 80 μg), for a total 
of 960 μg (12 administrations). Directions for use of the Pharmajet Tropis® device will be 
provided separately. 
Each of the 6 components of BI 1361849 will be administered on the same day as 2 intradermal 
injections of 100 μL each, for a total of 12 administrations distributed across 4 different lymph 
node targeting areas (i.e., the inner parts of the right and left upper arm and the right and left 
thigh).  The 2 administrations of each of the 6 components are applied into the thigh and the 
upper arm, respectively, of the same side of the body, alternating body sides for the first 5 
vaccinations.  Thereafter the components will be injected at the same sites for the rest of the 
trial period.  See detailed application scheme below: 
Drug product component  
F2408 
A 
F2409 
B 
F2410 
C 
F2624  
D 
F2625 
E 
F2626 
F 
Day 1/Week 1 
and  
Day 1 / Week 3 
Upper 
arm 
left 
x 
x 
x 
 
 
 
right 
 
 
 
x 
x 
x 
Thigh 
left 
x 
x 
x 
 
 
 
right 
 
 
 
x 
x 
x 
Day 1 / Week 2 
and  
Day 1 / Week 5 
Upper 
arm 
left 
 
 
 
x 
x 
x 
right 
x 
x 
x 
 
 
 
Thigh 
left 
 
 
 
x 
x 
x 
right 
x 
x 
x 
 
 
 
all subsequent 
vaccinations 
Upper 
arm 
left 
x 
x 
x 
 
 
 
right 
 
 
 
x 
x 
x 
Thigh 
left 
x 
x 
x 
 
 
 
right 
 
 
 
x 
x 
x 
A single dose of BI 1361849 represents a total dose of 960 μg mRNA at each vaccination time 
point, as follows: 
• 
2 administrations of F2624 coding for 5T4; 
• 
2 administrations of F2410 coding for NY-ESO-1; 
• 
2 administrations of F2409 coding for survivin; 


 
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• 
2 administrations of F2626 coding for MAGE-C1; 
• 
2 administrations of F2625 coding for MAGE-C2; 
• 
2 administrations of F2408 coding for MUC1. 
There are no specific requirements concerning the day or time when the vaccine is to be 
administered. Injections should occur after any blood drawings on the day of the visits, and 
injections will start at least 60 minutes after the infusion of durvalumab is completed when 
injections and infusions occur on the same day. 
See Section 6.5.2 for monitoring of subjects post vaccinations. 
There are defined maximal time windows in case a vaccine cannot be given within the scheduled 
administrative time window (e.g. due to AEs; see Section 8.4).  If the vaccine cannot be given 
within this maximal time frame, it is to be omitted.   
6.4 Estimated Study Requirements 
Drug 
Required Quantity 
(vials) 
Durvalumab (500 mg / 10 ml vials) 
2400 
Tremelimumab (400 mg / 20 ml vials) 
128 
BI 1361849 (2 X 100 μL from 1 vial each of: 
F2408, F2409, F2410, F2624, F2625, and F2626); 
the 6 components will be provided in a box 
containing 1 vial of each component. 
Ringer’s lactate solution will also be provided 
(one bottle per subject per dosing day). 
1000 boxes 
containing 6 vials 
(1 vial for each of 
the 6 components) 
6.5 Monitoring of Tremelimumab, Durvalumab, and BI 1361849 Dose 
Administration 
6.5.1 Monitoring for Tremelimumab and Durvalumab Administration 
Subjects will be monitored before, during and after tremelimumab and durvalumab infusion 
with assessment of vital signs according to the table below: 
Vital Signs Assessment on Study Drug Administration Days 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
30 (± 5) Minutes 
Post Infusion  
60 (± 5) Minutes 
Post Infusion  
Tremelimumab 
X 
Every 30 (± 5) 
minutes 
X 
 
 
Durvalumab  
X 
Every 15 (± 5) 
minutes 
X 
X 
x 
Note: When durvalumab and tremelimumab are to be administered on the same day, 
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though vital signs assessment is not required during the entire 60 minute period post 
tremelimumab. 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions in that subject can be monitored according to the table below.  
A longer duration of observation after the end of infusion can be used if the Investigator deems 
it clinically necessary. 
Vital Signs Assessment on Study Drug Administration Days (after first 4 doses) 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes Post 
Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 
6.5.2 Monitoring for BI 1361849 Administration 
For the first and second vaccination visits, subjects will be monitored for 2 hours with 
assessment of vital signs at 30 (± 5), 60 (± 5) and 120 (± 5) minutes post completion of 
injections.  For all subsequent vaccinations, subjects will be monitored for 1 hour with 
assessment of vital signs at 30 (± 5) and 60 (± 5) minutes post completion of injections, provided 
no undue occurrences were observed during the initial vaccinations. Note: on dosing days when 
durvalumab vital assessments do not precede the BI 1361849 dose, pre-dose vital assessments 
must be done for BI 1361849.  
6.6 Drug Overdose Management 
There are no known antidotes available for durvalumab, tremelimumab, or BI 1361849.  Any 
overdoses with these drugs should be managed symptomatically.  An overdose is defined as a 
subject receiving any dose in excess of that specified in this protocol by > 10%.  All such 
overdoses must be reported, with or without associated AEs/SAEs, according to Section 7.1.2.2. 
 
 


 
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7 Administrative, Legal and Ethical Requirements 
7.1 
Documentation and Reporting of Adverse Events 
7.1.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the 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 (investigational) product, whether or not related to the medicinal 
(investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of LICR studies to include any events, intercurrent diseases and accidents observed 
while the patient/subject is on study, i.e., during the actual treatment period, as well as during 
drug-free, pre- and post-treatment periods, under placebo or in a reference group receiving 
drug or non-drug therapy or no treatment. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. 
Results in death, 
2. 
Is life-threateningA, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly / birth defect or 
6. 
Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient/subject is at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient/subject or may require intervention to 
prevent one of the outcomes listed in the definition above.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious”, which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to 
patient’s life or vital functions.  Seriousness (not severity) serves as a guide for defining 
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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (see Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
• 
Pregnancy 
• 
Overdose (as defined in Section 6.6) 
• 
Hepatic Function Abnormality (as defined in Section 7.1.8) 
• 
New Cancers 
• 
Deaths 
 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab, 
whichever is longer (see Section 5.2, #8). 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug 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 (see Section 7.1.6).  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 subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, 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 for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available. 
7.1.2.1.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab, 
whichever is longer (see Section 5.2, #8).   
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   


 
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Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the subject’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.  
 Overdose 
Any overdose (as defined in Section 6.6) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor. If the 
overdose results in an AE, the AE must also be recorded as an AE according to Section 7.1.5. 
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 according to Section 7.1.6. There is currently no specific treatment in the 
event of an overdose of the study drugs. The Investigator will use clinical judgment to treat any 
overdose. See Section 6.6 for additional details. 
 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8 in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
 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 subject’s inclusion in this study. 
 Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period (On Study Follow-up) after the administration of the last dose of study 
drug, must be reported as follows: 
• Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the 
eCRF. It should be reported as an SAE if it meets SAE reporting criteria per 
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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 eCRF. 
• The report should contain a comment regarding the co involvement of PD, if 
appropriate, and should assign main and contributory causes of death. 
• Deaths with an unknown cause should always be reported as an SAE. It should 
also be documented in the eCRF. 
• A post mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results should be forwarded to LICR 
within the usual timeframes. 
Deaths occurring after the protocol-defined safety follow-up period after the 
administration of the last dose of study drug should be documented only in the Post 
Study Follow-up eCRF form. 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. 
LICR and AstraZeneca retain the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will 
be determined by the Investigator on the basis of their clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship.  Information provided in the IB and/or in “Background” of this protocol may 
support these evaluations. 


 
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7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on 
the respective section of the CRF, regardless of severity or the assumption of a causal 
relationship.  The documentation includes: dates of onset and resolution, severity, seriousness, 
study drug intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4.  This documentation is required for 
all AEs that occur: 
a. from the date of signing the informed consent, and 
b. until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 90 days after the last dose of the last study treatment (regardless of initiation of 
another therapy). 
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE per Section 7.1.1, irrespective of suspected causation, must be 
reported by the Investigator to the Sponsor’s Drug Safety Contact (primarily) or, alternatively, 
to the Primary Sponsor Contact, within 24 hours of becoming aware of the event (see contact 
information below). SAEs should be reported via the Medidata RAVE data capture system 
(which utilizes “Safety Gateway”), using the respective Adverse Event and Safety Case 
Summary eCRFs.  This includes any deaths that occur after the off-study date, but within 30 
days of last study drug administration. In the event that the SAE cannot be reported via 
Medidata RAVE, the SAE should be reported using the “Initial Serious Adverse Event Report 
Form,” provided by the Sponsor. 
Note: If an SAE cannot be reported via Medidata RAVE or the “Initial Serious Adverse Event 
Report Form” within 24 hours of becoming aware of the event, the Sponsor’s Drug Safety 
Contact (primarily) or, alternatively, the Primary Sponsor Contact, must be contacted by 
phone or email within 24 hours of becoming aware of the event. In this case, the phone or 
email notification can then be followed up through Medidata RAVE or an “Initial Serious 
Adverse Event Report Form” within one working day of the event. 
If the “Initial Serious Adverse Event Report Form” is being used, the expedited reports should be 
directed by fax or e-mail to the Drug Safety Contact (primarily) or, alternatively, the Primary 
Sponsor Contact.  Studies utilizing Medidata RAVE (and the “Safety Gateway”), built into the 
eCRF, and respective SAE reporting procedures, do not require reporting by fax or email.  
Questions related to Medidata RAVE and “Safety Gateway” procedures should be directed to 
the Drug Safety Contact or Primary Sponsor Contact (see table below for contact information). 
In urgent cases, pre-notification via phone or informal e-mail should be considered. 


 
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Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@lcr.org 
Primary Sponsor Contact: 
Mary Macri 
Director 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1546 
Fax: 
+1 212 450 1535 
mmacri@lcr.org  
 
Serious adverse events must also be reported by the Principal Investigator to the respective 
Institutional Review Board after being assigned a serious adverse event tracking number by the 
Sponsor.  Institutional Review Boards may have specific rules on which Adverse Events need to 
be reported expeditiously, as well as, the time frames for such reporting. 
SAE Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory authorities and 
other investigators, as well as institutional and corporate partners, will be informed by the 
Sponsor as required by ICH guidelines, laws and regulations in the countries where the 
investigational agent is being administered.  In particular, SAEs that are unexpected and for 
which a causal relationship with the study drug cannot be ruled out, will be reported by the 
Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported within 
7 calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune and to Boehringer Ingelheim is 
described in separate respective agreements. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to the 
understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid recording of all AEs, including AESIs, allows ongoing surveillance of these events in order 
to characterize and understand them in association with the use of the investigational products.   
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-related adverse event (irAE) is 
defined as an adverse event that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate aetiology. 


 
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Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with durvalumab and tremelimumab and those considered AESIs for the 
purpose of this study are listed below. Further information on these AESIs (e.g. presenting 
symptoms) can be found in the current versions of the durvalumab (MEDI4736) and 
tremelimumab Investigator’s Brochures. Guidelines for the management of subjects 
experiencing toxicities for durvalumab and tremelimumab can be found in Section 8.3 and in the 
following Medimmune guideline: “Medimmune’s Dosing Modification and Toxicity 
Management Guidelines for Immune- mediated, Infusion Related, and Non Immune-mediated 
Reactions (MEDI4736 (durvalumab) Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab monotherapy).” 
• 
Diarrhea/Colitis and intestinal perforation 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs 
following dosing with study medications.  In rare cases, colon perforation may occur 
that requires surgery (colectomy) or can lead to a fatal outcome, if not properly 
managed. 
• 
Pneumonitis/Interstitial lung disease (ILD)  
Adverse events of pneumonitis have been observed with anti-PD-1, and anti-PD-L1 
antibodies (see IB). Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Typically, pulmonary consultation is required. 
• 
Hepatic Function Abnormality (Hepatitis / transaminase increases 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-
1 antibodies (see IB).  Inflammatory hepatitis has been reported in 3% to 9% of subjects 
treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, 
nausea and/or mild fever and increased liver function tests such as AST, ALT, alkaline 
phosphatase, and/or total bilirubin. Hepatic function abnormality is defined as any 
increase in ALT or AST to greater than 3 × ULN and concurrent increase in total bilirubin 
to be greater than 2 × ULN.  Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other.  Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a concurrent or pre-existing disease (e.g., 
cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other 
than the investigational product. Cases where a subject shows an AST or ALT ≥ 3 x ULN 
or total bilirubin ≥ 2 x ULN may need to be reported as SAEs. These cases should be 
reported as SAEs if, after evaluation they meet the criteria for a Hy’s Law case or if any 
of the individual liver test parameters fulfill any of the SAE criteria.  


 
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• 
Neurotoxicity (Neuropathy / neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis. 
• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism, and Type 1 diabetes mellitus. 
Type 1 diabetes mellitus: For subjects with suspected diabetes mellitus, Investigators 
should obtain an endocrinology consult and institute appropriate management which 
may include the administration of insulin.  
• 
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as 
per current established toxicity management guidelines. 
• 
Nephritis and increases in serum creatinine 
A consult with a Nephrologist should be done as well as monitoring for signs and 
symptoms that may be related to changes in renal function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, etc.). Subjects should be thoroughly 
evaluated to rule out any alternative etiology (e.g., disease progression, infections, etc.). 
Steroids should be considered in the absence of clear alternative etiology even for low 
grade events (Grade 2), in order to prevent potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis or labs suggestive of 
pancreatitis (increased serum lipase, increased serum amylase). 
• 
Myocarditis 
Myocarditis, a rare, but severe immune-mediated adverse event, presents with 
signs/symptoms such as decreased ejection fraction, arrhythmias, in particular 
occurrences of atrioventricular block. For patients with suspected myocarditis, 
investigators should obtain a cardiology consult and institute full diagnostic work-up 
(that includes exclusion of other alternate causes such as infection). 
• 
Myositis /Polymyositis 
Myositis or polymyositis should be suspected in patients who present with proximal 
muscle weakness and the evaluation should include an examination of the skin, muscle 
enzyme measurement, antibody testing, any systemic disease manifestations and 
exclusion of other diseases including drug-induced myopathy. Cases of myositis have 
been reported with myocarditis in which immune infiltration has been described in 
skeletal and cardiac muscle (see IB). 
• 
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and 
other events involving the eye, skin, haematological and rheumatological events. 
• 
Hypersensitivity and Infusion Reactions 


 
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Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (see IB).  As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of monoclonal 
antibodies (MAbs) can be caused by various mechanisms, including acute anaphylactic 
(IgE-mediated) and anaphylactoid reactions against the MAb, and serum sickness.  
Acute allergic reactions may occur, may be severe, and may result in death.  Acute 
allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, 
dizziness, fatigue, headache, hypertension, myalgia, vomiting and unresponsiveness. 
Guidelines for the management of subjects experiencing toxicities for BI 1361849 can be found 
in Section 8.4. 
7.2 Administrative Sponsor Requirements 
7.2.1 Trial Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Trial Master File” or “Study Master File”) of all trial-related documentation that is suitable for 
inspection by the Sponsor and regulatory authorities.  Upon completion of the trial, the 
Investigator is required to submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.2 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data 
entry, query management and sign-off.  Systems used for electronic data capture will be 
compliant with FDA regulations 21 CFR Part 11 and within the constraints of the applicable local 
regulatory agency guidelines (whichever provides the greatest protection to the integrity of the 
data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigator will sign and date the completed eCRF sections.  The Investigator’s signature 
will indicate a thorough inspection of the data in the CRF and will certify its content. 
7.2.3 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 


 
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7.2.4 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
qualification, site initiation, routine monitoring and site close-out.  Clinical Monitors and/or 
other sponsor staff will meet with the investigator staff and require direct access to source 
data/documents.  Such access may also be required for Institutional Review Board review, and 
regulatory inspection/audits.  Direct access is defined as permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study.  All 
reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
maintain the confidentiality of subjects’ identities and sponsor’s proprietary information will be 
exercised. 
It is the Clinical Monitor’s responsibility to inspect the case report forms at regular intervals 
throughout the trial to verify adherence to the protocol, the completeness, accuracy and 
consistency of the data, and adherence to Good Clinical Practice guidelines.  The Clinical 
Monitor should have access to patient charts, laboratory reports and other subject records 
needed to verify the entries on the case report forms (“source data verification”). 
7.2.5 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals.  However, in this case, approval must be obtained as soon as possible after 
implementation.  Implementation of administrative amendments that do not affect the safety of 
the subjects usually do not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor if circumstances permit, to discuss the 
planned course of action.  Any departures from the protocol must be fully documented in the 
source documentation. 
7.2.6 Premature Subject Withdrawal from Treatment or from Study 
A subject may withdraw from study treatment or from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the study site.  Likewise, 
the Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study.  Specific subject withdrawal criteria are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw from study treatment or from 
the study, all efforts will be made to complete the required study procedures and report the 
treatment observations as thoroughly as possible. 
For all subject withdrawals, a complete final evaluation should be made at the time of 
withdrawal.  The appropriate form in the Case Report Form should be completed with an 
explanation of why the subject is withdrawing, and an attempt should be made to perform a 
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7.2.7 Early Trial Termination 
Sponsor and Investigator have the right to terminate the study early.  Specific study stopping 
rules are listed in Section 3.1.14.  In such case, one party must notify the other in advance in 
writing about the intent of and the reasons for the termination.  The investigator must also 
notify the appropriate Institutional Review Board accordingly. 
7.2.8 Study Drug Shipments and Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably, the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the investigator/pharmacy (if applicable) 
• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor.  The 
Investigator is responsible for seeing to it that all used and unused trial supplies are accounted 
for.  At the end of the study, the Clinical Monitor will also collect the original study drug 
dispensing records. 
At the end of the study or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed-off 
by a second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 Regulatory, Legal and Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The Investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines and 
applicable local laws and regulations, with the understanding that local laws and regulations 
take precedence over respective sections in the Declaration of Helsinki and/or the ICH 
Guidelines. 
7.3.2 Informed Consent 
The investigator must obtain witnessed (if applicable) written informed consent from the 
subject or the subject’s legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any study 
procedures are performed.  The subject should be given a copy of the informed consent 
documentation.  The original signed and dated informed consent form must be retained in the 


 
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study records at the study site, and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 
7.3.3 Institutional Review Board 
The investigator must obtain written approval from the appropriate Institutional Review Board 
for the protocol and informed consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The investigator must report Serious Adverse Events (SAEs) to the appropriate Institutional 
Review Board in accordance with the Institutional Review Board’s rules and guidelines (see also 
Section 7.1). 
The Investigator must assure that continuing review (at least once per year) of the study is 
performed by the Institutional Review Board throughout the duration of the study.  If so 
required by the Institutional Review Board, the investigator must provide study reports on an 
annual basis and upon completion of the study. 
All correspondence with, and reports to, the Institutional Review Board must be maintained in 
the study files at the study site and copies must be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained.  A subject should only be 
identified by their initials, date of birth and subject number on the case report forms or other 
documents submitted to the Sponsor.  Documents that are not submitted to the Sponsor (e.g., 
signed informed consent form) should be kept in a strictly confidential section of the study file 
by the Investigator. 
The Investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As 
part of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 
 


 
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8 Appendices 
8.1 Protocol Version History 
Original Issue 
Issue date: 14-DEC-2016 
Summary of Changes: not applicable 
 
Amendment 1 
Issue date: 12-APR-2017 
Summary of Changes: 
 
1. Synopsis: Control Group B was added, Control Group A was modified, and total dose for BI 
1361849 was changed from 1920 µg to 12 x 80 µg due to introduction of needle-free device. 
These change were made throughout based on updated information from Boehringer 
Ingelheim.   
a. Paragraph 3 was updated as follows (changes in bold): “For each arm of the study, there 
is a dose escalation phase in which the Recommended Combination Dose (RCD) is 
determined according to a standard 3 + 3 design. The dose escalation phase is followed 
by an expansion phase, in which the cohort at the RCD is expanded to 20 subjects 
(inclusive of the subjects from the dose escalation cohort). For Arm A, there will be an 
additional Control group (n = 10) added to the expansion phase in which the subjects 
will receive only durvalumab every 4 weeks.  During expansion, there will be an 
additional Control Group (n = 10) added to expansion for Arm B, where the subjects in 
the Control Group will receive only durvalumab + tremelimumab. If Arm B is not 
expanded, the Control Group will be added to the expansion for Arm A, where the 
subjects in the Control Group will receive only durvalumab.” 
b. Table was changed FROM: 
Dose Level Table 
Dose 
Level 
Arm A Escalation 
Dose 
Level 
Arm B* 
BI 1361849 
Durvalumab 
BI 1361849 
Durvalumab 
Tremelimumab 
-1 
1920 µg 
750 mg 
 
 
 
 
Starting 
1920 µg 
1500 mg 
Starting 
1920 µg 
Arm A RCD 
75 mg 
*Dose in Arm B is based on RCD determined in Arm B. If there is unacceptable toxicity, dosing will continue at RCD 
from Arm A, without tremelimumab.   
NOTE 1: See Section 3.1.7.1 for durvalumab and tremelimumab doses for instances when a subject’s body weight 
drops to ≤ 30 kg while on the study. 
NOTE 2: The BI 1361849 drug product is a vaccine comprising six drug product components (F2408, F2409, F2410, 
F2624, F2625, and F2626), which are provided and administered separately. 
TO: 
Dose Level Table 
Dose 
Level 
Arm A Escalation 
Dose 
Level 
Arm B* 
BI 1361849 
Durvalumab 
BI 1361849 
Durvalumab 
Tremelimumab 
-1 
12 x 
80 µg** 
750 mg 
 
 
 
 
Starting 
12 x 
80 µg** 
1500 mg 
Starting 
12 x 
80 µg** 
Arm A RCD 
75 mg 


 
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*If there is unacceptable toxicity in Arm B, dosing will continue at RCD from Arm A, without tremelimumab.  **See 
Note 2 below. 
NOTE 1: See Section 3.1.7.1 for durvalumab and tremelimumab doses for instances when a subject’s body weight 
drops to ≤ 30 kg while on the study. 
NOTE 2: The BI 1361849 drug product is a vaccine comprising six drug product components (F2408, F2409, F2410, 
F2624, F2625, and F2626), which are provided and administered separately; each component is administered twice, 
thus there are 12 administrations of 100 µL (80 µg) each. 
2. Section 1.2.3 (BI 1361849): section was updated according to data available as of March 2017 
from Boehringer Ingelheim: 
a. Data supporting a needle-free device, the PharmaJet Tropis®, were provided 
b. Summary for Trial CV-9202-006 was updated 
3. Section 2.1 (BI 1361849 dose), the following paragraphs were added for the needle-free 
device and dosing: “BI 1361849 may also be administered by a needle-free device, the 
PharmaJet Tropis® device. See Section 1.2.3 for additional details.  Due to the filling volume 
of 100 μL, the device allows for administration of half the previously established doses, i.e., 
160 μg instead of 320 μg per antigen when using the same manner of administration of two 
inoculations per antigen and vaccination time point. Advantages include improved patient 
convenience, handling safety, ease, and reliability of intradermal administration. Preclinical 
data showed that using a needle-free device such as the PharmaJet Tropis® device, the 
efficiency of delivery increases and protein production is higher even at half or a quarter of 
the administered dose, hence lower doses can be used. Clinical data from a Phase 2 trial, CV-
9104-007, suggests that administration of half the dose by the PharmaJet Tropis® device 
results in at least similar immunogenicity compared to needle administration of the full dose. 
For this study, the Pharmajet Tropis® device will be used for the administration of the 
BI 1361849 components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations 
per component, the recommended dose per each of the 6 antigen components will be 160 μg 
(2 x 80 µg), for a total of 960 μg (12 administrations).” 
4. Section 2.2 (Durvalumab and tremelimumab dose): The last paragraph was changed because 
weight based dosing was added for subjects whose weight drops to ≤ 30 kg during the study. 
The paragraph was changed FROM: This dosing of durvalumab and tremelimumab is 
recommended only for subjects with > 30kg body weight due to endotoxin exposure.  
Subjects with a body weight ≤ 30 kg are not eligible for enrollment in the current study.  If a 
subject’s body weight drops to ≤ 30 kg while on the study, the subject will be dosed at 600 
mg Q4W for durvalumab and 30 mg Q4W for tremelimumab as long as the body weight 
remains ≤ 30 kg.  See Section 3.1.7.1 for additional details regarding the dose de-escalation 
cohort for durvalumab. TO: “This dosing of durvalumab and tremelimumab is recommended 
only for subjects with > 30kg body weight due to endotoxin exposure.  Subjects with a body 
weight ≤ 30 kg are not eligible for enrollment in the current study.  See Section 3.1.7.1 for 
additional details regarding the dose de-escalation cohort for durvalumab and for dose 
requirements for instances when a subject’s body weight drops to ≤ 30 kg while on the study. 
5. Section 3.1 (Study Design), Control Group B was added and Control Group A was modified.  
The language was changed FROM: 
“For Arm A, there will be an additional Control Group (n = 10) added to the expansion phase 
in which the subjects will receive only durvalumab every 4 weeks: 
• 
Arm A1 (Expansion group): 
BI 1361849 + durvalumab (n=20) 
• 
Arm A2 (Control Group): 
durvalumab (n=10)” 


 
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TO:  “During expansion, there will be an additional Control Group (n = 10) added to the 
expansion for Arm B, where the subjects in the Control Group will receive only durvalumab + 
tremelimumab (no BI 1361849 components):  
• 
Arm B Expansion Cohort: BI 1361849 + durvalumab +tremelimumab (n=20) 
• 
Arm B Control Group: durvalumab + tremelimumab (n=10) 
If Arm B is not expanded due to toxicities, the Control Group will be added after the 
completion of expansion for Arm A, where the subjects in the Control Group will receive only 
durvalumab (no BI 1361849): 
• 
Arm A Expansion Cohort: BI 1361849 + durvalumab (n=20) 
• 
Arm A Control Group: durvalumab (n=10)” 
6. Section 3.1.2 (Enrollment/Randomization): Control Group B was added and Control Group A 
was modified.   
a. The language was changed FROM: “Enrollment will start in the Arm A dose escalation 
cohorts in a sequential fashion.  After the RCD is determined for Arm A, enrollment will 
start for the dose evaluation of Arm B (see Section 3.1.7.1) and for the Arm A expansion 
phase (Arm A1 Expansion + Arm A2 Control; see Figure 1), whereby no randomizations 
will be performed.  Any new subject will be assigned to the Arm B dose evaluation 
cohort, unless no slot is available, in which case the subject will be assigned to the Arm A 
expansion cohort.  After the dose evaluation in Arm B is complete and enrollment is 
completed in the Arm A (A1 and A2) expansion cohorts, enrollment will begin in the Arm 
B expansion cohort.”  TO: “Enrollment will start in the Arm A dose escalation cohorts in a 
sequential fashion.  After the RCD is determined for Arm A, enrollment will start for the 
dose evaluation of Arm B (see Section 3.1.7.1) and for the Arm A Expansion Cohort (see 
Figure 1), whereby no randomizations will be performed.  Any new subject will be 
assigned to the Arm B dose evaluation cohort, unless no slot is available, in which case 
the subject will be assigned to the Arm A Expansion Cohort.  After the dose evaluation in 
Arm B is complete and enrollment is complete in Arm A Expansion Cohort, enrollment 
will begin in the Arm B Expansion Cohort and Arm B Control Group in an alternating 
fashion (see Figure 1 and description below).  If Arm B is not expanded due to toxicities, 
the Control Group will be added to the expansion for Arm A. The Arm A Control Group, 
will then start enrolling after the completion of Arm A Expansion Cohort, in a non-
alternating fashion.” 
b. Figure 1 was updated to add Control Group B and modify Control Group A.  The following 
footnote was added: ”*If Arm B Expansion Cohort and Arm B Control Group are not 
initiated due to toxicities, an Arm A Control Group (n=10 subjects; durvalumab only) will 
be added, which will start enrollment (in a non-alternating fashion) after Arm A 
Expansion Cohort has completed.” 
c. Language in the last paragraph was changed FROM: 
“For the expansion phase for Arm A, subjects will be enrolled in an alternating fashion so 
that there are a total of 20 subjects (inclusive of the subjects from the dose escalation 
cohort that is being expanded) for the expansion cohort (Arm A1) and 10 subjects for the 
Control Group (Arm A2).  In order to have only 14 additional subjects in Arm A1, 
enrollment will start with the 6th subject of the Arm A dose escalation cohort.  Thus, 3 
subjects will be enrolled in Arm A1, followed by 2 subjects in Arm A2, and so forth, as 
depicted below: 


 
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Enrolling subjects in this fashion will result in the following: 
• 
A total of 20 subjects in Arm A1 expansion cohort (6 subjects from the Arm A dose 
escalation cohort + 14 additional subjects) 
• 
10 subjects in Arm A2 Control Group.” 
TO:  “For the expansion phase for Arm B, subjects will be enrolled in an alternating fashion 
into the Expansion Cohort and the Control Group. This is done so that there is a total of 
20 subjects (inclusive of the subjects from the dose evaluation cohort that is being expanded) 
for the Arm B Expansion Cohort and 10 subjects for the Arm B Control Group.  In order to have 
only 14 additional subjects in the Arm B Expansion Cohort, enrollment will start with the 6th 
subject of the Arm B dose evaluation cohort.  Thus, 3 subjects will be enrolled in Arm B 
Expansion Cohort, followed by 2 subjects in Arm B Control Group, and so forth, as depicted 
below: 
Exp = Expansion Cohort; Con = Control Group 
Enrolling subjects in this fashion will result in the following: 
• 
A total of 20 subjects in Arm B Expansion Cohort (6 subjects from the Arm B dose 
evaluation cohort + 14 additional subjects) 
• 
10 subjects in Arm B Control Group. 
NOTE: If Arm B is not expanded due to toxicities, an Arm A Control Group (n = 10 subjects; 
durvalumab only) will be added after the completion of Arm A Expansion Cohort. The 
subjects the Arm A Control Group will be enrolled in a non-alternating fashion. “ 
7. Section 3.1.6 (Sample Size Considerations). Paragraph 2 was updated to reflect the changes in 
the control groups (changes in bold): “In the expansion phase, 20 subjects per arm are 
thought to provide sufficient data to adequately identify essential safety and preliminary 
efficacy signals.  Therefore, up to 14 additional subjects will be added to the 6 subjects 
treated at the RCD in each arm (A and B). For Arm A, an additional 10 subjects will be added 
to expansion phase for Arm A2 (Control Group).  The control group is added primarily for 
the analysis of the immune response in this group (see Section 3.1.7.2). For Arm B, an 
additional 10 subjects will be added to expansion phase for the Control Group.  The control 
group is added primarily for the analysis of the immune response in this group (see Section 
3.1.7.2). If Arm B is not expanded, the Arm A Control Group will open for enrollment (in a 
non-alternating fashion) after completion of Arm A Expansion Cohort.” 
Subj. 
No. 
Arm 
A1 
Arm 
A2 
Subj. 
No. 
Arm 
A1 
Arm 
A2 
Subj. 
No. 
Arm 
A1 
Arm 
A2 
Subj. 
No. 
Arm 
A1 
Arm 
A2 
Subj. 
No. 
Arm 
A1 
Arm 
A2 
6 
X 
 
11 
X 
 
16 
X 
 
21 
X 
 
26 
X 
 
7 
X 
 
12 
X 
 
17 
X 
 
22 
X 
 
27 
X 
 
8 
X 
 
13 
X 
 
18 
X 
 
23 
X 
 
28 
X 
 
9 
 
X 
14 
 
X 
19 
 
X 
24 
 
X 
29 
 
X 
10 
 
X 
15 
 
X 
20 
 
X 
25 
 
X 
30 
 
X 
Subj. 
No. 
Arm 
B 
Exp 
Arm 
B 
Con 
Subj. 
No. 
Arm 
B 
Exp 
Arm 
B 
Con 
Subj. 
No. 
Arm 
B 
Exp 
Arm 
B 
Con 
Subj. 
No. 
Arm 
B 
Exp 
Arm 
B 
Con 
Subj. 
No. 
Arm 
B 
Exp 
Arm 
B 
Con 
6 
X 
 
11 
X 
 
16 
X 
 
21 
X 
 
26 
X 
 
7 
X 
 
12 
X 
 
17 
X 
 
22 
X 
 
27 
X 
 
8 
X 
 
13 
X 
 
18 
X 
 
23 
X 
 
28 
X 
 
9 
 
X 
14 
 
X 
19 
 
X 
24 
 
X 
29 
 
X 
10 
 
X 
15 
 
X 
20 
 
X 
25 
 
X 
30 
 
X 


 
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8. Section 3.1.7 (Treatment Arms and Treatment Schema). The table footnote was changed 
FROM: “Note: For Arm A, there will be an additional Control Group (n = 10) added to the 
expansion phase in which the subjects will receive only durvalumab every 4 weeks (see 
Section 3.1.7.2).” TO: “Note: During expansion, there will be an additional Control Group (n = 
10) added to the expansion phase for Arm B, where the subjects in the Control Group will 
receive only durvalumab + tremelimumab. If Arm B is not expanded, the Control Group will 
be added to the expansion for Arm A, where the subjects in the Control Group will receive 
only durvalumab. See Section 3.1.2 for details.”  
9. Section 3.1.7.1 (Dose Escalation Phase).  Pharmajet Tropis® device was added and doses for 
BI 1361849 were updated. Weight based dosing was added for subjects whose weight drops 
to ≤ 30 kg during the study. The language was changed as follows:  
FROM: 
Dose Level Table 
Dose 
Level 
Arm A Escalation 
Dose 
Level 
Arm B* 
BI 1361849 
Durvalumab 
BI 1361849 
Durvalumab 
Tremelimumab 
-1 
1920 µg 
750 mg 
 
 
 
 
Starting 
1920 µg 
1500 mg 
Starting 
1920 µg 
RCD from Arm A 
75 mg 
*If there is unacceptable toxicity, dosing will continue at RCD from Arm A, without tremelimumab. 
Note: The durvalumab and tremelimumab doses are for subjects > 30 kg.  
• 
Durvalumab starting dose:1500 mg Q4W for subjects > 30 kg.  If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will be dosed at 600 mg Q4W for 
durvalumab as long as the body weight remains ≤ 30 kg. 
• 
Durvalumab dose de-escalation: 750 mg Q4W for subjects > 30 kg.  If a subject’s body 
weight drops to ≤ 30 kg while on the study, the subject will be dosed at 300 mg Q4W for 
durvalumab as long as the body weight remains ≤ 30 kg. 
• 
Tremelimumab dose: 75 mg Q4W for subjects > 30 kg. If a subject’s body weight drops 
to ≤ 30 kg while on the study, the subject will be dosed at 30 mg Q4W for tremelimumab 
as long as the body weight remains ≤ 30 kg. 
TO: 
Dose Level Table 
Dose 
Level 
Arm A Escalation 
Dose 
Level 
Arm B* 
BI 1361849 
Durvalumab 
BI 1361849 
Durvalumab 
Tremelimumab 
-1 
12 x 
80 µg** 
750 mg 
 
 
 
 
Starting 
12 x 
80 µg** 
1500 mg 
Starting 
12 x 
80 µg** 
RCD from Arm A 
75 mg 
*If there is unacceptable toxicity in Arm B, dosing will continue at RCD from Arm A, without tremelimumab. 
**BI 1361849 is a vaccine comprising six drug product components (F2408, F2409, F2410, F2624, F2625, and F2626), 
which are provided and administered separately; each component is administered twice, thus there are 12 
administrations of 100 µL (80 µg) each. 
NOTE: The Pharmajet Tropis® device will be used for the administration of the BI 1361849 
components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per 
component, the recommended dose per each of the 6 antigen components will be 160 μg (2 x 80 
μg), for a total of 960 μg (12 administrations). 
Note: The durvalumab and tremelimumab doses are for subjects > 30 kg.  
• 
Durvalumab starting dose:1500 mg Q4W for subjects > 30 kg.  If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 


 
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equivalent to 20 mg/kg of durvalumab  as long as the body weight remains ≤ 30 kg (e.g., 
a 30 kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 mg 
dose; etc.).  When the weight improves to >30 kg, the subject may return to fixed dosing 
of durvalumab 1500 mg. 
• 
Durvalumab dose de-escalation: 750 mg Q4W for subjects > 30 kg.  If a subject’s body 
weight drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 
equivalent to 10 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg (e.g., a 
30 kg subject would receive a 300 mg dose; a 25 kg subject would receive a 250 mg dose; 
etc.).  When the weight improves to >30 kg, the subject may return to fixed dosing of 
durvalumab 750 mg. 
• 
Tremelimumab dose: 75 mg Q4W (x4) for subjects > 30 kg. If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 
equivalent to 1mg/kg tremelimumab  as long as the body weight remains ≤ 30 kg (e.g., a 
30 kg subject would receive a 30 mg dose; a 25 kg subject would receive a 25 mg dose; 
etc.).  When the weight improves to >30 kg, the subject may return to fixed dosing of 
tremelimumab 75 mg 
 
10. Section 3.1.7.2 (Dose Expansion Phase), Paragraph 2 was changed FROM: “There will be an 
additional Control Group (Arm A2, n = 10) added to the expansion phase for Arm A in which 
the subjects receive only durvalumab.  The control group is added primarily for the analysis of 
the immune response in this group.” TO: “During expansion, there will be an additional 
Control Group (n = 10) added to the expansion phase for Arm B, where the subjects in the 
Control Group will receive only durvalumab + tremelimumab. If Arm B is not expanded, the 
Control Group will be added to the expansion for Arm A, where the subjects in the Control 
Group will receive only durvalumab. See Section 3.1.2 for details.  The control group is added 
primarily for the analysis of the immune response in this group.”  
11. Section 3.2 (flowchart): 
a. Treatment section was updated to reflect changes for Control Groups 
b. Footnote i was updated to reflect changes to Arms A and B Control Groups 
c. Added Concom meds and AEs to Week 46 
d. Footnote g was updated to clarify timing of optional tumor progressions (see changes to 
Section 4.1.3.1. 
e. Optional tumor biopsy was removed from Cycle 12 per change to Section 4.3.1.1 
12. Section 4.3.1.1 (Tumor Microenvironment): Paragraph 5 was updated to clarify timing of 
optional tumor progressions (changes in bold): Optional core biopsies will be obtained at the 
time of tumor progression or at the end of the study completion of treatment from subjects 
who consent to this procedure.  A minimum of 3 cores will be required. 
13. Section 4.3.1.2.1 (Immune Monitoring for Responses to BI 1361849 Vaccine), Paragraph 2 
was updated per updated information from Boehringer Ingelheim (Changes in bold):  “Assays 
for antigen-specific immune responses encompass e.g, for example, intracellular cytokine 
staining (ICS) and ELISpot and/or CFSE-based proliferation, for detection of antigen-specific 
T-cells by their functional capacity to produce various effector cytokines or proliferate in 
response to the vaccine (NY-ESO-1, MageC1, MageC2, 5T4, Survivin, Muc-1) and/or non-
vaccine tumor antigens (e.g. MAGE-A3).  Humoral responses against vaccine antigens are 
routinely analyzed by immunoassay techniques such as ELISA and can easily be extended to 
non-vaccine antigens (antibody chips antigen arrays).  If possible, the immune analyses will 


 
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also include a detailed phenotypic characterization of, e.g., circulating T-cells subsets, 
including follicular helper T-cells, T memory stem cells, Th1 and Th2 lineages, activation and 
differentiation states of immune cells, and checkpoint marker expression.  Furthermore, B 
cells, NK cells, DCs, monocytes and the peripheral immune-suppressive environment 
mediated by myeloid derived suppressor cells (MDSCs) and regulatory T-cells are evaluated.  
Measurements of systemic immunological lymphoid repertoire, e.g., T-cell receptor 
sequencing, and immune-related transcriptional changes, e.g., T-cell receptor sequencing, 
cytokine and chemokine profiling and genome-wide transcriptional profiling are additional 
approaches of interest suitable to identify potential blood-derived biomarkers.”  
14. Section 4.3.2 (Subject Evaluation and Statistics) was updated, per updated information from 
Boehringer Ingelheim (changes in bold): “For each arm of the study, only subjects who 
receive at least 1 dose of the respective drugs and who provide the baseline and at least 1 
on-treatment sample (if applicable) will be evaluated.  As these analyses represent 
exploratory evaluations of potential biomarkers of response or resistance to therapy, 
descriptive statistics will be used to describe findings and potential relationships to outcomes 
to therapy.  Criteria for assay positivity (changes compared to baseline) of individual assays 
will be described in the statistical analysis plan (SAP). The exploratory pharmacodynamic 
assessment of the immunologic changes in the tumor microenvironment will include the 
correlation between clinical activity and the expression level of PD-L1 and tumor-infiltrating 
lymphocyte (TILs) changes in biopsies pre and post treatment. The association between 
response and PD-L1 expression within each arm will be assessed descriptively. Confidence 
intervals for the overall odds ratio and the odds ratio within each arm will be presented. The 
association between response and TILs changes (increase, decrease, or no change) will be 
evaluated similarly.  Subjects are considered to show an immune response against BI 
1361849 if at least one of the two post-baseline time points show assay positivity for at 
least one of the assessments by ICS, ELISpot or ELISA for at least one of the six antigens (see 
table below). Criteria for assay positivity (changes compared to baseline) of individual 
assays will be described in the statistical analysis plan (SAP).  
 
PBMCs 
Serum 
ICS 
ELISpot 
ELISA 
CD8 
CD4 
PBMCs 
 
IFN-γ 
TNF-α 
IL-2 
CD107a 
IFN-γ 
TNF-α 
IL-2 
CD107a 
IFN-γ 
lgM 
lgG 
MUC-1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survivin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MAGE-C1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MAGE-C2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5T4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NY-ESO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subjects are considered fully evaluable for immune response if the following criteria are met: 


 
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• 
Subjects have received at least 4 treatments with BI 1361849 including all 
vaccine antigens according to protocol 
• 
Samples from baseline and both post-baseline sample 7 days (±2 days) after 
treatment are available 
• 
Subjects have not received any prohibited concomitant treatments (see Section 
5.3.1) within 21 days before on-treatment blood sampling. Immunosuppressive 
medication that has been taken by subjects 2 to 3 weeks prior to randomization 
will be documented so that any potential influence on baseline values may be 
evaluated. 
• 
Sufficient amount and quality of blood sample and isolated PBMCs is available to 
fully perform and analyze, in accordance with respective assay SOPs, at least the 
ICS assay, as a measure for antigen-specific cellular immune response one of 
the two antigen-specific cellular immune assay according to assay priority (ICS 
is prioritized over ELISpot)  
• 
The analysis of antigen-specific cell-mediated immune assays response by ICS 
are is required to include all BI 1361849 antigens and negative controls to be 
fully evaluable 
• 
Amount and quality of serum samples need to be sufficient to perform and 
analyze serum antibody ELISA according to assay SOP  
• 
Measurement of serum antibody ELISAs against all available BI 1361849 
antigens and negative controls could be performed 
All other exploratory results will be summarized descriptively.” 
15. Section 5.1 (Inclusion Criteria): Criterion # 5 was updated per Medimmune guidelines; 
creatinine clearance “≥50 mL/min” was changed to “> 40 mL/min” (by Cockcroft-Gault 
formula) 
16. Section 5.2 (Exclusion Criteria) was updated per current Medimmune guidelines 
a. #3 was changed FROM: “Active, suspected or prior documented autoimmune disease 
(including but not restricted to inflammatory bowel disease, celiac disease, irritable 
bowel syndrome, Wegner’s granulomatosis, Hashimoto’s thyroiditis, rheumatoid 
arthritis, systemic lupus, scleroderma and its variants, multiple sclerosis, myasthenia 
gravis).  Vitiligo, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted.” 
TO: “Active, suspected or prior documented autoimmune disease or inflammatory 
disorders (including but not restricted to inflammatory bowel disease [e.g., colitis or 
Crohn's disease], celiac disease, diverticulitis [with the exception of diverticulosis], 
Sarcoidosis syndrome, Wegner’s granulomatosis with polyangiitis, Hashimoto’s 
thyroiditis, rheumatoid arthritis, systemic lupus, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, scleroderma and its variants, multiple sclerosis, myasthenia gravis, 
etc. ).  Vitiligo, alopecia, residual hypothyroidism (e.g., following Hashimoto syndrome) 
due to autoimmune condition only requiring hormone replacement, psoriasis or any 
chronic skin condition not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger are permitted. Subjects without active disease 
in the last 5 years may be included but only after consultation with the study physician. 
Subjects with celiac disease controlled by diet alone may also be included.” 


 
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b. #12 was changed FROM: “Other serious illnesses (e.g., serious infections requiring 
antibiotics, bleeding disorders).” TO: “Uncontrolled intercurrent illness, including but not 
limited to, ongoing or active infection, bleeding disorders, symptomatic congestive heart 
failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 
interstitial lung disease, or serious chronic gastrointestinal conditions associated with 
diarrhea.”  
c. #13 was changed FROM: “Mental impairment that may compromise compliance with the 
requirements of the study.” 
TO: “Mental impairment or social situations that may compromise compliance with the 
requirements of the study or compromise the ability of the subject to give written 
informed consent.” 
d. # 19 and # 20 were added. 
17. Section 6.1.3 (Durvalumab Prep) and 6.2.3 (Tremelimumab Prep): Weight based dosing was 
added for subjects whose weight drops to ≤ 30 kg during the study. See changes made to 
Section 3.1.7.1. 
18. Section 6.1.4 (Durvalumab administration) was updated per current Medimmune guidelines: 
a. Bullet 8 was changed FROM: “The total time between needle puncture of the 
durvalumab vial to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2°C to 8°C (36°F to 46°F). Standard infusion time is 60 ± 5 
minutes. However, if there are interruptions during infusion (total infusion time not to 
exceed 4 hours), the total allowed time for preparation and administration should not 
exceed 8 hours at room temperature.  In the event that either preparation time or 
infusion time exceeds the time limits, a new dose must be prepared from new vials.” TO:  
“The total time between needle puncture of the durvalumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C 
(36°F to 46°F). Standard infusion time is 60 ± 5 minutes (an infusion of less than 55 
minutes is considered a deviation). However, if there are interruptions during infusion, 
the total allowed infusion time should not exceed 8 hours at room temperature.  In the 
event that either preparation time or infusion time exceeds the time limits, a new dose 
must be prepared from new vials.” 
b. The last bullet was summarized as “See Section 8.3.1 for guidelines for infusion-related 
reactions.” 
19. Section 6.2.4 (Tremelimumab Administration) was updated per current Medimmune 
guidelines: 
a. Bullet 8 was changed FROM: “The total time between needle puncture of the 
tremelimumab vial to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2°C to 8°C (36°F to 46°F). Standard infusion time is 60 ± 5 
minutes. However, if there are interruptions during infusion (total infusion time not to 
exceed 4 hours), the total allowed time for preparation and administration should not 
exceed 8 hours at room temperature.  In the event that either preparation time or 
infusion time exceeds the time limits, a new dose must be prepared from new vials.” TO:  
“The total time between needle puncture of the tremelimumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C 
(36°F to 46°F). Standard infusion time is 60 ± 5 minutes (an infusion of less than 55 
minutes is considered a deviation). However, if there are interruptions during infusion, 
the total allowed infusion time should not exceed 8 hours at room temperature.  In the 


 
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event that either preparation time or infusion time exceeds the time limits, a new dose 
must be prepared from new vials.” 
20. Section 6.3.2 (Preparation of Components of BI 1361849): Language was updated per 
Boehringer Ingelheim; changed FROM: “BI 1361849 comprises 6 drug product components, 
each of which is provided separately as a sterile lyophilizate in a 2 mL glass vial with rubber 
stopper closure that will be reconstituted with 600 µL (0.6 mL) of Ringer-Lactate solution to 
provide an extractable volume for intradermal injection of 400 μL (0.40 mL) of solution 
containing the drug substance at a concentration of 0.8 g/L (equivalent to 0.48 mg per vial 
and 0.32 mg per injection of 400 μL). NOTE: The Ringer-Lactate solution used for 
reconstitution must be obtained from Fresenius Kabi (or alternatively, it will be provided by 
Boehringer Ingelheim), and must include the following ingredients in the respective 
concentrations: Sodium Chloride 103 mM, Potassium Chloride 5.5 mM, Calcium Chloride 
dehydrate 1.8 mM, Sodium lactate 28 mM.  Other Ringer-Lactate solutions may contain Mg, 
which may seriously impair the vaccine according to CureVac.” TO: “BI 1361849 comprises 6 
drug product components. Each box of BI 1361849 contains one vial of each of the 
components, which are formulated as a sterile lyophilizate in a 2 mL glass vial with rubber 
stopper closure. Each vial will be reconstituted with 600 µL (0.6 mL) of Ringer’s Lactate 
solution to provide a solution containing the drug substance at a concentration of 0.8 g/L 
(equivalent to 0.48 mg per vial and 0.16 mg (80 μg) per injection of 100 μL).  NOTE: The 
Ringer’s Lactate solution (from Fresenius Kabi) used for reconstitution will be provided to the 
sites; the solution contains the following ingredients in the respective concentrations: 
Sodium Chloride 103 mM, Potassium Chloride 5.5 mM, Calcium Chloride dehydrate 1.8 mM, 
Sodium lactate 28 mM.  Other Ringer’s Lactate solutions may contain Mg, which may 
seriously impair the vaccine according to CureVac.” 
21. Section 6.3.3 (Administration):  
a. the following language was added regarding the needle-free device, Pharmajet Tropis®: 
“The Pharmajet Tropis® device will be used for the administration of the BI 1361849 
components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per 
component, the recommended dose per each of the 6 antigen components will be 
160 μg (2 x 80 μg), for a total of 960 μg (12 administrations). Directions for use of the 
Pharmajet Tropis® device will be provided separately.” 
b. “injections” was changed to “administrations” (this was changed throughout) 
c. Filling volume was changed from 200 to 100 µL (80 µg); total for all 12 administrations 
changed from 1920 to 960 µg. 
d. Paragraph regarding use of 30 gauge needle was deleted. 
22. Section 6.4 (Estimated Study Requirements): Table was changed to clarify supply of BI 
1361849 components and Ringer’s lactate solution; it was changed FROM: 
 
 
Drug 
Required Quantity 
(vials) 
Durvalumab (500 mg / 10 ml vials) 
2400 
Tremelimumab (400 mg / 20 ml vials) 
128 
BI 1361849 (2 X 200 μL from 1 vial each of: 
F2408, F2409, F2410, F2624, F2625, and F2626) 
1000 for each of 
the 6 components 
 


 
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TO:  
Drug 
Required Quantity 
(vials) 
Durvalumab (500 mg / 10 ml vials) 
2400 
Tremelimumab (400 mg / 20 ml vials) 
128 
BI 1361849 (2 X 100 μL from 1 vial each of: 
F2408, F2409, F2410, F2624, F2625, and F2626); 
this will be provided in a box containing 1 vial of 
each component. 
Ringer’s lactate solution will also be provided 
(one bottle per subject per dosing day). 
1000 boxes 
containing 6 vials 
(1 vial for each of 
the 6 components) 
 
23. Section 7.1.6 (Expedited SAE Reporting Requirements): the last paragraph was updated to 
include Boehringer Ingelheim (changes in bold):  “Serious adverse event reporting to 
AstraZeneca/Medimmune and to Boehringer Ingelheim is described in a separate respective 
agreements. 
24. Section 7.18 (AESIs): additional detail was provided for each of the listed AESIs per current 
Medimmune guidelines. The last paragraph was also updated (changes in bold):  “Guidelines 
for the management of subjects experiencing toxicities for BI 1361849 can be found in 
Section 8.4.” 
25. Section 8.3.1 (Durvalumab and tremelimumab Dose Modifications due to Toxicity): For 
Infusion related reactions Grades 1 and 2, the phrase “total infusion time not to exceed 4 
hours.” was deleted per Medimmune current guidelines. 
26. Administrative:  
a. Spelling, grammar and typographical errors were corrected; formatting changes were 
implemented, as applicable. 
b. List of abbreviations was updated 
 
Amendment 2 
Issue date: 10-AUG-2017 
Summary of Changes: 
 
1. IND # was added. 
2. For clarification, dose escalation phase was renamed as dose evaluation phase in the 
Synopsis, Figure 1, and Sections 3.1, 3.1.2, 3.1.6, 3.1.7.1, 3.1.7.2, 3.1.9, 3.1.11, 3.1.13, 3.1.14, 
4.0, 4.1.1, and 4.1.2. The following clarification was added in the Synopsis and Section 
3.1.7.1: “For Arm A, the RCD of BI 1361849 + durvalumab is determined. The starting dose of 
durvalumab is 1500 mg with possible de-escalation to 750 mg; the dose for BI 1361849 
remains constant. For Arm B, the RCD of BI 1361849 + durvalumab from Arm A with the 
addition of tremelimumab 75 mg is evaluated. There is no dose escalation/de-escalation for 
Arm B; if there is unacceptable toxicity in Arm B, the arm will be discontinued.” 
3. The administration method for BI 1361849 was changed from the Pharmajet Tropis® device 
to standard needle. 
a. Section 2.1 (BI 1361849): deleted: “Due to the filling volume of 100 μL, the device allows 
for administration of half the previously established doses, i.e., 160 μg instead of 320 μg 
per antigen when using the same manner of administration of two inoculations per 


 
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antigen and vaccination time point. Advantages include improved patient convenience, 
handling safety, ease, and reliability of intradermal administration. Preclinical data 
showed that using a needle-free device such as the PharmaJet Tropis® device, the 
efficiency of delivery increases and protein production is higher even at half or a quarter 
of the administered dose, hence lower doses can be used. Clinical data from a Phase 2 
trial, CV-9104-007, suggests that administration of half the dose by the PharmaJet 
Tropis® device results in at least similar immunogenicity compared to needle 
administration of the full dose.” 
b. Section 2.1 (BI 1361849): Last paragraph was changed FROM “For this study, the 
Pharmajet Tropis® device will be used for the administration of the BI 1361849 
components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per 
component, the recommended dose per each of the 6 antigen components will be 
160 μg (2 x 80 µg), for a total of 960 μg (12 administrations).” TO “For this study, the 
Pharmajet Tropis® device will not be used for the administration of the BI 1361849 
components. Instead, standard intradermal injections using needles will be performed 
(see Section 6.3.3 for details).”   
c. The change from Tropis® device to needle administration resulted in different volume 
requirements for each of the BI 1361849 components. Thus 80 µg was changed to 160 µg 
and 100 µL was changed to 200 µL in the Synopsis and Sections 3.1.7.1, 6.3.3, and 6.4. 
d. The following clarification was added to the first paragraph in Section 2.1 (changes in 
bold) “The BI 1361849 drug product is a vaccine comprising six drug product components 
(F2408, F2409, F2410, F2624, F2625, and F2626), which are provided and administered 
separately.  The recommended dose per antigen constituent is 320 μg (160 μg x 2), for a 
total of 1920 μg (320 μg x 6 constituents). 
e. Section 3.1.7.1: The first NOTE was changed FROM “The Pharmajet Tropis® device will be 
used for the administration of the BI 1361849 components. Allowing for a filling volume 
of 100 μL (80 μg) and 2 administrations per component, the recommended dose per each 
of the 6 antigen components will be 160 μg (2 x 80 μg), for a total of 960 μg (12 
administrations).” TO: “See Section 6.3.3 for details on the administration of BI 
1361849.” 
f. Section 6.3.3 (BI 1361849 Administration):  
i. The following paragraph was deleted “The Pharmajet Tropis® device will be used for 
the administration of the BI 1361849 components. Allowing for a filling volume of 
100 μL (80 μg) and 2 administrations per component, the recommended dose per 
each of the 6 antigen components will be 160 μg (2 x 80 μg), for a total of 960 μg (12 
administrations). Directions for use of the Pharmajet Tropis® device will be provided 
separately.” 
ii. The following paragraph was added: “A 30-gauge needle will be used for the 
injection.  The needle should penetrate the skin at an angle of about 15 degrees and 
the injection should be administered slowly until a bubble appears underneath the 
skin surface.  Subcutaneous injection (characterized by a missing bubble after the 
injection) must be avoided as it may result in reduced efficacy of the vaccine.  
However, if an injection is administered subcutaneously by error, the injection must 
not be repeated for this vaccination time point.  Incorrect injections will be 
documented.” 


 
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4. Section 3.2 (Flowchart): Per FDA recommendation, Footnote “a” was changed FROM “pre-
dose, when applicable. Note: It is strongly recommended that hematology, chemistry and 
pregnancy test (when applicable) results are reviewed before dosing.” TO “pre-dose, when 
applicable. Note: Review of results for hematology, chemistry and pregnancy test (when 
applicable) is required prior to dosing.” 
5. Sections 6.1.4 (Durvalumab Administration) and 6.2.4 (Tremelimumab Administration): In 
bullet 8, the following sentence was modified to provide clarification (changes in bold): 
“However, if there are interruptions during infusion, the total allowed infusion time should 
not exceed 8 hours at room temperature.” 
6. Section 7.1.8 (AESI): 
a. Bullet 2 (changes in bold): Pneumonitis/Interstitial lung disease (ILD) 
b. Bullet 5 (Endocrine disorders): diabetes insipidus was added per current MedImmune 
recommendations. 
c. Last bullet was added, per current MedImmune recommendations: “Other inflammatory 
responses that are rare with a potential immune-mediated aetiology include, but are not 
limited to, myocarditis, pericarditis, and uveitis.” 
7. Section 8.3.1 (Durva and Treme Dose Modification due to toxicity): per FDA 
recommendations, added myocarditis to Pneumonitis/ILD bullet In Grades 1, 2, and 3. 
8. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 3 
Issue date: 23-OCT-2017 
Summary of Changes: 
1. The administration method for BI 1361849 was changed from the standard needle to the 
Pharmajet Tropis® device. 
a. The change from needle administration to Tropis® device resulted in different volume 
requirements for each of the BI 1361849 components. Thus 160 µg was changed to 80 µg 
and 200 µL was changed to 100 µL in the Synopsis and Sections 3.1.7.1, 6.3.3, and 6.4. 
b. Section 2.1 (BI 1361849 dose): the following additions/changes were made (changes in 
bold):  
“Due to the filling volume of 100 μL, the device allows for administration of half the 
previously established doses, i.e., 160 μg instead of 320 μg per antigen when using the 
same manner of administration of two inoculations per antigen and vaccination time 
point. Advantages include improved patient convenience, handling safety, ease, and 
reliability of intradermal administration. Preclinical data showed that using a needle-
free device such as the PharmaJet Tropis® device, the efficiency of delivery increases 
and protein production is higher even at half or a quarter of the administered dose, 
hence lower doses can be used. Clinical data from a Phase 2 trial, CV-9104-007, 
suggests that administration of half the dose by the PharmaJet Tropis® device results in 
at least similar immunogenicity compared to needle administration of the full dose. For 
this study, the Pharmajet Tropis® device will not be used for the administration of the 
BI 1361849 components.  Instead, standard intradermal injections using needles will be 
performed (see Section 6.3.3 for details). Allowing for a filling volume of 100 μL (80 μg) 
and 2 administrations per component, the recommended dose per each of the 6 


 
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antigen components will be 160 μg (2 x 80 µg), for a total of 960 μg (12 
administrations). 
c. Section 3.1.7.1 (Dose Evaluation Phase): the following note was added: 
“The Pharmajet Tropis® device will be used for the administration of the BI 1361849 
components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per 
component, the recommended dose per each of the 6 antigen components will be 
160 μg (2 x 80 μg), for a total of 960 μg (12 administrations).” 
d. Section 6.3.3 (BI 1361849 Administration): the following paragraph was added: 
“The Pharmajet Tropis® device will be used for the administration of the BI 1361849 
components. Allowing for a filling volume of 100 μL (80 μg) and 2 administrations per 
component, the recommended dose per each of the 6 antigen components will be 
160 μg (2 x 80 μg), for a total of 960 μg (12 administrations). Directions for use of the 
Pharmajet Tropis® device will be provided separately.” 
f. Section 6.3.3(BI 1361849 Administration): the following paragraph was deleted: 
“A 30-gauge needle will be used for the injection.  The needle should penetrate the skin 
at an angle of about 15 degrees and the injection should be administered slowly until a 
bubble appears underneath the skin surface.  Subcutaneous injection (characterized by a 
missing bubble after the injection) must be avoided as it may result in reduced efficacy of 
the vaccine.  However, if an injection is administered subcutaneously by error, the 
injection must not be repeated for this vaccination time point.  Incorrect injections will be 
documented.” 
2. Section 3.1.9 (DLT and MTD/RCD for the Combination Therapy): The following exception 
bullet was added to Point #3: “Grade 3 or 4 asymptomatic increases in amylase or lipase 
levels for which appropriate evaluation shows no clinical evidence of pancreatitis.” This was 
done to align with the amylase/lipase information in Section 8.3.1 dose modifications. 
3. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 4 
Issue date: 19-MAY-2018 
Summary of Changes: 
1. Synopsis: The following clarification was added (changes in bold: The dose evaluation phase is 
followed by an expansion phase, in which the cohort at the RCD for each arm is expanded to 
20 subjects (inclusive of the subjects from the dose evaluation cohort). 
2. Section 3.2 (Flowchart) 
a. Vital sign assessments were deleted from Cycle 2/Day 8, Cycle 4/Day 8, and Cycle 7/Day 
22, as these visits require blood collection only, and no drug is being administered; vital 
sign assessments are not required. 
b. Footnote e: the following note was added “Note: when durva vital assessments do not 
precede the BI 1361849 dose, pre-dose vital assessments must be done for BI 1361849.” 
This was added for clarification. 
c. Footnote g was updated for clarification of biopsy sample collections and to align with the 
details and updates in Section 4.3.1.1.  
3. Section 4.3.1.1 (Tumor Microenvironment) was re-organized and clarification was provided 
regarding the biopsy samples. It was clarified that on-treatment biopsy samples will only be 


 
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collected if pre-treatment fresh biopsy samples were provided (so that paired biopsies may 
be examined); other clarifications were also provided. The text was changed  
FROM: 
“A minimum of 25 slides (5-µm, formalin-fixed, paraffin embedded (FFPE)) will be requested 
from archival (diagnostic) or pre-treatment biopsy specimens and post-treatment (end of study, 
if clinically feasible) biopsy specimens to evaluate PD-L1 expression as assessed by 
immunohistochemistry, neoantigen signature and immune biomarker expression in tissue, and to 
assess the correlation of these evaluations with clinical response as well as changes in profiling 
associated with resistance.  Analyses may include the following: 
• 
Mutational burden, gene expression profiling, and immune profiling from before therapy 
• 
Immune markers of response and resistance in pre-treatment and post-treatment tumor 
biopsies. 
A fresh core biopsy (minimum 3 cores from lung tissue or 4 cores from another site) obtained 
within 60 days of study start will be required prior to study entry; archival sample may be used if 
pre-treatment biopsy is not feasible.  If possible, a post treatment biopsy will be collected 1 week 
after the 3rd or 5th BI 1361849 treatment. 
If possible and as determined by the Investigator, a minimum of 8 subjects in each arm will have 
fresh tissue sampling from which fine needle aspiration (FNA) can be also obtained for immune 
profiling.  
Remaining core biopsies will be formalin-fixed and paraffin-embedded as per institutional 
standards for further evaluation with immunohistochemistry (IHC) or tumor DNA/RNA extraction 
for microarrays sequencing or nanostring. 
Optional core biopsies will be obtained at the time of tumor progression or at the completion of 
treatment from subjects who consent to this procedure.  A minimum of 3 cores will be required.” 
TO: 
Samples: 
• 
A fresh core pre-treatment biopsy (minimum 3 cores from lung tissue or 4 cores from 
another site) obtained within 60 days of study start will be requested prior to study 
entry; archival sample may be used if a pre-treatment fresh biopsy is not feasible.  
• 
If a fresh core pre-treatment biopsy was obtained, an on-treatment biopsy will be 
collected 1 week after the 3rd or 5th BI 1361849 treatment, if feasible. This on-treatment 
biopsy should only be collected if a pre-treatment fresh biopsy was obtained so that 
paired biopsies may be examined. 
• 
Optional post-treatment core biopsies (minimum 3 cores from lung tissue or 4 cores 
from another site) will be obtained at the time of tumor progression or at the completion 
of treatment from subjects who consent to this procedure and if clinically feasible.   
• 
If possible and as determined by the Investigator, a minimum of 8 subjects in each arm 
will have fresh tissue sampling from which fine needle aspiration (FNA) can be also 
obtained for immune profiling.  
A minimum of 25 slides (5 µm formalin-fixed, paraffin embedded (FFPE)) will be requested from 
the biopsy specimens to evaluate PD-L1 expression as assessed by immunohistochemistry, 
neoantigen signature and immune biomarker expression in tissue, and to assess the correlation 
of these evaluations with clinical response as well as changes in profiling associated with 
resistance.  Analyses may include the following: 
• 
Mutational burden, gene expression profiling, and immune profiling from before therapy 
• 
Immune markers of response and resistance. 


 
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Remaining core biopsies will be formalin-fixed and paraffin-embedded as per institutional 
standards for further evaluation with immunohistochemistry (IHC) or tumor DNA/RNA extraction 
for microarrays sequencing or nanostring. 
4. Section 4.3.1.1.1 (Immunohistochemistry). Language was clarified (changes in bold): 
a. Paragraph 1: “Quantitative immunofluorescence will be used to evaluate multiple immune 
biomarkers simultaneously in FFPE archival tissue or in pre- and post-treatment biopsy 
samples, as available.” 
b. Paragraph 3: “In this study, a pre-treatment biopsy will allow the evaluation of PD-L1 and 
other immune biomarkers to determine correlation with response to combination therapy.  
In addition to PD-L1 immunohistochemistry, CD3, CD4 and CD8 immunostaining will be 
performed to evaluate the degree of immune infiltrate in tumor specimens pre-and post-
therapy, as available.  Finally, other markers of immune suppression (FoxP3 to stain T 
regulatory cells, TIM-3, Lag-3 and others) will be evaluated, as feasible.” 
5. Section 4.3.1.1.3 (Gene Expression). Language was clarified (changes in bold): 
“Inflammatory or immune-related gene expression signatures may serve as predictors of 
clinical benefit and will be evaluated in pre-treatment and post-treatment biopsies biopsy 
samples, as available.” 
6. Section 4.3.1.1.5 (Cytokines & Chemokines). Language was clarified (changes in bold): 
“Cytokine and chemokine environment will be determined on protein level in pre-and post-
treatment biopsies biopsy samples, as available.” 
7. Section 4.3.2 (Subject Evaluation and Statistics), Paragraph 2, Sentence 1. Language was 
clarified (changes in bold):  “The exploratory pharmacodynamic assessment of the 
immunologic changes in the tumor microenvironment will include the correlation between 
clinical activity and the expression level of PD-L1 and tumor-infiltrating lymphocyte (TILs) 
changes in biopsy samples, as available. biopsies pre and post-treatment.” 
8. Section 5.1 (Inclusion Criteria) #3 was modified for clarification (changes in bold): 
“Availability of archival (diagnostic) specimens or willing Willing to undergo a pre-treatment 
biopsy, or if not feasible, availability of archival (diagnostic) specimens.”  
9. Section 5.2 (Exclusion Criteria), #16 was clarified as follows (changes in bold): “Any condition 
that, in the clinical judgment of the treating physician, is likely to interfere with the 
interpretability of the data or prevent the subject from complying with any aspect of the 
protocol or that may put the subject at unacceptable risk.” This was updated to reflect 
current protocol language. 
10. Section 5.2 (Exclusion Criteria), #20 was changed FROM: “History of another primary 
malignancy except for: Malignancy treated with curative intent and with no known active 
disease ≥5 years before the first dose of study drug and of low potential risk for recurrence; 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease; Adequately treated carcinoma in situ without evidence of disease.” TO: “Active or 
prior malignancy except for history of other prior malignancy treated with curative intent 
which, in the opinion of the treating investigator and the Sponsor, has minimal risk of 
interfering with safety or efficacy endpoints of the study.”   
Rationale: The language was updated to be consistent with current standards. 
11. Section 6.5.2 (Monitoring for BI 1361849): the following Note was added for clarification: 
“Note: on dosing days when durvalumab vital assessments do not precede the BI 1361849 
dose, pre-dose vital assessments must be done for BI 1361849.” 


 
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12. Section 7.1.8 (AESIs): The section was updated and reorganized based on updated 
recommendations from Medimmune in the updated IB. Specifically: 
a. Endocrine disorders-deleted diabetes insipidus. 
b. Myocarditis and myositis/polymyositis were added 
c. Other inflammatory responses section was updated (changes in bold):  
“Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, myocarditis, pericarditis, sarcoidosis, 
uveitis, and other events involving the eye, skin, hematological and rheumatological 
events. 
13. Section 8.3.1 (Durvalumab and tremelimumab dose modification due to toxicity): Immune-
related AEs were updated based on updated Toxicity Mgt Guidelines from Medimmune 
(Dated 01Nov2017). Specifically, myocarditis, myositis/polymyositis were added; 
Diarrhea/colitis and endocrinopathies were updated. 
14. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 5 
Issue date: 06-AUG-2018 
Summary of Changes: 
1. The signature page was updated: 
a. Leena Gandhi was removed 
b. Local Sponsor in EU was added 
c. Coordinating Investigator in Germany was added 
2. Section 2.2 (Durvalumab and Tremelimumab Dose). Last paragraph was clarified (changes in 
bold): “The 1500 mg Q4W dosing of durvalumab and tremeimumab is recommended only for 
subjects with > 30kg body weight due to in order to limit endotoxin exposure.  Subjects with 
a body weight ≤ 30 kg are not eligible for enrollment in the current study.  See Section 3.1.7.1 
for additional details regarding the dose de-escalation cohort for durvalumab and for 
durvalumab and tremelimumab dose requirements for instances when a subject’s body 
weight drops to ≤ 30 kg while on the study.” 
3. Section 3.1.2 (Enrollment/Randomization).  
a. First paragraph was updated to reflect change in prioritization from Cohort A Expansion 
to Cohort B Expansion, based on discussion with BI: 


 
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b. Figure 1 was updated FROM: 
 
TO: 
 
4. Section 3.1.7.1 (Dose Evaluation Phase).  
a. Numbers 1 and 2 were added to the notes 
b. Clarification was provided to indicate that weight-based dosing for subjects whose body 
weight drops to ≤ 30 kg while on study only applies to durvalumab 1500 mg Q4W and 
tremelimumab when it is given with durvalumab 1500 mg Q4W. 


 
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5. Section 4.3.1.1.2 (DNA Sequencing). Information was updated to remove Dana Farber Cancer 
Institute as the assay facility. 
6.  Section 6.1.3 (Durvalumab Preparation). Clarification was provided to indicate that weight-
based dosing for subjects whose body weight drops to ≤ 30 kg while on study only applies to 
durvalumab 1500 mg Q4W. 
7.  Section 6.1.4 (Durvalumab Administration). Clarification was provided to indicate that a 0.2- 
or 0.22-μm in-line filter is required for durvalumab infusion. 
8. Section 6.2.3 (Tremelimumab Preparation). Clarification was provided to indicate that 
weight-based dosing for subjects whose body weight drops to ≤ 30 kg while on study applies 
to tremelimumab only when it is given along with durvalumab 1500 mg Q4W. 
9. Section 6.2.4 (Tremelimumab Administration). Clarification was provided to indicate that a 
0.2- or 0.22-μm in-line filter is required for tremelimumab infusion. 
10. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
11. Added EudraCT# to cover page. 
 
Amendment 6 
Issue date: 18-SEP-2018 
Summary of Changes: 
1. The signature page was updated because German sites will not be included in the study: 
a. Deleted Signature lines for Local Sponsor in EU and Coordinating Investigator in Germany. 
b. Deleted EudraCT# on cover page. 
2. Section 3.1.4 (Subject Population) and  
Section 5.1 (Inclusion Criterion #1).  
Changes in bold:  “Subjects with histologically confirmed metastatic NSCLC.  For subjects with 
known EGFR or ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine 
kinase inhibitor or ALK/ROS-1 inhibitor, respectively. Subjects must not have ALK 
rearrangement. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy and must 
not have had progression at or before 12 weeks after start of treatment.” 
Rationale: The reason for the change is that the number of patients who have not received 
anti-PD-1/PD-L1 antibody therapy is low due to the approval of pembrolizumab for first line 
in combination with chemotherapy as well as a single agent first line or after failure of 
platinum-based therapy as well as the approved indication for nivolumab and atezolizumab. 
Patients who received one of these therapies would now be eligible for this study. 
3. Section 5.2 (Exclusion Criterion #2). Language was updated based on changes in Inclusion 
Criterion 1 (changes in bold): “Prior treatment with anti-PD-1, PD-L1, or CTLA4 therapyor 
other immunotherapy.” 


 
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4. Sections 6.1.1 and 6.2.1 (Study Drug Information). The following correction was made: 
 
5. Section 6.1.3 (Durvalumab Preparation). The following changes were made to align with 
current Medimmune recommendations: 
 
6. Section 6.2.3 (Tremelimumab Preparation). The following changes were made to align with 
current Medimmune recommendations: 
a. 
 
b. 
 
7. Section 6.2.4 (Tremelimumab Administration). The following changes were made to align 
with current Medimmune recommendations: 
 
8. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 


 
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Amendment 6.1 
Issue date: 01-NOV-2018 
Summary of Changes: 
Section 5.1, (Inclusion Criterion #1): last sentence was changed to provide clarification.  
Changed FROM: “Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy and must not 
have had progression at or before 12 weeks after start of treatment.” 
Changed TO: “Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy. Subjects who 
received prior anti-PD-1/PD-L1 therapy must have progressed during or after treatment, but not 
prior to Week 12 of treatment.” 
 
Amendment 7 
Issue date: 21-MAY-2019 
Summary of Changes: 
1. Section 3.1.10.1 (Treatment Beyond Progression). The first paragraph was changed (changes 
in bold), as irRECIST is the primary method for determining response and progression in 
this study. 
“Subjects meeting criteria for radiographic progression by irRECIST RECIST 1.1 (Section 8.5) 
will be allowed to continue on therapy until confirmation of progression by irRECIST if the 
subject agrees and signs an appropriate informed consent form regarding continuation of 
treatment and as long as the following criteria are met at the discretion of the Investigator:” 
2. Section 5.3.1 (Non-permitted concomitant therapies). Criterion # 5 was updated as follows 
(changes in bold):  
“Drugs with laxative properties and herbal or natural remedies for constipation should 
generally be avoided through 90 days post last dose of tremelimumab because of the 
potential for exacerbation of diarrhea, but, for example, opiate-induced constipation may 
be treated with laxatives at the Investigator’s discretion.” 
3. Section 6.2.1 (Tremelimumab Study Drug Information). The following was added: 
Tremelimumab is also available in a 25 mg/vial format; the concentration remains 20 mg/mL. 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented on the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: Single-use vial 
Material: Clear glass 
Size: 2 mL 
Formulation 
Liquid solution containing 25 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.27 
mM disodium edetate dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 5.5. 
Active Ingredient 
Content 
Mass/Weight: 
25 mg/vial 
Volume: 
1.25 mL/vial 
Concentration: 
20 mg/mL 
Storage Conditions 
+2°C to +8°C (36°F to 46°F). Do not freeze. 
Labeling 
Product name, lot number, and storage conditions 
4. Section 6.3.2 (Preparation of Components of BI 1361849). The following paragraph was 
added:  “NOTE (per Amendment 7):  
The first lot for this study (Lot E142087-008L002) expired at the end of May 2019. 
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hours after reconstitution in Ringer Lactate Solution (the precipitate was identified as 
protamine and RNA). Therefore, F2409 must be used within 2 hours of reconstitution. It 
is recommended that all of the components should be administered within the 2-hour 
timeframe, if possible. If this is not feasible, the 4-hour in use period is still applicable to 
the other 5 components.” 
5. Formatting/administrative changes were implemented, as applicable. 
Amendment 8 
Issue date: 24-JUL-2019 
Summary of Changes: 
1. Section 5.1 Inclusion criteria 5. The following change was made (changes in bold): 
Lymphocyte count 
>800 ≥ 400 cells/µL. (See Section 3.3 for 
instructions for blood draws for PBMC collection.) 
2. Section 3.2 (Study Flowchart). Footnote L was added. 
3. Section 3.3 (Additional Instructions for Blood Draws for PBMC Collection) was added. 
 
Rationale for the changes: 
The original lymphocyte requirement of 800 cells/µL was intended to allow for enough PBMCs to be 
collected for correlative analyses. However, the requirement was not allowing otherwise qualified subjects 
to enroll in the study. As the restriction was intended only to optimize the PBMC collection, it was decided 
to lower the lymphocyte requirement to 400 cells/µL with adjustment to blood volume collection for 
PBMCs when appropriate for the particular subject (See Laboratory Manual for additional details on blood 
volume and weight restriction). 
 
Amendment 8.1 
Issue date: 17-SEP-2019 
 
Rationale for the changes: 
The decision was made not to enroll any subjects into the Control Group for Arms A and B. As the 
protocol was previously amended to allow subjects pretreated with PD-1/PD-L1 inhibitors, 
baseline correlative sample testing can serve the purposes of the Control Group. In addition, 
reported results of the Phase III MYSTIC, ARCTIC and NEPTUNE studies of durvalumab plus 
tremelimumab in NSCLC did not find the combination to be superior to standard of care 
chemotherapy making it inappropriate to recruit subjects to the control treatment arm with 
tremelimumab and/or durvalumab without vaccine. 
 
Summary of Changes: 
All references to the Control Group for Arms A and B were removed. The following sections were 
affected: 
• 
Synopsis 
• 
Section 3.1 (Study Design) 
• 
Section 3.1.2 (Enrollment Randomization), including Figure 1 (Enrollment Schema) 
• 
Section 3.1.6 (Sample Size Considerations) 
• 
Section 3.1.7 (Treatment Arms and Treatment Schema) 
• 
Section 3.1.7.2 (Dose Expansion Phase) 


 
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• 
Section 3.2 (Study Flowchart).  
o Removed footnote “I” which referenced the Control Group for Arm A/Arm B. 
o Footnote “L” (“See Section 3.3 for instructions for blood draws for PBMC collection”) 
was repositioned as Footnote “i”. Note: Footnote L was added per Amendment 8. 
• 
Section 4.3.1.2.1 (Immune Monitoring for Responses to BI 1361849 Vaccine). The last 2 
sentences in the first paragraph were deleted as they referred to the Control Group. 
• 
Section 4.3.2 (Subject Evaluation and Statistics). The last bullet was changed as follows: 
 
Amendment 9 (27-AUG-2020) 
 
NOTE: Amendment 9 was not released. Further clarifications were added and all changes were 
incorporated into Amendment 9.1. 
 
Amendment 9.1 
Issue date: 01-SEP-2020. 
 
1. Section 4.3.1.2 (Biological Activity in Blood Samples): Based on the decision of 
CureVac/Boehringer Ingelheim to discontinue immune monitoring testing, the collection of 
blood samples for this purpose was also discontinued. A note was added to Section 4.3.1.2 to 
indicate that the following sample collections were discontinued: 
• 
Blood for PaxGene RNA and DNA 
• 
Blood (PBMC and plasma) for flow cytometry and biological assays 
• 
Blood for humoral responses and other biomarkers 
Blood collections for exosomal profiling and tumor biopsy collections were continued. 
2. ctDNA testing was removed from Section 4.3.1.2 . 
3. Section 3.2 (Study Flowchart). 
• 
Notes were added to indicate discontinued blood collection for PaxGene RNA/DNA, 
PBMC, and humoral responses 
• 
Notes were added to footnotes i, J, and k to indicate the discontinuation of blood 
collection for PaxGene RNA/DNA, PBMC, and humoral responses 
• 
Note was added to footnote J to indicate that Visits 6, 14, and 28 would no longer be 
required per Amendment 9.1 
• 
ctDNA was deleted from the blood for exosomal profiling collection 
4. References to the Note in Section 4.3.1.2 were also added to Section 3.3 (Additional 
Instructions for Blood Draws for PBMC Collection), Section 4.3.1 (Endpoints and Assessment 
Methods); Section 4.3.1.2.1 (Immune Monitoring for Responses to BI 1361849 Vaccine), and 
Section 4.3.2 (Subject Evaluation and Statistics). 
5. Section 5.1 (Inclusion Criteria): The following note was added to criterion #2 for clarification: 
NOTE: Per Amendment 9.1, biopsies should not be taken from a target lesion unless that is 
the only suitable lesion, in which case it should be of reasonable size. 


 
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The same note was added to Section 4.3.1.1 (Tumor Microenvironment) for item #1 and to 
Section 3.2 (Flowchart), footnote g, item #1. 
Amendment 10.0 
Issue date: 30-JUL-2021. 
Boehringer Ingelheim (BI), one of the Financial Sponsors of the study, has terminated the 
agreement with the Regulatory Sponsor, the Ludwig Institute for Cancer Research (LICR); thus, 
the final data cutoff date for the study will be 31 October 2021, with a study termination date of 
17 November 2021. As a result, the following changes were made to the protocol: 
1. All post study follow-up will be discontinued as of 31 October 2021. The following note was 
added to Sections 3.1.15 (Duration of Study), 3.1.16 (On Study and Post Study Follow-up), 
and 4.2.1 (Efficacy Endpoints and Assessment Methods): 
“NOTE: Per Amendment 10.0, all post study follow-up will be discontinued as of 31 October 
2021.”  
2. Section 4.3.1 (Biological Activity Endpoints and Assessment Methods) and Section 4.3.2 
(Subject Evaluation and Statistics). The following note was added: “NOTE: Per Amendment 
10.0, all correlative testing will be discontinued, with the possible exception of PD-L1 
expression and whole exome sequencing.” 
3. Section 3.2 (Flowchart). Footnote “L” was added:  “Per Amendment 10, Post Study Follow-up 
will be discontinued as of 31 October 2021; and all correlative testing will be discontinued, 
with the possible exception of PD-L1 expression and whole exome sequencing.” 
4. In addition to the above changes, AstraZeneca provided updated language for Section 7.1.2 
(Additional reporting requirements for this study). Section 7.1.2.4 (New Cancers) and Section 
7.1.2.5 (Deaths) were added. 
 
 
 


 
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8.2 Participating Study Sites, Investigators and Staff, Laboratories, and 
Sponsor Information 
This information is provided in the Clinical Study File. 
 
 


 
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8.3 Dose Adjustments and Delays for Durvalumab and Tremelimumab 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
8.3.1 Durvalumab and Tremelimumab Dose Modification Due to Toxicity 
Durvalumab (MEDI4736) and tremelimumab administration may be modified or discontinued as 
a result of toxicities as described in the table below.  
Additional information and guidance regarding dose modification due to toxicity are provided 
from Medimmune in the following guidelines: 
“Medimmune’s Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 (durvalumab) 
Monotherapy or Combination therapy with Tremelimumab or Tremelimumab monotherapy).” 
Dose modifications will not be required for AEs that are clearly not attributed to durvalumab or 
tremelimumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant. 
MEDI4736 (M) and Tremelimumab (T) Dose Modification Due to Toxicity 
Note: If M and T dosing is held temporarily until resolution of the event as per instructions 
below, treatment should resume at the next scheduled treatment date. 
Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in 
the absence of a clear alternative etiology.  Maximum supportive care, including 
immunosuppressive medications, such as high dose steroids, is allowed to induce resolution 
of the event.  However, infliximab should not be used for management of immune-related 
hepatitis. 
In addition to the criteria for permanent discontinuation of M and T depicted below, 
permanently discontinue M and T also for:  
• Any Grade rash with bullous skin formations. 
• Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen. 
• Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
• Any Grade biopsy-proven immune-mediated myocarditis. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease and myocarditis, consider holding M and T dosing as 
clinically appropriate and during diagnostic work-up for other etiologies. 


 
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Grade 2 
• 
In general, hold M and T until resolution to ≤ Grade 1 and after the end of any steroid taper, and 
discontinue M and T permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities).  Criteria for temporary hold or permanent discontinuation of M and T may differ 
by event as detailed below. 
• 
For myositis/polymyositis, hold M and T until resolution to ≤ Grade 1; permanently discontinue M 
and T if it does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory 
insufficiency. 
• 
For pneumonitis/interstitial lung disease and myocarditis, the decision to reinitiate M and T upon 
resolution shall be based upon treating physician’s clinical judgment (as long as the event does not 
meet DLT criteria). 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, follow 
general instructions above, but always discontinue M and T permanently if there are signs of 
respiratory insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism and isolated Type 1 diabetes mellitus, 
follow general instructions above, but subjects may be retreated if the endocrinopathy is 
controlled and the subject is clinically stable while requiring steroid doses of ≤ 10 mg/day 
prednisone equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, isolated Type 1 
diabetes mellitus treated with appropriate diabetic therapy, and for sensory 
neuropathy/neuropathic pain, holding M and T is at the discretion of the Investigator. 
• 
For elevated creatinine or rash, M and T should be held until resolution to ≤ Grade 1 or baseline 
and after completion of steroid taper. 
• 
For vitiligo, no dose modification required. 
Grade 3 
• 
In general, hold M and T until resolution to ≤ Grade 1, and after the end of any steroid taper, and 
discontinue M and T permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities and rash).  Criteria for permanent discontinuation of M and T may differ by event 
as detailed below. 
• 
For myositis/polymyositis, follow Grade 2 instructions above. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), apply 
respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For diarrhea/colitis, permanently discontinue M and T if toxicity does not improve to ≤ Grade 1 
within 14 days. 
• 
For pneumonitis/interstitial lung disease, myocarditis, and elevated serum creatinine (e.g., 
nephritis or renal dysfunction), always discontinue M and T permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold M and T, and if complete work up 
shows no evidence of pancreatitis, M and T may be continued. 
• 
For hepatitis, discontinue M and T permanently for (1) transaminases or bilirubin not resolving to ≤ 
Grade 1 or baseline within 14 days, (2) transaminases > 8 × the upper limit of normal (ULN) or 
bilirubin > 5 × ULN, or (3) any case meeting Hy’s law criteria (as defined in FDA Guidance Document 
“Drug-Induced Liver Injury”). 
• 
For rash, M and T should be held until resolution to ≤ Grade 1 or baseline. 
 


 
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MEDI4736 (M) and Tremelimumab (T) Dose Modification Due to Toxicity 
Grade 4 
• 
In general, discontinue M and T permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold M and T, and if complete work up 
shows no evidence of pancreatitis, M and T may be continued.  
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of M and T may be decreased 50% or temporarily interrupted until resolution of 
the event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at the 
discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion reactions 
Grade 2: 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion rate. 
Grade 3 and 4: 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2  
• 
Hold M and T until resolution to ≤ Grade 1 or baseline, and discontinue M and T permanently if 
such resolution does not occur within 60 days. 
Grade 3 
• 
Hold M and T. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline 
within 14 days, resume M and T administration at next scheduled dose. Otherwise, discontinue M 
and T permanently. 
Grade 4 
• 
In general, discontinue M and T permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment and in consultation with the Sponsor. 
 
8.3.2 Durvalumab and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities 
Durvalumab and tremelimumab administration may be modified or discontinued as a result of 
events other than toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby 
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1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 
be made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 21 days. All resulting protocol deviations should be documented. 
2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
4. If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary.   
 


 
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8.4 BI 1361849 Toxicity Management and Dose Modification  
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
In case of adverse events considered related to BI 1361849 or to the combination of BI 1361849 
with durvalumab or with durvalumab and tremelimumab, treatment with the vaccine (or with 
the vaccine as well as durvalumab and/or tremelimumab) may have to be withheld. If a subject 
experiences any ≥ CTCAE Grade 3 treatment-related AE not fulfilling the criteria for permanent 
discontinuation, study drug treatment may be resumed after the toxicity has returned to 
baseline or Grade ≤ 1 within a time period ≤ 4 weeks for vaccination. No dose reduction of the 
vaccine dose is foreseen.  
Administration of BI 1361849 must be withheld in the following cases and may be postponed to 
later time points within the allowance windows defined in the table below: 
• 
Subject has fever ≥ 38.5 °C or other signs of an acute systemic infection on the day of 
administration. 
• 
Subject has a suspected autoimmune disease - in this case BI 1361849 should be 
omitted until the diagnosis is confirmed or excluded. In case of a confirmed 
autoimmune disease the Sponsor should be contacted to decide whether BI 1361849 
should be permanently discontinued. 
• 
Subject has ongoing BI 1361849 related systemic toxicity of initially CTCAE grade 3 or 
higher that has not yet resolved to at least grade 1 or baseline. 
• 
Subject has a suspected pneumonitis or other interstitial lung disease (ILD). In this case 
BI 1361849 should be omitted until the diagnosis is confirmed or excluded. In case of 
confirmed pneumonitis or other ILD, BI 1361849 should be discontinued. 
• 
Subject has an important medical event that in the investigators opinion might be 
worsened by the administration of BI 1361849 (e.g. acute cardiac events that may 
deteriorate in case of fever induced by BI 1361849). 
Vaccinations should always be administered within the planned time windows given in Section 
3.2.  However, vaccinations may have to be delayed to allow for recovery of AEs prior to 
continuation of vaccine treatment. For these circumstances, maximal allowance windows have 
been specified below. After the delayed vaccination all subsequent vaccinations must be 
continued within the schedule relative to the first vaccination presented in the flow chart. If a 
vaccination cannot be administered within the maximal allowance windows for an 
administration time point, the vaccine administration for this time point has to be omitted, and 
further vaccinations should be given at subsequent planned time points according to the 
flowchart in Section 3.2.  


 
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Maximal allowance windows due to AEs: 
Vaccination  
Scheduled Week  
(Day 1 of) 
Total extended visit window 
from originally scheduled 
vaccination (days) 
2nd  
2 
3 
3rd, 4th,5th, 6th, 7th 
3, 5, 7, 9, 11 
7 
8th, 9th  
13, 17 
10 
10th and continuing 
21, 27 and every 6 weeks 
28 
 
In the event that prior to a planned blood sampling time point for immunomonitoring, the 
immediately preceding vaccination has to be delayed or omitted, the blood sampling has to be 
delayed in the same fashion to ensure that the blood sample has been obtained within 7 ± 2 
days after the immediately preceding vaccination.  In the event that the vaccination had to be 
omitted, blood sampling should occur after the next subsequent vaccine administration. 
The following toxicities prohibit continuation of study treatment: 
• 
Grade ≥ 3 study treatment-related anaphylactic reactions.  
• 
Study treatment related AEs that are potentially life threatening or may result in 
permanent disability.  
• 
Grade ≥ 3 pneumonitis pneumonitis/inflammatory lung disease, or other ILD  
• 
Grade ≥ 3 study treatment-related AEs not recovering to baseline or grade 1 within 4 
weeks in case of vaccination. The Sponsor should be contacted in case it is considered 
justifiable to continue treatment at a later time point, to approve continuation of 
treatment of BI 1361849, which in any case must not occur before the AE finally has 
resolved or recovered to baseline or grade 1. 
• 
Grade ≥ 3 study treatment-related AEs that reoccur after re-exposure to BI 1361849 
(with the exception of local reactions at individual injections sites if they are considered 
tolerable by the investigator and the patient).  
Note: After occurrence of related grade 1 or 2 anaphylactic reactions, a re-exposure may be 
considered, at the investigator’s discretion, if anti-allergic premedication will be added 
(antihistaminergic agents and/or a steroid). A minimal acceptable allergy prophylaxis regimen 
will be 50 mg oral prednisone, to be taken at 13 hours, 7 hours and 1 hour prior to 
vaccination (or other equivalent) and/or 50 mg diphenhydramine i.v. 1 hour prior to 
vaccination (or other equivalent). 
 
 
 


 
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8.5 RECIST 1.1 and irRECIST Guidelines  
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines were revised in 2009 as 
RECIST 1.1.(31) These guidelines have been the widely accepted criteria to assess response and 
progression in solid tumors; however, limitations have been noted in the use of RECIST 1.1 for 
immunotherapy trials. With immunotherapeutic agents, clinical trials have shown that complete 
response, partial response, or stable disease status can still be achieved after an initial increase 
in overall tumor burden, and regression of initial lesions may occur despite development of new 
lesions. The Immune-related Response Criteria (irRC) were developed to address the need for 
response criteria in an immunotherapy setting.(32)  The main difference with irRC was that it 
considered the subject's total tumor burden at each subsequent assessment and required 
confirmation of suspected disease progression with subsequent imaging, approximately four 
weeks later.  In addition, a greater number of lesions (10 vs. 5) were measured in a 
bidimensional manner instead of unidimensionally as in RECIST 1.1.  In 2013, Nishino et al. 
demonstrated that immune-related response criteria using unidimensional measurements were 
highly concordant with the bidimensional results of irRC, but with less measurement 
variability.(33)  Based on these findings and in order to utilize both the established criteria of 
irRC and RECIST 1.1, the two systems have been adapted, modified, and combined into the 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).(34)  The adapted 
irRECIST criteria are modifications to the irRC, incorporating the findings of Nishino et al. and the 
advantages of RECIST 1.1 while overcoming the shortcomings of each of the other guidelines.   
The guidelines for RECIST 1.1 are summarized below, followed by a summary for irRECIST. 
RECIST 1.1 
The following section outlines the RECIST 1.1 guidelines as published (31) and as summarized by 
National Cancer Institute for CTEP-involved clinical trials.   
I. 
Disease Parameters for RECIST 1.1 
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 1.1 criteria. 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
NOTE for irRECIST: During target lesion selection the radiologist will consider information on 
the anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, 
surgery, etc.). Lesions undergoing prior intervention will not be selected as target lesions 
unless there has been a demonstration of progress in the lesion. 


 
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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 subject, these are preferred for selection 
as target lesions. 
NOTE for irRECIST:  
Lesions that are partially cystic or necrotic can be selected as target lesions. The longest 
diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of all 
target lesions at baseline. If other lesions with a non-liquid/non-necrotic component are 
present, those should be preferred. 
Brain lesions detected on brain scans can be considered as both target or non-target lesions 
depending on the protocol definition. 
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. 
Non-target lesions.  All other lesions (or sites of disease) including any non-measureable as well 
as 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.  


 
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II. 
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 4 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. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
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 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 


 
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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 alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published.(35-37)  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer.(38)  
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:  
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. 


 
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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. 
III. 
Response Criteria for RECIST 1.1 
 
A. 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 
B. 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 
subject 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). 
C. 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 subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


 
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1. For Subjects 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 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      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: 
Subjects 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. 
 
2. For Subjects 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 end-
point for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
 
D. 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.  
 


 
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irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. (34) are presented 
below. 
I. 
Baseline Assessments in irRECIST 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1. One new definition is 
added: If a subject has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-up time 
points unless new measurable lesions are identified and contribute to the total measured tumor 
burden (TMTB).  irND is a valid assessment in studies with adjuvant setting where the protocol 
and study design allow the inclusion of subjects with no visible disease. 
II 
Follow-up Assessments in irRECIST 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not automatically 
indicate progression.  Instead, all measured lesions (baseline-selected target lesions and new 
measurable lesions) are combined into the total measured tumor burden (TMTB) at follow up.  
Baseline-selected target lesions and new measurable lesions are NOT assessed separately. 
Measurements of those lesions are combined into the TMTB, and one combined assessment 
provided. 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
time point), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in 
short axis for new measurable lymph nodes. New measurable lesions should be prioritized 
according to size, and the largest lesions elected as new measured lesions.  
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non-target 
lesions primarily contributes to the overall response assessments of irCR and irNon-CR/Non-PD 
(irNN). Non-target lesions do not affect irPR and irSD assessments. Only a massive and 
unequivocal worsening of non-target lesions alone, even without progress in the TMTB is 
indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target lesions can never 
convert to measurable lesions, not even if they increase in size at subsequent time points and 
become measurable. Only true new lesions can be measured and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions  
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new non-
measurable lesions leads to an overall assessment of irPD for the time point. Persisting new 
non-measurable lesions prevent irCR.  


 
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III 
Overall Assessments for irRECIST 
The irRECIST overall tumor assessment is based on TMTB of measured target and new lesions, 
non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment, the SumD of 
the target lesions and of new, measurable lesions (up to 2 new lesions per organ, total 5 new 
lesions) are added together to provide the total measurable tumor burden (TMTB). 
Overall Assessments by irRECIST 
Complete Response 
(irCR) 
Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 
Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions 
• 
If new measurable lesions appear in subjects with no target lesions at 
baseline, irPD will be assessed. That irPD time point will be considered a new 
baseline, and all subsequent time points will be compared to it for response 
assessment. irPR is possible if the TMTB of new measurable lesions 
decreases by ≥ 30% compared to the first irPD documentation 
• 
irRECIST can be used in the adjuvant setting, in subjects with no visible 
disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. These 
subjects can achieve a response if the TMTB decreases at follow-up, as a sign 
of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease 
(irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive Disease 
(irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan may be recommended for subjects 
with a minimal TMTB %-increase over 20% and especially during the flare time-
window of the first 12 weeks of treatment, depending on the compound efficacy 
expectations, to account for expected delayed response. 
• 
In irRECIST a substantial and unequivocal increase of non-target lesions is 
indicative of progression. 
• 
IrPD may be assigned for a subject with multiple new non-measurable 
lesions if they are considered to be a sign of unequivocal massive worsening 
Other 
irNE: used in exceptional cases where insufficient data exist.  
irND: in adjuvant setting when no disease is detected 
irNN: no target disease was identified at baseline, and at follow-up the subject 
fails to meet criteria for irCR or irPD 
 
 


 
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8.6 Exploratory Assessment of Correlative Immunologic Research 
Please refer to the Study Laboratory Manual for information on testing to be done and 
instructions on specimen handling and logistics. 
 
 


 
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8.7 ECOG Performance Status 
Eastern Cooperative Oncology Group Performance Status   
Grade 
ECOG PS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all 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. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Reference: (39) 
 
 
 


 
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8.8 List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CD 
Cluster of differentiation 
CI 
confidence intervals  
CR 
Complete response 
CRF 
Case report form 
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4  
DC 
Dendritic cell 
DCR 
Disease Control Rate 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
FNA 
Fine needle aspiration 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GMP 
Good manufacturing practice 
HCC 
hepatocellular carcinoma 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
ICS 
intracellular cytokine staining 
IL 
interleukin 
ILD 
Interstitial lung disease 
IND 
Investigational new drug 
IMP 
Investigational medicinal product 
IP 
Investigational product 
irAE 
Immune-related adverse event 
irRC 
immune-related response criteria 


 
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irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous 
IRB 
Institutional Review Board 
LICR 
Ludwig Institute for Cancer Research 
mAb 
Monoclonal antibody 
MDSC 
myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-small cell lung cancer 
NK 
Natural killer 
ORR 
Objective Response Rate 
OS 
Overall survival 
OVA 
ovalbumin 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed death-1  
PD-L1 
Programmed death ligand 1 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
Q4W 
Every 4 weeks 
QTc 
corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RCC 
Renal cell carcinoma 
RCD 
Recommended combination dose 
SAE 
Serious Adverse Event 
SCCHN 
squamous cell carcinoma of the head and neck  
SD 
Stable disease 
TAA 
Tumor-associated antigens  
TIL 
tumor-infiltrating lymphocyte 
TME 
Tumor microenvironment 
TMTB 
Total Measured Tumor Burden  
Tregs 
regulatory T-cells 
ULN 
Upper limit of normal 
WFI 
Water for Injection 
 
 


 
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Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
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Antonia S, Goldberg S, Balmanoukian A, et al.  Phase 1b Study of MEDI4736, a 
programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a 
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Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III 
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Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II 
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Fotin-Mleczek M, Zanzinger K, Heidenreich R, Lorenz C, Thess A, Duchardt KM, et al. 
Highly potent mRNA based cancer vaccines represent an attractive platform for combination 
therapies supporting an improved therapeutic effect. J Gene Med. 2012;14(6):428-39. 
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Fairman D, Narwal R, Liang M, et al.  Pharmacokinetics of MEDI4736, a fully human anti-
PDL1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol. 
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Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K. Population pharmacokinetic 
and pharmacodynamics analysis of tremelimumab in patients with metastatic melanoma. J Clin 
Pharmacol. 2014;54(10):1108-16. 
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Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab 
in cancer patients based on population pharmacokinetic analysis. Pharm Res. 2006;23(6):1275-
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Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
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Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
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Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
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Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya N, Hodi F. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clin Cancer Res. 2013;19(14):3936-43. 
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Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response criteria: 
irRECIST. Annals of Oncology ESMO 2014 Poster. 2014;25 (Suppl 4):iv361-iv72. 
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Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New 
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Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility 
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response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
 

SAP_001.pdf: 
 
Ludwig Institute for Cancer Research 
 
Statistical Analysis Plan 
 
A Phase 1/2 Study of Combination Immunotherapy and mRNA 
Vaccine in Subjects with Non-small Cell Lung Cancer (NSCLC) 
Protocol Number 
LUD2014-012-VAC 
 
NCT03164772 
 
Amendment 9.1, 01-SEP-2020 
 
SAP Version 
3.0 (09DEC2020) 
 
Prepared By: 
Advanced Clinical 
10 Parkway North, Suite 350 
Deerfield, IL 60015 
 
 


TABLE OF CONTENTS 
1.0 
PURPOSE ............................................................................................. 1 
2.0 
OVERALL STUDY DESIGN AND OBJECTIVES ....................................... 1 
2.1 
Trial Objectives .................................................................................. 1 
2.2 
Study Endpoints ................................................................................. 2 
2.3 
Trial Design and Trial Procedures ........................................................ 3 
2.4 
Treatments and Assignment to Treatments .......................................... 4 
2.5 
Determination of Sample Size .............................................................. 4 
3.0 
GENERAL ANALYSIS CONVENTIONS ................................................... 5 
3.1 
General Conventions ........................................................................... 5 
3.2 
Trial Periods ....................................................................................... 5 
3.3 
Visit Windows ..................................................................................... 6 
3.4 
Baseline ............................................................................................. 6 
4.0 
ANALYSIS POPULATIONS .................................................................... 6 
4.1 
Intent-to-Treat Population .................................................................. 6 
4.2 
Per-Protocol Population (Clinical Efficacy) ............................................. 6 
4.3 
Per-Protocol Population (DLT Assessments) ......................................... 7 
5.0 
SUBJECT DISPOSITION ........................................................................ 7 
6.0 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................... 8 
6.1 
Demographic Characteristics ............................................................... 8 
6.2 
Medical History ................................................................................... 8 
6.3 
Prior and Concomitant Medications and Procedures .............................. 9 
7.0 
EFFICACY ANALYSIS ........................................................................... 9 
7.1 
Response Rate ................................................................................... 9 
7.2 
Objective Response Rate (ORR) .......................................................... 9 
7.3 
Disease Control Rate (DCR) .............................................................. 10 
7.4 
Progression-free Survival (PFS) ......................................................... 10 
7.5 
Overall Survival (OS) ........................................................................ 11 
7.6 
Duration of Response (DoR) .............................................................. 11 
7.7 
Analysis of Time to Event (TTE) Variables .......................................... 11 
8.0 
TRIAL DRUG EXPOSURE AND COMPLIANCE ..................................... 12 


9.0 
SAFETY ANALYSIS ............................................................................ 12 
9.1 
Adverse Events ................................................................................ 12 
9.1.1 
Treatment-Emergent Adverse Events ................................... 13 
9.1.2 
Adverse Events of Special Interest (AESIs) .......................... 15 
9.2 
Clinical Laboratory Data .................................................................... 15 
9.3 
Vital Signs and Weight ...................................................................... 17 
9.4 
Electrocardiograms ........................................................................... 17 
9.5 
ECOG Performance ........................................................................... 18 
9.6 
Physical Examinations ....................................................................... 18 
9.7 
Pregnancy Testing ............................................................................ 18 
10.0 
EXPLORATORY ANALYSIS ................................................................ 18 
11.0 
STATISTICAL/ANALYTICAL ISSUES ................................................... 19 
11.1 
Handling of Dropouts or Missing Data ................................................ 19 
11.2 
Safety Data Handling ........................................................................ 19 
11.3 
Coding Dictionaries ........................................................................... 20 
11.4 
Pooling of Centers in Multi-Center Trials............................................. 20 
11.5 
Multiple Comparisons/Multiplicity ....................................................... 20 
11.6 
Examination of Subgroups ................................................................ 20 
11.7 
Interim Analysis and Data Monitoring ................................................ 20 
12.0 
QUALITY CONTROL .......................................................................... 20 
13.0 
TABLES AND LISTING CONVENTIONS ............................................... 21 
14.0 
REFERENCES .................................................................................... 22 
15.0 
RECORD RETENTION ........................................................................ 22 
16.0 
CHANGE HISTORY ............................................................................ 23 
17.0 
APPENDICES...................................................................................... 24 
17.1 
Appendix A: Study Flowchart............................................................. 24 
17.2 
Appendix B: Drug Administrative Schedules per Cycle ......................... 27 
 
 


ACRONYMS 
Below is the list of acronyms that will be used throughout this document. 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
CI 
confidence intervals 
CR 
Complete response 
CTCAE V.4.03 
Common Terminology Criteria for Adverse Events v. 4.03 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4 
DNA 
Deoxyribonucleic Acid 
DCR 
Disease Control Rate 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
ILD 
Interstitial lung disease 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
d
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-L1 
Programmed death ligand 1 
PFS 
Progression free survival 
PR 
Partial response 
Q4W 
Every 4 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RCD 
Recommended combination dose 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SD 
Stable disease 
TEAE 
Treatment Emergent Adverse Event 
TIL 
tumor-infiltrating lymphocyte 
TME 
Tumor microenvironment 


 
Sponsor:  Ludwig Institute for Cancer Research.         
Protocol Number: LUD2014-012-VAC.   
 
CONFIDENTIAL  
SAP Version: 3.0   
Effective Date: 09DEC2020  
 
  Page 1 of 27 
 
1.0 PURPOSE  
This SAP describes the methods to be used in the analysis of trial data from clinical protocol “A 
Phase 1/2 Study of Combination Immunotherapy and mRNA Vaccine in Subjects with Non- 
small Cell Lung Cancer (NSCLC)” in order to answer the trial objective(s), and is based on 
Amendment 9.1 of the trial protocol (LUD2014-012-VAC), dated 01 September 2020.   
Populations for analysis, data handling rules, statistical methods, and formats for data 
presentation are described within this document.  The statistical analyses and summary 
tabulations described in this SAP will provide the basis for the results sections of the CSR for 
this trial. The SAP outlines any differences in data analysis methods relative to those planned in 
the trial protocol.  Any changes to the data analysis methods after the SAP is finalized will be 
described in the CSR. 
2.0 OVERALL STUDY DESIGN AND OBJECTIVES 
2.1 
Trial Objectives 
This study will evaluate the safety and efficacy of the addition of a vaccine therapy (BI 1361849, 
previously known as CV9202) to 1 or 2 checkpoint inhibitors (durvalumab and tremelimumab) 
for NSCLC. The study has two phases; the dose evaluation phase and the dose expansion phase. 
In the dose expansion phase, there are two cohorts as follows: 
Arm A: mRNA Vaccine [BI 1361849 (formerly CV9202)] + anti-PD-L1 [durvalumab] 
Arm B: mRNA Vaccine [BI 1361849] + anti-PD-L1 [durvalumab] + anti-CTLA-4 
[tremelimumab]. 
The primary trial objectives are: 
• Dose evaluation Phase: To evaluate safety and tolerability, including Dose Limiting 
Toxicities (DLTs) and Recommended Combination Dose (RCD) of a combination 
immunotherapy with durvalumab or durvalumab and tremelimumab together with an 
RNA vaccine BI 1361849. 
• Expansion Phase: To evaluate safety and tolerability of a combination immunotherapy 
with durvalumab or durvalumab and tremelimumab together with an RNA vaccine BI 
1361849. 
The secondary trial objective is: 
• To evaluate the clinical efficacy of the combination immunotherapy for all subjects in 
both the dose evaluation and the dose expansion phases. 
The exploratory trial objective is: 


  
Sponsor:  Ludwig Institute for Cancer Research.         
Protocol Number: LUD2014-012-VAC.   
 
 
CONFIDENTIAL                                   SAP Version: 3.0                       Effective Date: 09DEC2020  
 
Page 2 of 27 
 
• To evaluate Biologic Activity and the effects on tumor microenvironment, and immune 
response for all subjects in both the dose evaluation and the dose expansion phases. 
2.2 
Study Endpoints 
Primary Endpoints 
The primary endpoint of the combination therapy of durvalumab and tremelimumab are: 
• Dose- Limiting Toxicities (DLTs). DLTs are defined as any adverse events that are 
possibly, probably, or definitely related to the administration of durvalumab, 
tremelimumab, or BI 1361849 components.  This applies to Dose Evaluation subjects 
during the DLT Evaluation period. 
• Safety and tolerability evaluated using CTCAE 4.03. 
• Recommended Combination Dose (RCD) determined in Dose Evaluation Phase. 
The safety endpoints for this study include: 
• Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) 
• Clinical laboratory tests (hematology and chemistry) 
• Vital signs and weight measurements  
• ECG  
• ECOG performance status evaluation  
• Any other medically indicated assessments, including subject interviews  
• All safety analyses will be reported separately for Arm A and Arm B 
The Clinical efficacy endpoints will be assessed by irRECIST and RECIST 1.1 and will include: 
• Objective Response rate (ORR) at 8 and 24 weeks.  ORR is defined as the percentage of 
subjects meeting criteria of Complete Response (CR) or Partial Response (PR) over a 
period of at least 4 weeks. 
• Duration of Response (DoR). DoR is defined as the interval between the date of earliest 
determination of CR or PR to the date of earliest determination of PD, or to the date of 
death, if PD does not occur. 
• Disease Control rate (DCR). DCR is defined as the percentage of subjects meeting 
criteria of Stable Disease (SD), PR, or CR over a period of at least 4 weeks.  
• Progressive Free Survival (PFS) at 8 and 24 weeks. PFS is defined as the interval 
between the date of first dose to the date of earliest determination of Progressive Disease 


  
Sponsor:  Ludwig Institute for Cancer Research.         
Protocol Number: LUD2014-012-VAC.   
 
 
CONFIDENTIAL                                   SAP Version: 3.0                       Effective Date: 09DEC2020  
 
Page 3 of 27 
 
(PD), or to the date of death, if PD does not occur.  Week 8 corresponds to Cycle 3 Day 1 
and Week 24 corresponds to Cycle 7 Day 1. 
• Overall Survival (OS). OS is defined as the interval between the date of first dose until 
the date of death or the date of last follow-up. 
• All efficacy analyses will be reported separately for Arm A and Arm B.  
Pharmacodynamics analyses on biologic activity related to study treatment will be performed for 
all subjects who receive at least one dose of any study drug.  These analyses will not be 
performed by Advanced Clinical but will be conducted by the Sponsor’s designated 
pharmacodynamics experts/vendors and the results will be summarized separately. 
2.3 
Trial Design and Trial Procedures 
This is an open-label multicenter 2-arm study to evaluate the safety and preliminary efficacy of 
the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors for NSCLC: 
• Arm A: mRNA Vaccine [BI 1361849 (formerly CV9202)] + anti-PD-L1 [durvalumab]. 
• Arm B: mRNA Vaccine [BI 1361849] + anti-PD-L1 [durvalumab] + anti-CTLA-4 
[tremelimumab]. 
For each arm of the study, there is a dose evaluation phase in which the Recommended 
Combination Dose (RCD) is determined according to a standard 3 + 3 design. For Arm A, the 
RCD of BI 1361849 + durvalumab is determined. The starting dose of durvalumab is 1500 mg 
with possible de-escalation to 750 mg; the dose for BI 1361849 remains constant at 12 x 80 ug. 
The 1500 mg Q4W dosing of durvalumab is recommended only for subjects with > 30kg body 
weight.  Subjects with a body weight ≤ 30 kg are not eligible for enrollment in the current study. 
If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will receive weight-
based dosing equivalent to 20 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg. 
When the weight improves to >30 kg, the subject may return to fixed dosing of durvalumab 1500 
mg. 
For Arm B, the RCD of BI 1361849 + durvalumab from Arm A with the addition of 
tremelimumab 75 mg is evaluated. There is no dose escalation/de-escalation for Arm B; if there 
is unacceptable toxicity in Arm B, the arm will be discontinued as presented in Figure 1.  
The dose evaluation phase is followed by an expansion phase, in which the cohort at the RCD 
for each arm is expanded to 20 subjects (inclusive of the subjects from the dose evaluation cohort 
i.e., 14 subjects will be added to the 6 treated at the RCD in the dose evaluation phase for each 
arm (A and B).  


  
Sponsor:  Ludwig Institute for Cancer Research.         
Protocol Number: LUD2014-012-VAC.   
 
 
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Page 4 of 27 
 
2.4 
Treatments and Assignment to Treatments 
Enrollment will start in the Arm A dose evaluation cohorts in a sequential fashion.  After the 
RCD is determined for Arm A, enrollment will start for the dose evaluation of Arm B  and for the 
Arm A Expansion Cohort, whereby no randomizations will be performed.  Any new subject will 
be assigned to the Arm B dose evaluation cohort, unless no slot is available, in which case the 
subject will be assigned to the Arm A Expansion Cohort.  After the dose evaluation and safety 
review for Arm B is complete, enrollment into the Arm B Expansion Cohort Group will be 
prioritized over Arm A. 
Figure 1: Enrollment Schema for Arms A and B 
 
* After the dose evaluation and safety review for Arm B is complete, enrollment into the Arm B 
Expansion Cohort will be prioritized over Arm A.  
2.5 
Determination of Sample Size  
The dose evaluation phase will utilize a standard 3 + 3 design for Arms A and B, which will 
result in the enrollment of 6 to 18 subjects. 
In the expansion phase, 20 subjects per arm are thought to provide sufficient data to adequately 
identify essential safety and preliminary efficacy signals.  Therefore, up to 14 additional subjects 
will be added to the 6 subjects treated at the RCD in each arm (A and B).  
The sample size n=20 for the expansion phase is deemed to provide sufficient precision for the 
estimation of incidence of adverse events as estimated by the Clopper Pearson confidence 
intervals (CI) for incidence of adverse events. 
Overall, approximately 56 subjects will be enrolled in up to 8 sites in the US. The enrollment 
period will take approximately 24 months. 


  
Sponsor:  Ludwig Institute for Cancer Research.         
Protocol Number: LUD2014-012-VAC.   
 
 
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Page 5 of 27 
 
3.0 
GENERAL ANALYSIS CONVENTIONS 
3.1 
General Conventions 
Data collected in this study will be documented using summary tables and subject data listings. 
Continuous endpoints will be summarized using descriptive statistics, e.g. number of subjects, 
mean, median, standard deviation, minimum and maximum values. The mean and median will be 
reported to 1 decimal place more than the level of precision of the data being reported and the SD 
will be reported to 2 decimal places more than the level of precision of the data being reported, 
unless otherwise  noted. Categorical endpoints will be presented in frequency tables with number 
and percentage of observations for each level.  
All efficacy analyses will be presented separately for Arm A and Arm B.  Tumor Response will 
be summarized and analyzed descriptively. A 95% Confidence Interval based on the binomial 
distribution will be constructed for the estimated PFS rate and ORR at 8 and 24 weeks and DCR.  
 
The number and percentage of subjects who died or had a confirmed progression, who survived 
without a confirmed progression, and who were lost to follow up (unknown survival and/or 
progression status) will be summarized.  
 
PFS rate at 8 and 24 weeks and the corresponding 95% CIs will be calculated based on Kaplan-
Meier product limit estimates and will be displayed along with the corresponding number of 
subjects at risk. (Note – this may include OS as well)  
PFS and OS will be summarized using the 25th percentile, Median, and 75th percentile as well as 
the minimum and maximum survival time, calculated by Kaplan-Meier method, and will be 
displayed graphically. 
The ORR, DCR and DOR will be summarized descriptively and a 95% Confidence Interval based 
on binomial distribution will be presented.  
3.2 
Trial Periods 
The overall length of study per subject is up to 15 months; comprising of 12 months for 
treatment and three months for on study follow-up. The screening period is up to one month 
prior to first drug administration. 
Study drug will be administered over 12 cycles with a cycle length of 28 days. The study drugs 
used in this study will be administered per cycle as shown in Appendix B. 
The overall length of the study is 39 months. However the length of the surviaval post study 
follow-up is up to  five years from initiation of treatment. 


  
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3.3 
Visit Windows 
The allowed visit windows are defined as shown in Table 1. Visits will be analyzed per the eCRF 
collection. 
Table 1: Visit Windows 
Visit Name 
Allowed window (Cycle Day ± Window)  
Screening 
Day -28 to -1 
Weeks 2, 3, 5, 6, 7, 9, 11, 13, 14 
+/- 2 day 
Weeks 17, 21, 25, 27 
+/- 3 day 
Week 28 
+/- 2 day 
Weeks 29, 33, 37, 39, 41, 45 
+/- 3 day 
Week 46 
+/- 2 day 
On study Follow-up   
28 (+/-4) days post last dose 
42 (+/-4) days post last dose 
91 (+/-7) days post last dose 
Post Study Follow-up 
Every 6 months until 5 years 
Note: Visit days are defined from baseline (Cycle 1, Day 1 visit). 
Vacinations may have to be delayed to allow for recovery of AEs prior to continuation of vaccine 
treatment. After the delayed vaccination all subsequent vaccinations must be continued within the 
schedule relative to the first vaccination presented in the flow chart.  
3.4 
Baseline 
Unless specified otherwise, baseline measurements will be the most recent value prior to receiving 
the first dose of study medication.   
4.0 
ANALYSIS POPULATIONS 
4.1 
Intent-to-Treat Population 
The Intent-To-Treat (ITT) Population is defined as all subjects who receive at least one dose of 
any of the study drugs. This population will be used for safety and efficacy analyses. 
4.2 
Per-Protocol Population (Clinical Efficacy) 
The Per-Protocol (PP) Population (Clinical Efficacy) is defined as all subjects who received at 
least 75% of the scheduled doses of durvalumab and tremelimumab and at least 4 of the 5 BI 
1361849 vaccinations over the first 2 cycles, as well as, respective disease assessments 
(irRECIST or RECIST, clinical progression or death), without major protocol violations. 
Efficacy analyses will also be presented for PP population. 


  
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4.3 
Per-Protocol Population (DLT Assessments) 
The Per-Protocol (PP) Population (DLT Assessments) is defined as  follows: 
• All subjects in the dose escalation who experience a DLT at any time during the DLT 
Evaluation Period (as defined in Section 3.1.9 of the protocol).  
• All subjects with no DLT who receive at least 75% of the scheduled doses of durvalumab 
and tremelimumab and at least 4 of the 5 BI 1361849 vaccinations over the first 2 cycles 
as well as respective safety assessments without major protocol violations during the 
DLT Evaluation Period . 
5.0 
SUBJECT DISPOSITION  
Subject disposition will be summarized overall for all subjects who entered the study in a 
disposition table (i.e., signed the informed consent for the study). In addition, the number of 
subjects in each population (ITT and PP) and subjects that were removed from a population will 
be summarized. The number and proportion of subjects who complete the study, as well as those 
who discontinue the study will be summarized along with the reason for discontinuation. 
Primary reason for treatment termination include the following criteria: 
• Withdrawal of consent for further treatment 
• Pregnancy or intent to become pregnant 
• DLT at any time  
• Progressive disease requiring alternative systemic treatment 
• Significant protocol violation or noncompliance that, in the opinion of the Investigator or 
Sponsor, warrants withdrawal 
• Development of intercurrent, non-cancer-related illnesses or complications that prevent 
either continuation of therapy or regular follow-up 
• Best medical interest of the subject (at the discretion of the Investigator) 
Primary reason for study discontinuation include the following criteria: 
• Best medical interest of the subject at the discretion of the Investigator 
• Initiation of alternative anticancer therapy (marketed or investigational) 
• Withdrawal of consent for all follow-up 
• Lost to follow-up 
• Death 


  
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Subject disposition data will also be presented in data listings. 
6.0 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
6.1 
Demographic Characteristics 
Demographic and baseline characteristics at study entry (Screening/baseline visit which will 
occur up to one month before start of treatment) will be summarized for the ITT and PP 
Populations. 
Demographic and baseline variables to be summarized include: 
• Continuous variables  
- Age (years) at time of consent 
- Height (cm) at screening 
- Weight (kg) at screening 
- Body mass index (BMI) (kg/m2) at screening 
• Categorical variables  
- Gender 
- Race 
- Ethnicity 
Demographic and baseline characteristics by subject will be presented in a table and data listings. 
6.2 
Medical History  
Medical History was collected at the Screening/Baseline visit. Medical history, including any 
ongoing and significant conditions or diseases that stopped at or prior to informed consent, must 
be elicited from each subject during screening. The medical history shall include a complete 
review of systems, past medical and surgical histories, and any allergies.  
The frequency count and percentage of subjects experiencing any medical conditions will be 
tabulated by system organ classifications (SOC) and preferred term (PT). If a preferred term or 
system organ class was reported more than once for a subject, the subject would only be counted 
once in the incidence for that preferred term or system organ class. 
Medical history data will also be listed for Safety Population. 


  
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6.3 
Prior and Concomitant Medications and Procedures 
Prior medications and procedures include any medication or non-drug therapy or procedure taken 
or performed within 30 days prior to screening and before the first dose of study drug. Prior 
medications will be coded using the World Health Organization Drug Dictionary [10]. 
Concomitant medications are all medications, other than the study drug, taken on or after the first 
day of study drug dose through 30 days after end of treatment. Concomitant medications  and 
procedures will be coded using the World Health Organization Drug Dictionary. 
Medications that started before the first dose of study drug and were ongoing on the date of the 
first dose will be considered concomitant medications. 
The number and proportion of the subjects who took each medication, or had qualifying 
concomitant procedures, will be tabulated by the ATC-2 level and preferred name for 
concomitant medications. A subject will only be counted once within each ATC-2 code and 
within each preferred name. 
Prior and concomitant medications will also be listed for ITT. 
7.0 
EFFICACY ANALYSIS  
Tumor Response will be summarized and analyzed descriptively for each arm for the ITT and PP 
populations.   
7.1 
Response Rate 
• Responses at Week 8 and Week 24 will be presented. The Number and Percent of 
subjects in each category (Complete Response, Partial Response, Stable Disease, 
Progressive Disease or Not Evaluable) will be presented. 
• Best Overall Response (BOR) will also be presented. In the determination of BOR, any 
subsequent scans on or after the date of a clinical progression will be ignored. 
7.2 
Objective Response Rate (ORR) 
• Objective Response Rate (ORR) is defined as the percentage of subjects meeting criteria 
of Complete Response (CR) or Partial Response (PR). 
• To be assigned a status of a CR or PR, changes in tumor measurements must be 
confirmed by repeat assessments that must be performed at least 4 weeks after the criteria 
for response are first met. If a response is not confirmed, it is considered stable disease. 
• If a subject had clinical progression (CP) , any recorded response (CR or PR) after the 
date of CP will be considered invalid.  


  
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• Subjects who drop out prior to having a response assessment (including clinical 
progression) for ORR will be considered as non-responders and they will be included in 
the denominator when calculating the proportion.  
• A 95% Confidence Interval based on binomial distribution will be constructed for the 
estimated ORR at 8 and 24 weeks. 
7.3 
Disease Control Rate (DCR) 
• Disease Control Rate (DCR) is defined as the percent of subjects with Stable Disease 
(SD), Partial Response (PR) and Complete Response (CR). 
• Subjects who drop out prior to meeting the responder criteria for DCR will be considered 
as non-responders.  
• A 95% Confidence Interval based on binomial distribution will be constructed for the 
estimated DCR at 8 and 24 weeks. 
7.4 
Progression-free Survival (PFS) 
• PFS is the interval between the date of first dose to the date of earliest determination of 
Progressive Disease (PD) (including clinical progression), or to the date of death, if PD 
does not occur.   
• Subjects without documentation of progression at the time of the analysis will be 
censored at the date of last response assessment.  
• Subjects with no tumor response assessment will be censored at the start date of the 
treatment.  
• Subjects who discontinued treatment or withdrew from the study for reasons other than 
documented PD (including clinical progression) or death will be censored at the date of 
last response assessment prior to discontinuation or withdrawal. 
Descriptive analyses of PFS, at Week 8, Week 24 and Overall, will include the following: 
• Number and percentage of subjects that died or had a progressive disease or clinical 
progression, 
• Number and percentage of subjects censored: 
o Number and percentage of subjects lost to follow up (unknown survival and/or 
progression status)  
o Number and percent of subjects survived without progression 
o Number and percentage of subjects missing tumor response assessment.  


  
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o Number and percent of subjects with initiation of alternative therapy. 
• The 25th percentile, Median and 75th percentileand the maximum and minimum PFS at 
Week 8, Week 24 and Overall and the corresponding 95% CIs will be displayed. 
• PFS rate at Week 8,Week 24 and Overall and the corresponding 95% CIs will be 
displayed.   
7.5 
Overall Survival (OS) 
• The interval between the date of first dose until the date of death or the date of last 
follow-up will be calculated. 
• The OS rate , including the 95% CI, will be presented. Duration of follow-up will also 
be presented. OS will also be updated at yearly intervals during the Post Study Follow-
up and can be provided as addendums to the final report.  
• Subjects who are still alive will be censored on the date of last follow-up.  Every 
effort will be made to follow subjects for OS after they discontinue the study. 
• OS will be summarized using the 25th percentile, Median, and 75th percentile as well 
as the minimum and maximum survival time, calculated by Kaplan-Meier method, 
and will be displayed graphically 
7.6 
Duration of Response (DoR) 
• Duration of response (DOR) will be calculated interval between the date of earliest 
determination of CR or PR to the date of first PD, clinical progression or death whatever 
occurs first. Patients who had a response and did not lose it subsequently and were alive will 
be censored at the time of last available tumor assessment.  
• DOR in weeks = (Earlier of Date of PD or death – date of first response + 1) / 7 
• The median DOR with 2-sided 95% confidence intervals will be presented for subjects 
who have a confirmed CR or PR at 8 and 24 weeks. 
7.7 
Analysis of Time to Event (TTE) Variables 
Progression Free Survival (PFS), OS and DoR will be analyzed using the Kaplan-Meier product 
limit estimates along with the corresponding number of subjects at risk. The Duration of follow-
up (in months) will be analyzed using the Reverse Kaplan-Meier product limit estimation 
method. 
For all time to event analyses the number of events, number censored, 25th percentile, median, 
75th percentile, corresponding 95% CIs as well as the minimum and maximum survival time will 
be presented in tables. In addition, survival curves will be presented graphically.  


  
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8.0 
TRIAL DRUG EXPOSURE AND COMPLIANCE  
Extent of treatment exposure to durvalumab, will be assessed for each of the two study arms. 
Durvalumab exposure (Arms A and B) will be summarized by the following parameters:  
• Duration of durvalumab treatment (week), calculated as: (Last dose date – first dose date 
+ 1) / 7  
• Number of durvalumab doses 
• Total durvalumab dose (mg), defined as the sum of the actual doses (mg) administered  
• Number of subjects with durvalumab dose de-escalated (only in Arm A) 
Tremelimumab exposure (Arm B) will be summarized by the following parameters:  
• Duration of Tremelimumab treatment (week), calculated as: (Last dose date – first dose 
date + 1) / 7  
• Number of tremelimumab doses 
• Total Tremelimumab dose (mg), defined as the sum of the actual doses (mg) 
administered  
BI 1361849 exposure (Arms A and B) will be summarized by the following parameters:  
• Duration of BI 1361849 treatment (week), calculated as: (Last dose date – first dose date 
+ 1) / 7  
• Number of doses  
• Total BI 1361849 dose (µg), defined as the sum of the actual doses (mg) administered  
9.0 
SAFETY ANALYSIS  
9.1 
Adverse Events 
Adverse events (AEs) will be coded using MedDRA v20 or later and will be classified by 
System Organ Class (SOC) and preferred term (PT). 
Severity of AEs will be assessed according to CTCAE (v4.03).  
Prior AEs are those occurring after subject sign off the informed consent and before the 
administration of the first dose of study treatment.  
Drug-relatedness to the study drugs is captured in five categories as follows: 
• Definitely related (The AE is clearly related to the investigational agent)  


  
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• Probably related (The AE is likely related to the investigational agent)  
• Possibly related (The AE may be related to the investigational agent)  
• Unlikely related (The AE is doubtfully related to the investigational agent)  
• Unrelated (The AE is clearly not related to the investigational 
TEAEs are considered as related to the study drug if enterd as definitely, probably or possibly 
related to study drug as assessed by the Investigator. If a subject has multiple occurrences of the 
same system organ class (SOC) or preferred term, then only the most severe event will be 
summarized in the tables for that SOC and preferred term. 
9.1.1 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as any AEs that started after dosing or 
worsened in severity after dosing. 
An overall AE summary for number of subjects will be presented for the following categories:  
• Any Adverse Event 
• Any TEAE  
• Any Deaths within the AE reporting period 
•  Any study drug-related adverse event (TRAE) (i.e., related to durvalumab, 
tremelimumab and/or vaccine)  
o Any durvalumab related TRAE 
o Any tremelimumab related TRAE 
o Any vaccine related TRAE 
• Any TEAE ≥ CTCAE Grade 3 
• Any TRAE ≥ CTCAE Grade 3 
• Any treatment-emergent Serious AEs (SAEs) 
• Any Serious TRAEs 
• Any TEAE leading to treatment (durvalumab, tremelimumab, and/or vaccine) 
discontinuation 
o Related to durvalumab 
o Related to tremelimumab  
o Related to vaccine 


  
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The following events will be tabulated by SOC and PT. Summaries will be sorted by decreasing 
frequency of PT within SOC which is sorted alphabetically.  
• TEAEs by SOC and PT 
• TEAEs by PT frequency only 
• Treatment-emergent SAEs  
• Treatment-related AEs 
o Durvalumab related 
o Tremelimumab related  
o Vaccine related 
• Treatment-related SAEs 
• TEAEs leading to treatment (durvalumab, tremelimumab, and/ or vaccine) 
discontinuation 
o Durvalumab discontinuation 
o Tremelimumab discontinuation 
o Vaccine discontinuation 
• DLTs 
A summary of TEAEs by SOC, PT and maximum severity, sorted by decreasing frequency of PT 
within SOC which is sorted alphabetically, will also be provided for:  
• TEAEs 
• TEAEs ≥ CTCAE Grade 3 
• Treatment related AEs 
o Durvalumab related 
o Tremelimumab related 
o Vaccine related 
• TRAEs ≥ CTCAE Grade 3 
In tabulation by severity grade,  
• For a given SOC, only the most severe SOC for each subject will be included.  
• For a given PT, only the most severe PT for each subject will be included.  
The following listings will be provided:  
• All AEs (flag TEAE)  


  
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• DLTs  
• SAEs  
• TEAEs leading to study treatment discontinuation 
• TEAEs leading to study drug (durvalumab or tremelimumab) dose modifications  
• Deaths in the AE reporting period 
9.1.2 
Adverse Events of Special Interest (AESIs) 
AESIs will not be separately presented in this analysis.   
9.2 
Clinical Laboratory Data 
Clinical Laboratory data (chemistry, hematology, coagulation, and urinalysis) will be collected 
as specified in the study flowchart in section 3.2 of the protocol.  
The Clinical lab tests are summarized in Table 3 below. 


  
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Table 3. Clinical Laboratory Tests 
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alanine transaminase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
(AST) 
Blood Urea Nitrogen (BUN) 
Calcium 
Carbon Dioxide (CO2) 
Chloride 
Creatinine 
Glucose 
Lactate Dehydrogenase 
(LDH) 
Magnesium 
Potassium 
Sodium 
Total bilirubin 
Total Protein 
Lipase 
Amylase 
Free T3 
Free T4 
TSH 
Hematocrit 
Hemoglobin 
Mean cellular volume 
(MCV) 
Mean corpuscular 
hemoglobin (MCH) 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
Mean Platelet Volume 
(MPV) 
Platelet count 
Red blood cell (RBC) 
count 
RBC Distribution Width 
(RDW) 
White blood cell (WBC) 
count  
Differential (% and 
absolute count for each) 
including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Activated partial 
thromboplastin time 
(aPTT) 
Prothrombin time 
(PT) 
INR 
Albumin 
Bilirubin  
Blood/Hemoglobin 
Glucose 
Ketones 
White Blood Cells 
Nitrite 
pH 
Protein 
Red Blood Cells 
Specific gravity 
Urobilinogen 
Color 
Turbidity 
 
The clinical lab data will be presented in tables and listings as follows:  
• 
All laboratory results will be presented in the listings.  


  
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• 
Abnormal laboratory values with their clinical significance status will be presented in a 
listing.  
• 
Urinalysis data, differentials (%), and RDW will be presented in listings only 
• 
Magnesium, MCV, MCH, MCHC, MPV, differentials (absolute count), aPTT, PT, and INR 
will be presented in listings and summary tables but NOT in shift tables. 
• The remaining analytes will be presented in listings, summary tables and shift tables 
The following summaries will be presented: 
• Overall values by time point utilizing continuous descriptive statistics for each arm 
and cohort. 
• For categorical parameters, the n and percentage will be displayed for each arm 
and cohort. 
• Frequencies and percentages for the shifts in these categories (i.e., low to normal, low 
to high, high to low, etc.) from baseline to each post-treatment assessment time point. 
For each continuous laboratory  parameter, results will be categorized as low, normal, 
or high based on the laboratory normal ranges. Frequencies and percentages will be 
presented by Arm A and Arm B and overall Safety population for the shifts in these 
categories from baseline to selected post-treatment assessment time points (e.g., low to 
normal, low to high, high to low). Percentages for the shift tables will be calculated 
based on the number of subjects who had results for both baseline and the 
corresponding post-treatment assessment time point.  
• For continuous  parameters, descriptive statistics will be presented for the changes from 
baseline to each selected post-treatment assessment time point. 
9.3 
     Vital Signs and Weight 
Subjects will be monitored before, during and after tremelimumab and durvalumab infusion with 
assessment of vital signs as presented in section 6.5 of the protocol. 
• Descriptive statistics will be presented each timepoint. 
• Descriptive statistics will also be presented for the changes in vital signs from baseline to 
each post-treatment assessment time point. 
9.4 
     Electrocardiograms 
12-Lead ECG will be completed at screening/baseline visit, Day 1 of cycles 1, 2, 4, 6, 8, 10 and  
12  and the +28 day post last treatment visit. 
• Baseline and post-baseline assessments will be classified as normal, abnormal – not 
clinically significant, or abnormal – clinically significant. The baseline value will be the 
pre-dose assessment for each formulation, and the post-baseline value will be the worst 
post-baseline assessment for each formulation.  


  
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• ECG data will be presented in a data listing. 
9.5 
   ECOG Performance 
ECOG perfomance will be evaluated on a 6-point scale from grade 0-5. ECOG PS assessments 
will be summarized overall by time point utilizing descriptive statistics. ECOG performance 
status will be taken except on Cycle 2 Day 8, Cycle 4 Day 8, Cycle 7 Day 22, Cycle 12 Day 8, 
and the post study follow-up. 
• ECOG PS assessments will also by summarized as categorical variable by timepoint with 
the n and percentage being displayed for each arm or indication-specific cohort. 
9.6 
   Physical Examinations  
A full physical examination will be performed at screening/baseline. There will also be targeted  
physical examinations at other timepoints except on Cycle 2 Day 8, Cycle 4 Day 8, Cycle 7 
Day 22, Cycle 12 Day  
8, and the post study follow-up.  
• Continuous and categorical variables at baseline and various timepoints will be 
summarized using descriptive statistics.  
• Clinically significant changes from baseline to postbaseline time points will be 
summarized using descriptive statistics. 
9.7 
   Pregnancy Testing  
Serum pregnancy testing (when applicable) is required prior to dosing up to 1 week before start 
of treatment. Pregnancy testing is also done on Day 1 of Cycles 1, 3, 5, 7, 9, 11, and On Study 
Follow-up Days +28 and +91 Days. Also, all subjects of childbearing potential who withdraw 
from study must have a serum pregnancy test done at the End of Study visit, unless it was done 
within 7 days prior to the End of Study Visit. 
• The results of pregnancy testing (Yes/No) will be summarized for every applicable 
timepoint with the n and percentage being displayed for each arm or cohort.  
10.0 
EXPLORATORY ANALYSIS 
Pharmacodynamics analyses on biologic activity related to study treatment will be performed for all 
subjects who receive at least one dose of any study drug.  These analyses will not be performed by 
Advanced Clinical but will be conducted by the Sponsor’s designated pharmacodynamics 
experts/vendors and the results will be summarized in a report which will be included as an 
appendix to the Clinical Study Report.  


  
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Per Protocol Amendment 9.1, some of the biological assessment tests will no longer be applicable. 
Hence, some blood sample collections for immune monitoring were discontinued as indicated in the 
study flow chart. 
11.0 
STATISTICAL/ANALYTICAL ISSUES  
11.1 
Handling of Dropouts or Missing Data 
In the dose evaluation phase, subjects who are not fully evaluable for DLT per section 4.1.2 of 
the protocol may be replaced. 
Subjects who are not fully evaluable for the PFS rate and ORR may be replaced. 
All available data will be presented on the data listings as collected. 
Algorithms for imputing partial or missing dates related to AEs and prior/concomitant 
medications are shown below in Table 4.  
Table 4 
Imputation Rules for Partially Missing Dates 
Variable 
Missing Day 
Missing Day, Month 
Missing Day, Month, 
Year 
Date of Last 
Therapy/Date of Initial 
Diagnosis 
Assign 1 
Assign January 1 if 
prior to date of 
informed consent, 
otherwise use date of 
informed consent 
Missing (do not 
impute) 
Adverse Event/Medication 
Start 
Date 
Assign first day of month 
unless it is the month of 
first dose of study 
medication. Otherwise, 
assign date of first dose of 
study medication. 
Assign January 1 
unless the year is year 
of first dose of study 
medication Otherwise, 
assign date of first 
dose of study 
medication. 
Assign date first 
dose of study 
medication. 
Adverse Event/Medication 
End Date 
Assign the last day of the 
month or end of study 
date, whichever is 
earlier. 
Assign December 31 
or end of study date, 
whichever is earlier. 
If ongoing, end date 
is missing. 
Otherwise, assign 
end of study date. 
11.2 
Safety Data Handling 
Adverse event toxicity grade will be classified using NCI-CTCAE Version 4.03 criteria (Grade 1 
– Grade 5). If a subject has multiple occurrences of the same system organ class (SOC) or 


  
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preferred term, then only the most severe event will be summarized in the tables for that SOC and 
preferred term. Adverse events of ≥Grade 3 will also be summarized. A missing toxicity grade 
will not be imputed. 
The AE analysis will be repeated for SAEs and AEs leading to dose reduction or discontinuation. 
11.3 
Coding Dictionaries 
Medical history, AEs, and concurrent procedures will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA V20). Prior and concomitant medications will be coded using 
the World Health Organization Drug Dictionary (WhoDrugDDEB2_201703). 
11.4 
Pooling of Centers in Multi-Center Trials 
There will be no pooling of centers. 
11.5 
Multiple Comparisons/Multiplicity 
No adjustments for multiple comparisons or multiplicity will be made. 
11.6 
Examination of Subgroups 
No subgroup analysis will be performed in this study. 
11.7 
Interim Analysis and Data Monitoring 
Interim Safety Reviews will be performed to assess DLTs in the dose evaluation cohorts for 
determination of RCD. Interim analyses may be performed to analyze the 8- and 24-week 
endpoints. 
12.0 QUALITY CONTROL  
All data displays and analyses will adhere to the International Conference on Harmonisation 
(ICH) Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports (ICH 
Topic E3). The clinical monitor will verify that the clinical study is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCPs, and any 
applicable regulatory requirements. 
Ludwig Institute for Cancer Research (LICR) or their designee will review all tables, listings, 
and figures prior to final database lock. Final SAS datasets, programs and outputs will be 
transferred to LICR at project completion. 


  
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13.0 
TABLES AND LISTING CONVENTIONS 
Mock-ups for statistical tables and listings will be provided. Final formats for the statistical 
tables and listings may deviate from these mock-ups upon agreement with LICR. Footnotes will 
be used as needed to clarify the information that is presented in the tables and listings. Unless 
otherwise requested by LICR, the term ‘subject’ will be used in all tables and listings, in 
accordance with CDISC standards. 
The numbering of tables, figures and listings will be in the following order: 
Table 14.x.y.z, Figures 15.x.y.z, Listings 16.x.y.z. 
 
 
 
The general layout of tables and listings will be as follows: 
 
 
 
All tables and listings will use landscape orientation. Margins will be at least 2.0 cm at the top 
and bottom and at least 0.8 cm on the left and right, excluding headers and footers, in accordance 
Ludwig Institute for Cancer Research. 
 
Page x of y 
Protocol: LUD2014-012-VAC
Run Date: DDMMMYY - HH:MM  
Clinical Study Report 
 
 
Listing 16.2_x (or Table 14.x_x) 
<Title> 
<Population>   
  
 
Col 1  
Col 2  
Col 3  
etc.  
  
 
 
 
 
 
 
 
 
 
 
_________________________________________________________________________________________ 
___________________________________________________________________________________________ 
  
 
<Any footnotes> 
 
File Name:   <pathname for SAS program>
 


  
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with electronic Common Technical Document (eCTD) guidelines. Font will be Courier New, 
unless otherwise specified, with an 8-point font size in most cases. Page numbering will be 
sequential within each table, listing, and figure. Column headers should be in initial capital 
letters. Units for numeric data will be included when appropriate. 
Tables and data listings will be created from different SAS programs. A single program may 
produce multiple tables or multiple data listings from the same dataset (e.g., all clinical 
chemistry data listings may be generated by a single program). 
 
14.0 REFERENCES 
1. 
Cancer Research Institute. Cancerresearchorg  http://wwwcancerresearchorg/cancer- 
immunotherapy/impacting-all-cancers/lung-cancer   Accessed 03 March 2016. 
2.      Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47. 
3. 
Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response criteria: 
irRECIST. Annals of Oncology ESMO 2014 Poster. 2014;25 (Suppl 4):iv361-iv72. 
4. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Published: 
November 27, 2017. National Cancer Institute, National Institutes of Health. U.S. 
Department of Health and Human Services. 
5.  
International Conference on Harmonization (ICH, 1996) E6 Guideline for Good Clinical 
Practice 
6. 
International Conference on Harmonization (ICH, 1997) E8 Guideline: General 
Considerations for Clinical Trials 
7.  
Medical Dictionary for Regulatory Activities (MedDRA), Version 20. 
8. 
World Health Organization (WHO) Drug Dictionary (WhoDrugDDEB2_201703). 
15.0 
RECORD RETENTION  
Records related to the activities listed in this plan will be retained according to AC SOP AD-005. 


  
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16.0 
CHANGE HISTORY  
Version 
Date 
Description of Changes  
0.1 
07OCT2019 
First draft version 
0.2 
10OCT2019 
Current version.  First version delivered to LICR by AC 
0.3 
01NOV2019 
Revised by AC, Sent to LICR  
0.4 
14NOV2019 
Version 0.3 Revised by AC, Version 0.4 sent to LICR 
1.0 
12DEC2019 
Final version 
1.1 
20AUG2020 
1. Section 7 revised to better expound on BOR, PFS, DOR 
2. Clinical Laboratory Data (Section 9.2 revised to reflect 
intended analysis 
3. Section 9.3 (Urinalysis) deleted as it is covered in Section 
9.2  
4. Section 3.4 inserted to explain baseline measurements 
2.0 
15SEP2020 
Alignment with protocol Amendment version 9.1 
(01SEP2020) 
Revisions to Section 7 as updated in version 1.1 and to align 
with mock shells, 
2.1 
02DEC2020 
Phase 2 tumor types in Section 9.2  changed to Arm A and 
Arm B 
(irRECIST or RECIST, clinical progression or death) 
inserted in the definition of per protocol analysis population 
to emphasize disease assessments methods 
3.0 
09DEC2020 
Final version 
 
 


  
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17.0 
APPENDICES 
17.1 
Appendix A: Study Flowchart 
 
Cycle 5 Cycle 6
Cycle Day 
1
8 (±2) 15 (±2) 1 (±2)
8 (±2) 15 (±2) 1 (±2) 15 (±2) 1 (±2)
8 (±2)
1 (±3)
1 (±3)
Cumulative Study  Day
Up to 1 month 
before Tx start
1
8
15
29
36
43
57
71
85
92
113
141
Treatment
Durvalumab (Arms A and B)
X
X
X
X
X
X
Tremelimumab (Arm B)
X
X
X
X
BI 1361849 - 6 components (Arms A and B)
X
X
X
X
X
X
X
X
X
X
Disease Staging (date/stage at 1st diagnosis and 
at study entry)
X
Disease Assessment  by  irRECIST/RECISTa
X
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)h
X
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
X
Medical history
X
Physical Exam (incl. weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
Vital Signs (T, HR, BP, RR)e
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication(s)/ Procedure(s) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)f 
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca,  
Mg, protein, albumin, Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa,c
X
X
X
X
X
X
X
Coagulation parametersa,d
X
Serum pregnancy test (Urine test  only on Day 1)a
Up to 1 week  
before Tx start 
X
X
X
Specimens for Other Peripheral Blood Assays
Blood for exosomal profiling a
X
X
Blood for PaxGene RNA and DNAa,k
Note: Discontinued per Amendment 9.1
X
XJ
XJ
Blood (PBMC and plasma) for flow cytometry and 
biological assays a,i,k
Note: Discontinued per Amendment 9.1
X
XJ
XJ
Blood for humoral responses and other 
biomarkersa,k
Note: Discontinued per Amendment 9.1
X
XJ
XJ
Biopsy or FFPE slides for tumor microenvironmentg
X
Overall Survival
Progression Free Survival
Specimens for Routine Laboratory Procedures
5
Study Week
1
11
X
(one week after 3rd or 5th 
BI 1361849 injection) 
Cycle 4
14J
Tumor and Disease Assessments
21
17
13
Treatment (each cycle = 4 weeks)
Long Term Follow-up
Tumor Biopsy
LUD2014-012-VAC 
Study Flowchart
Screening / 
Baseline
Cycle 2
Cycle 3
2
3
7
Cycle 1
6J
9


  
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Cycle 8 Cycle 9
Cycle 
11
Cycle Day 
1 (±3) 15 (±3) 22(±2)
1 (±3)
1 (±3)
1 (±3) 15 (±3) 1 (±3)
1 (±3)
8 (±2)
Cumulative Study  Day
169
183
190
197
225
253
267
281
309
316
Treatment
Durvalumab (Arms A and B)
X
X
X
X
X
X
Tremelimumab (Arm B)
BI 1361849 - 6 components (Arms A and B)
X
X
X
X
Disease Staging (date/stage at 1st diagnosis and 
at study entry)
Disease Assessment  by  irRECIST/RECISTa
X
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)h
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
Medical history
Physical Exam (incl. weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
Vital Signs (T, HR, BP, RR)e
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication(s)/ Procedure(s) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)f 
X
X
X
X
X
X
X
X
X
X
X
X
X
Specimens for Routine Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca,  
Mg, protein, albumin, Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa,c
X
X
X
X
X
X
X
Coagulation parametersa,d
X
Serum pregnancy test (Urine test  only on Day 1)a
X
X
X
X
X
Specimens for Other Peripheral Blood Assays
Blood for exosomal profiling a
X
X
Blood for PaxGene RNA and DNAa,k
Note: Discontinued per Amendment 9.1
XJ
XJ
X
Blood (PBMC and plasma) for flow cytometry and 
biological assaysa,i,k
Note: Discontinued per Amendment 9.1
Blood for humoral responses and other 
biomarkersa,k
Note: Discontinued per Amendment 9.1
XJ
XJ
X
Biopsy or FFPE slides for tumor microenvironmentg
optional
post-
treatment 
Overall Survival
Progression Free Survival
LUD2014-012-VAC 
Study Flowchart (cont.)
X
X
Treatment (each cycle = 4 weeks)
Cycle 12
Long Term Follow-up
Tumor Biopsy
Every 6 months 
until 5 years post 
initiation of 
treatment
33
37
39
41
 Last Study 
Drug Dose + 
91
( ±7) days  
End of  Study
45
Cycle 7
28J
Tumor and Disease Assessments
46
Last Study 
Drug Dose 
+42  
(±4) days
Last Study 
Drug Dose 
+28
( ±4) days
29
27
Post Study Follow-
up
On Study Follow-upf,K
Cycle 10
Q8W starting 8 weeks after
 last disease assessment
25
Study Week


  
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Flowchart Footnotes
a - pre-dose, when applicable. Note: Review of results for hematology, chemistry and pregnancy test (when applicable) is required prior to dosing.
b - Full physical examination at baseline; targeted physical examination at other time points
c - Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated.
d - Coagulation tests: prothrombin time, APTT and INR – only performed at Screening, first On Study Follow-up,  and as clinically indicated.
e - See Section 6.5 for assessment of vital signs on drug admin days. Note: when durvalumab vital assessments do not precede the BI 1361849 dose, 
      pre-dose vital assessments must be done for BI 1361849.
f - See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration
g - Biopsy Samples:
      1. A fresh core pre-treatment  biopsy (minimum 3 cores from lung tissue or 4 cores from another site) obtained within 60 days of study start will 
      be requested prior to study entry; archival sample may be used if a pre-treatment fresh biopsy is not feasible.  
     NOTE: Per Amendment 9.1, biopsies should not be taken from a target lesion unless that is the only suitable lesion, in which case it should be of
      reasonable size (refer to Section 4.3.1.1).
      2. If a fresh core pre-treatment biopsy was obtained, an on-treatment biopsy will be collected 1 week after the 3rd or 5th BI 1361849 treatment, if feasible; 
       this on-treatment biopsy should only be collected if a pre-treatment fresh biopsy was obtained (so that paired biopsies may be examined).
      3. Optional post-treatment core biopsies (minimum 3 cores from lung or 4 cores from another site) will be obtained at the time of tumor progression 
      or at the completion of treatment from subjects who consent to this procedure, and if clinically feasible. See Section 4.3.1.1 for details
      4. If possible and as determined by Investigator, a minimum of 8 subjects in each arm will have fresh tissue sampling from which fine needle aspiration  
      (FNA) can be also obtained for immune profiling
h - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
i -  See Section 3.3 for instructions for blood draws for PBMC collection. Note: PBMC collection is discontinued per Amendment 9.1.
J - Sampling at 7(±2) days after preceding vaccine administration. If vaccine administration time points are delayed, the PBMC & biological specimen collection
     time points should also be delayed to maintain the 5-9 day time frame after preceding vaccination. If the vaccination is omitted, blood sampling  
     should occur after the next subsequent vaccine administration. 
     Sample for WBC (hematology) must be available for the day of the blood samples for immunomonitoring.
    Note: Sample collection for PaxGene, PBMC, and humoral response is discontinued per Amendment 9.1 (See Section 4.3.1.2)
    Visits 6, 14, and 28 are no longer required per Amendment 9.1.
k - If treatment is discontinued after <14 weeks of treatment, samples for PBMC, PaxGene and humoral response should be collected within 5-9 days after the 
     last preceding vaccination or as close as possible to this time frame if the 5-9 day window is not feasible. 
     Note: Sample collection for PaxGene, PBMC, and humoral response is discontinued per Amendment 9.1 (See Section 4.3.1.2)


  
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17.2 
Appendix B: Drug Administrative Schedules per Cycle