Clinical trial NCT04101357
Conditions: Solid Tumor Extensive-stage Small Cell Lung Cancer
Keywords: Solid Tumor Extensive-stage Small Cell Lung Cancer
Sponsor: BioNTech SE
Start date: 2020-06-19; Completion date: 2024-05-23
Enrollment: 54 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This first-in-human (FIH) trial aimed to establish a safe dose of BNT411 as a monotherapy and in combination with atezolizumab, carboplatin and etoposide. BNT411 is a toll-like receptor 7 (TLR7) agonist which is expected to mount broad innate and adaptive immune reactions, especially in combination with cytotoxic therapies and immune checkpoint inhibitors.

Detailed description:
The first part (Part 1A) of this trial was a FIH, open-label, dose-escalation trial studying BNT411 monotherapy in patients with different types of malignant solid tumors in order to determine the safety profile of BNT411. The second part (Part 1B) aimed to determine further the safety profile of BNT411 in combination with atezolizumab, carboplatin and etoposide in patients with chemotherapy-naïve ES-SCLC. The third part (Part 2) was the expansion phase to explore BNT411 further as a monotherapy or in combination with atezolizumab, carboplatin and etoposide in select tumor indications. Different treatment schedules and other indications were planned to be explored in Part 2 of this trial, however, the sponsor decided not to continue with this part of this trial.

Arms: arm 1: BNT411 monotherapy arm 2: BNT411 in combination with atezolizumab, carboplatin, and etoposide. arm 3: BNT411 either as monotherapy or in combination with atezolizumab, carboplatin, and etoposide. Please note that the sponsor decided not to continue with this part of this trial.
Interventions: intervention 1: BNT411 intervention 2: Atezolizumab intervention 3: Carboplatin intervention 4: Etoposide
Intervention descriptions: intervention 1: intravenous intervention 2: intravenous intervention 3: intravenous intervention 4: intravenous

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Phase 1/2a, first-in-human, open-label, dose-escalation trial with 
expansion cohorts to evaluate safety, pharmacokinetics, 
pharmacodynamics, and preliminary efficacy of BNT411 as a 
monotherapy in patients with solid tumors and in combination with 
atezolizumab, carboplatin and etoposide in patients with 
chemotherapynaïve extensive-stage small cell lung cancer 
(ES-SCLC)
Protocol Number:
BNT411-01
Amendment Number:
6.0
Short Title / Acronym:
Safety, pharmacokinetics, pharmacodynamics, and 
preliminary efficacy trial of BNT411
Trial Phase:
Phase 1/2a
Compound:
BNT411
Sponsor:
BioNTech SE
An der Goldgrube 12
55131 Mainz, Germany
Regulatory Agency Identifier 
Number(s)
IND 144377
EudraCT 2019-003593-17
NCT04101357
Version Number and Date:
Version 6.0, 04 July 2023
The information in this document is confidential and is proprietary to BioNTech SE. It is understood that 
information in this document shall not be disclosed to any third party, in any form, without prior written consent of 
an authorized officer of BioNTech SE.


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STATEMENT OF COMPLIANCE
GCP Compliance
This trial will be conducted in compliance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP E6 [R2]), and applicable regulatory requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by 
applicable law or regulations. In any event, persons to whom the information is disclosed must 
be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you 
that is indicated as privileged or confidential.


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Sponsor Signatory:
Dan Zhou, MD
Medical Expert Clinical Trials
Date


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Principal Investigator Signatory:
Principal Investigator Signature
Name:
Institution:
Date


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PROTOCOL UPDATE SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 6.0
04 July 2023
Version 5.0_DEU (Germany only)
09 January 2023
Version 5.0
01 July 2022
Version 4.2 (Germany only)
24 June 2021
Version 4.1 (Germany only)
14 May 2021
Version 4.0
13 Nov 2020
Version 3.0
07 May 2020
Version 2.1 (UK only)
11 March 2020
Version 2.0
30 October 2019
Version 1.0
30 September 2019
Overall Rationale for the update to Version 6.0:
In version 6.0, changes were made to global protocol version 5.0 in order to clarify that some 
endpoints are only applicable to Part 2 of the trial. Other changes were made for 
clarification/correction. Details are provided in Appendix 11.6.
Overall Rationale for the update to Version 5.0_DEU:
In version 5.0_DEU (Germany-specific protocol), changes were made to global protocol version 
5.0 in response to feedback from the German Health Authority (Bundesinstitut für Arzneimittel 
und Medizinprodukte, BfArM). Details are provided in Appendix 11.5.
Overall Rationale for the update to Version 5.0:
In version 5.0, changes were made in response to the COVID-19 pandemic, an inclusion 
criterion was updated, backfilling of cohorts was introduced, and Germany-specific safety 
reporting of death events was introduced. Details are provided in Appendix 11.4.
Overall Rationale for the update to Version 4.0:
In Version 4.0, the sponsor changed from BioNTech Small Molecules GmbH to BioNTech SE. 
SAEs due to disease progression were exempted from the standard expedited reporting process 


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and some inconsistencies to the previous versions were corrected. Details are provided in 
Appendix 11.3.
Overall Rationale for the update to Version 3.0:
In Version 3.0, changes for better clarification and consistencies were made as requested by 
relevant regulatory authorities and ethics committees. Details are provided in Appendix 11.2.
Overall Rationale for the update to Version 2.0:
In Version 2, inconsistencies to the previous versions were corrected. Details have been provided 
in Appendix 11.1.


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TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................1
STATEMENT OF COMPLIANCE.............................................................................................2
PROTOCOL UPDATE SUMMARY OF CHANGES TABLE.................................................5
TABLE OF CONTENTS ..............................................................................................................7
TABLE OF TABLES...................................................................................................................11
TABLE OF FIGURES.................................................................................................................11
1
Protocol Summary........................................................................................................13
1.1
Synopsis..........................................................................................................................13
1.2
Schema............................................................................................................................18
1.3
Schedule of Activities (SoA)..........................................................................................19
1.3.1
Dose Escalation Phases (Parts 1A and 1B).....................................................................19
2
Introduction...................................................................................................................34
2.1
Background.....................................................................................................................34
2.1.1
Overview of the Disease.................................................................................................34
2.1.2
Standard Treatment Options for Patients with ES-SCLC...............................................35
2.1.3
High Unmet Medical Need in ES-SCLC........................................................................37
2.1.4
Introduction to the Investigational Treatment.................................................................37
2.2
Trial Rationale ................................................................................................................41
2.2.1
Rationale for Testing BNT411 in Combination with 
Chemotherapy and Checkpoint Inhibitors ......................................................................41
2.3
Benefit/Risk Assessment ................................................................................................42
2.3.1
Risk Assessment .............................................................................................................42
2.3.2
Potential Risks Associated with BNT411 in Combination with 
Atezolizumab, Carboplatin, and Etoposide ....................................................................43
2.3.3
Benefit Assessment.........................................................................................................44
2.3.4
Potential Benefits Associated with BNT411 in Combination with 
Atezolizumab, Carboplatin and Etoposide .....................................................................44
2.3.5
Overall Benefit: Risk Conclusion...................................................................................45
3
Objectives and Endpoints ............................................................................................46
4
Trial Design ...................................................................................................................48
4.1
Overall Design................................................................................................................48
4.1.1
Dose Escalation (Part 1A and 1B) ..................................................................................49
4.1.2
Expansion Phase (Part 2) ................................................................................................52
4.1.3
Adaptive Trial Design Elements.....................................................................................52
4.2
Planned Number of Patients ...........................................................................................53
4.2.1
Replacement of Patients..................................................................................................53
4.3
Trial Design Rationale....................................................................................................53
4.3.1
Rationale for Bifurcated Design .....................................................................................54


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4.3.2
Rationale for Body Weight-Based Dosing .....................................................................54
4.4
Dose and Schedule Rationale .........................................................................................55
4.5
End of Trial Definition ...................................................................................................56
5
Trial Population............................................................................................................56
5.1
Inclusion Criteria ............................................................................................................56
5.2
Exclusion Criteria ...........................................................................................................57
5.3
Screen Failures................................................................................................................60
6
Trial Treatment.............................................................................................................61
6.1
Trial Treatment(s) Administered ....................................................................................61
6.1.1
BNT411...........................................................................................................................61
6.1.2
Atezolizumab, Carboplatin, and Etoposide ....................................................................62
6.2
Preparation/Handling/Storage/Accountability................................................................63
6.3
Measures to Minimize Bias: Randomization and Blinding............................................63
6.4
Trial Treatment Compliance...........................................................................................63
6.5
Concomitant Therapy and Procedures............................................................................63
6.5.1
Premedication .................................................................................................................64
6.5.2
Rescue Medication..........................................................................................................64
6.6
Dose Modifications.........................................................................................................64
6.6.1
Dose Limiting Toxicity for Part 1A................................................................................65
6.6.2
Dose Limiting Toxicity for Part 1B................................................................................66
6.6.3
Dose Modification Guidance..........................................................................................67
6.6.4
Dose Modification for Specific Adverse Events ............................................................71
6.6.5
Safety Stopping Criteria..................................................................................................74
6.6.6
Safety Alert Communication Plan ..................................................................................75
6.6.7
Atezolizumab Dose Modification and Management of Specific 
Adverse Events ...............................................................................................................76
6.6.8
Carboplatin Dose Modification and Management of Specific 
Adverse Events ...............................................................................................................76
6.6.9
Etoposide Dose Modification and Management of Specific 
Adverse Events ...............................................................................................................76
6.7
Treatment after the End of the Trial ...............................................................................76
7
Discontinuation of Trial Treatment and Patient 
Discontinuation/Withdrawal .......................................................................................77
7.1
Discontinuation of Trial Treatment ................................................................................77
7.1.1
Temporary Discontinuation ............................................................................................77
7.1.2
Rechallenge.....................................................................................................................77
7.2
Withdrawal from the Trial..............................................................................................77
7.2.1
Withdrawal from the Use of Research Samples .............................................................78
7.2.2
Safety Follow-up Evaluations.........................................................................................78
7.3
Lost to Follow up............................................................................................................78
8
Trial Assessments and Procedures..............................................................................79
8.1
Screening Procedures......................................................................................................79
8.2
Procedures During Treatment Visits for Cycles 1-N......................................................80


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8.3
Treatment Discontinuation .............................................................................................80
8.4
Other Visits.....................................................................................................................80
8.4.1
Safety Follow-up.............................................................................................................80
8.4.2
Survival Follow-up .........................................................................................................80
8.4.3
Unscheduled Visits .........................................................................................................81
8.5
Efficacy Assessments .....................................................................................................81
8.5.1
Anti-tumor Activity Assessment – CT/MRI Imaging ....................................................81
8.6
Safety Assessments.........................................................................................................82
8.6.1
Physical Examination......................................................................................................82
8.6.2
Vital Signs.......................................................................................................................82
8.6.3
Electrocardiograms .........................................................................................................82
8.6.4
Clinical Safety Laboratory Assessments ........................................................................83
8.6.5
Eye Examination.............................................................................................................83
8.6.6
ECOG Performance Status .............................................................................................85
8.6.7
Pregnancy Testing...........................................................................................................85
8.6.8
Echocardiogram or multigated acquisition scan.............................................................85
8.7
Adverse Events and Serious Adverse Events .................................................................85
8.7.1
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................86
8.7.2
Method of Detecting AEs and SAEs ..............................................................................86
8.7.3
Follow-up of AEs and SAEs...........................................................................................86
8.7.4
Regulatory Reporting Requirements for SAEs...............................................................86
8.7.5
Pregnancy........................................................................................................................87
8.7.6
Death Events...................................................................................................................87
8.7.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs.............................................................................................87
8.7.8
Dose Limiting Toxicity...................................................................................................88
8.8
Treatment of Overdose ...................................................................................................88
8.9
Pharmacokinetics............................................................................................................89
8.10
Pharmacodynamic Biomarkers.......................................................................................89
8.11
Genetics ..........................................................................................................................90
8.12
Immunogenicity Assessments ........................................................................................90
8.13
24/7 Coverage for Urgent Protocol-related Medical Questions .....................................90
9
Statistics.........................................................................................................................91
9.1
Statistical Hypotheses.....................................................................................................91
9.2
Sample Size Determination ............................................................................................91
9.3
Analysis Sets...................................................................................................................91
9.4
Statistical Analyses.........................................................................................................91
9.4.1
General Considerations...................................................................................................92
9.4.2
Primary Endpoint(s)........................................................................................................92
9.4.3
Secondary Endpoint(s)....................................................................................................93
9.4.4
Exploratory Endpoint(s)..................................................................................................94
9.4.5
Other Safety Analyses.....................................................................................................94
9.4.6
Other Analyses................................................................................................................94
9.5
Interim Analyses.............................................................................................................94


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9.6
Safety Review Committee (SRC)...................................................................................95
10
Supporting Documentation and Operational Considerations..................................96
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations ................................................................................................................96
10.1.1
Regulatory and Ethical Considerations...........................................................................96
10.1.2
Financial Disclosure........................................................................................................96
10.1.3
Informed Consent Process ..............................................................................................96
10.1.4
Data Protection................................................................................................................97
10.1.5
Data Quality Assurance ..................................................................................................97
10.1.6
Source Documents ..........................................................................................................98
10.1.7
Trial and Site Start and Closure......................................................................................98
10.1.8
Publication Policy...........................................................................................................99
10.1.9
Dissemination of Clinical Trial Data..............................................................................99
10.2
Appendix 2: Clinical Laboratory Tests.........................................................................101
10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................103
10.3.1
Definition of AE ...........................................................................................................103
10.3.2
Definition of SAE .........................................................................................................105
10.3.3
Recording and Follow-Up of AE and/or SAE..............................................................106
10.3.4
Reporting of SAEs........................................................................................................116
10.4
Appendix 4: Definition of Reproductive Potential and 
Contraception................................................................................................................118
10.4.1
Collection of Pregnancy Information............................................................................119
10.5
Appendix 5: Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) ............................................................................................121
10.6
Appendix 6: iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics.................................................................................124
10.7
Appendix 7: Veterans Administration Lung Study Group 
(VALG) Staging System for SCLC..............................................................................128
10.8
Appendix 8: Risk-benefit assessment of COVID-19 vaccination 
in BNT411-01 trial .......................................................................................................129
10.9
Appendix 9: COVID-19 vaccination in BNT411-01 trial during 
the pandemic.................................................................................................................131
10.10
Appendix 10: Abbreviations.........................................................................................132
10.11
Appendix 11: Protocol Version/Amendment History ..................................................137
10.11.1 Version 2: 30 October 2019..........................................................................................137
10.11.2 Version 3.0: 07 May 2020 ............................................................................................142
10.11.3 Version 4.0: 13 November 2020...................................................................................151
10.11.4 Version 5.0: 01 July 2022.............................................................................................155
10.11.5 Version 5.0_DEU: 09 January 2023.............................................................................159
10.11.6 Version 6.0: 04 July 2023.............................................................................................159
11
References....................................................................................................................161
12
Attachments.................................................................................................................167


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12.1
Management Recommendations in Case of a Cytokine Release 
Syndrome (CRS)...........................................................................................................167
12.2
Country Specific Information.......................................................................................170
12.2.1
Germany........................................................................................................................170
12.2.2
Spain .............................................................................................................................170
TABLE OF TABLES
Table 1-1:
Schedule of Activities – Part 1A .......................................................................20
Table 1-2:
Schedule of Activities – Part 1B .......................................................................23
Table 1-3:
PK (blood and urine) sampling and ECG assessment in Part 1A .....................26
Table 1-4:
PK (blood and urine) sampling and ECG assessment in Part 1B......................28
Table 1-5:
Overview of Safety Reporting in Different Countries ......................................30
Table 1-6:
Vital Signs during Parts 1A and 1B ..................................................................31
Table 1-7:
Biomarker table – in Part 1A.............................................................................32
Table 1-8:
Biomarker table – in Part 1B.............................................................................33
Table 3-1:
Objectives and Endpoints..................................................................................46
Table 4-1:
Dose escalation table.........................................................................................50
Table 4-2:
BNT411 dose increments..................................................................................51
Table 6-1:
BNT411 Dose Modification and Management of irAEs...................................72
Table 10-1:
Protocol-Required Safety Laboratory Assessments........................................102
Table 10-2:
Highly Effective Methods of Contraception ...................................................119
Table 10-3:
Evaluation of Overall Response......................................................................123
Table 12-1:
CRS grading per CTCAE version 5.0 .............................................................167
Table 12-2:
American Society for Transplantation and Cellular Therapy CRS consensus 
grading.............................................................................................................168
Table 12-3:
Guidelines for management of cytokine release syndrome.............................168
TABLE OF FIGURES
Figure 1-1:
Overall Trial Design..........................................................................................18
Figure 2-1:
Structure of BNT411.........................................................................................38
Figure 2-2:
Modified Cancer Immunity Cycle from Chen & Mellman, Immunity, 2013. ..42


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Figure 4-1:
Overall Trial Design..........................................................................................49
Figure 6-1:
Handling of adverse events fulfilling the DLT criteria after the DLT-
observation period has ended – Part 1A............................................................67
Figure 6-2:
Handling of adverse events fulfilling the DLT criteria after the DLT-
observation period has ended – Part 1B ............................................................69


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1
Protocol Summary
1.1
Synopsis
Title
Phase 1/2a, first-in-human, open-label, dose-escalation trial with expansion 
cohorts to evaluate safety, pharmacokinetics, pharmacodynamics, and 
preliminary efficacy of BNT411 as a monotherapy in patients with solid 
tumors and in combination with atezolizumab, carboplatin and etoposide in 
patients with chemotherapy-naïve extensive-stage small cell lung cancer 
(ES-SCLC)
Brief Title
Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy trial of 
BNT411
Clinical Phase
Phase 1/2a
Purpose and 
Rationale
This first-in-human (FIH) trial aims to establish a safe dose of BNT411 as a 
monotherapy and in combination with atezolizumab, carboplatin and 
etoposide. BNT411 is a toll-like receptor 7 (TLR7) agonist which is expected 
to mount broad innate and adaptive immune reactions, especially in 
combination with cytotoxic therapies and immune checkpoint inhibitors.
Objectives and 
Endpoints
Objectives
Endpoints
Primary
•For Parts 1 and 2: Assess 
safety profile
•
Occurrence of DLTs within a patient 
during the DLT evaluation period
•
Occurrence of TEAEs within a patient 
including grade ≥3, serious, fatal TEAE 
by relationship
•
Occurrence of dose reduction and 
discontinuation of BNT411 within a 
patient due to TEAEs
•For Part 1: Determine MTD 
and/or RP2D
•
MTD defined as the highest tolerated 
dose
•
RP2D based on integrated evaluation of 
safety, tolerability, clinical benefit, PK, 
and pharmacodynamic data, for all 
dose levels tested
Secondary
•For Parts 1 and 2: Establish 
PK profile
•
PK parameters (AUC, CL and VD, Cmax, 
Tmax, Ctrough, and T1/2)
•For Part 2: Evaluate anti-
tumor activity according to 
RECIST 1.1
•
ORR defined as the proportion of 
patients in whom a CR or PR is observed 
as best overall response. 
•
DCR defined as the proportion of 
patients in whom a CR or PR or SD 
(assessed at least 6 weeks after first 


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dose) is observed as best overall 
response.
•
DOR defined as the time from first 
objective response (CR or PR) to the 
date of the first occurrence of objective 
tumor progression or death from any 
cause, whichever occurs first.
Exploratory
•For Part 2: Evaluate anti-
tumor activity according to 
iRECIST
•
iORR defined as the proportion of 
patients in whom a iCR or iPR is 
observed as best overall response. 
•
iDCR defined as the proportion of 
patients in whom a iCR or iPR or iSD 
(assessed at least 6 weeks after first 
dose) is observed as best overall 
response.
•
iDOR defined as the time from first 
objective response (iCR or iPR) to the 
date of the first occurrence of objective 
tumor progression (iCPD) or death from 
any cause, whichever occurs first.
•For Part 2: Evaluate 
preliminary efficacy
•
PFS defined as the time from first dose 
of BNT411 to first occurrence of 
objective tumor progression (per 
RECIST 1.1), or death from any cause, 
whichever occurs first. 
•
OS defined as the time from first dose of 
BNT411 to death from any cause.
•For Parts 1 and 2: 
Preliminary assessment of 
biomarkers that might act as 
pharmacodynamics, anti-
tumor, and safety indicators 
of activity of BNT411 
monotherapy and in 
combination with 
chemotherapy and 
atezolizumab
•
Changes in selected cytokines and other 
activation markers compared to baseline
•
Changes in systemic and intra-tumoral 
immune response in blood and tumor 
tissue compared to baseline (e.g. 
immunophenotyping of immune cells in 
peripheral blood, absolute and relative 
changes compared to baseline in tissues 
and/or PBMCs)
Key: AUC, area-under-the-concentration-time curve; CL, clearance; Cmax, maximum 
concentration; (i)CR, (immune) complete response; Ctrough, trough concentration; 
(i)DCR, (immune) disease control rate; DLTs, dose-limiting toxicities; DOR, duration 
of response; iCPD, immune confirmed progressive disease; iRECIST, immune 
RECIST; MTD, maximal tolerated dose; (i)ORR, (immune) objective response rate; OS, 
overall survival; PBMCs, peripheral blood mononuclear cells; PFS, progression-free 
survival; PK, pharmacokinetic; (i)PR, (immune) partial response; RECIST, Response 
Evaluation Criteria in Solid Tumors; RP2D, recommended Phase 2 dose; (i)SD, 


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(immune) stable disease; T1/2, terminal half-life; TEAEs, treatment emergent AEs; 
Tmax, time to Cmax; VD, volume of distribution. 
Trial Design
This is an open-label, multicenter, dose -escalation, safety, PK and 
pharmacodynamic trial of BNT411 with expansion cohorts in a mixed 
population of patients with solid tumors. The trial consists of three parts: 
•
Part 1A will be a monotherapy dose escalation in patients with advanced 
solid cancers until the MTD and/or RP2D of BNT411 as monotherapy are 
defined.
•
Part 1B will be a combination dose escalation in patients with 
chemotherapy-naïve ES-SCLC until the MTD and/or RP2D of BNT411 in 
combination with atezolizumab, carboplatin and etoposide are defined.
•
Part 2 will consist of expansion cohorts in solid cancers based on data 
generated in Part 1A and Part 1B.
Part 1B is planned to start before the MTD/RP2D is reached in Part 1A using a 
bifurcated trial design. The dose level of BNT411 in Part 1B at any given time 
will always be one dose level below that in Part 1A.
In Parts 1A and 1B, patients will receive one infusion of BNT411 every week 
in a 3-week cycle for the first 4 cycles (on Days 1, 8 and 15 in Part 1A; on 
Days 2, 8 and 15 in Part 1B). In the following cycles thereafter, BNT411 will 
be administered every 3 weeks (on Day 1 [Part 1A] or Day 2 [Part 1B] of each 
3-week cycle). Treatment will continue until protocol-defined treatment 
discontinuation criteria are met.
The dose escalation in Part 1A starts with an accelerated phase consisting of 
single patient cohorts followed by larger patient cohorts in Parts 1A and 1B 
informed by a classical 3+3 design. BNT411 dosing in Part 1A will start at 
0.05 µg/kg/administration. 
To be eligible for DLT assessment, patients should receive all three infusions 
of BNT411 during the DLT assessment period (Cycle 1). After completion of 
the DLT period, the Safety Review Committee (SRC) will review the data and 
propose the dose level for the next cohort of patients. The RP2D will be 
decided based on integrated evaluation of safety, tolerability, clinical benefit, 
PK, and pharmacodynamic data, for all dose levels tested.
Efficacy will be assessed by on-treatment imaging at Week 6 (+7 days), every 
6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) thereafter until 
disease progression is assessed by the investigator (unless the investigator 
elects to continue treatment), withdrawal of consent, trial termination by the 
sponsor, or death, whichever occurs first, regardless of whether patients start a 
new anti-cancer therapy.
Population
Between 6 to 60 DLT evaluable patients are planned to be enrolled in Part 1A. 
Between 6 to 30 DLT evaluable patients are planned to be enrolled in Part 1B. 


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For the dose escalation (Parts 1A and 1B), approximately 12 sites will be 
opened in North America and Europe. For possible expansion, approximately 
25 to 35 sites will be opened in North America, Europe, and potentially the 
rest of the World.
Note: "Enrolled" means a patient's, or their legally acceptable representative’s 
agreement to participate in a clinical trial following completion of the 
informed consent process. Potential patients who are screened for the purpose 
of determining eligibility for the trial, but do not participate in the trial, are not 
considered enrolled, unless otherwise specified by the protocol.
Key Inclusion 
Criteria
For Part 1A:
•
Histologically confirmed solid tumor (cytology is allowed for NSCLC, 
SCLC and pancreatic cancer) that is metastatic or unresectable and for 
which there is no available standard therapy likely to confer clinical 
benefit, or patients who are not candidates for such available therapy. 
For Part 1B:
•
Histologically or cytologically confirmed ES-SCLC (per the Veterans 
Administration Lung Study Group [VALG] staging system) who 
received no prior chemotherapy for extensive stage disease.
•
Those treated with prior chemo/radiotherapy with curative intent for 
limited-stage small cell lung cancer (LS-SCLC) should be treatment 
-free for at least 6 months since last chemo/radiotherapy.
•
No interstitial lung disease or active, non-infectious pneumonitis.
For both Part 1A and Part 1B:
•
Male and female ≥18 years of age.
•
Eastern Cooperative Oncology Group (ECOG) performance status of 0 
to 1.
•
Measurable disease according to RECIST 1.1. 
Key Exclusion 
Criteria
•
Has received prior systemic therapy with a TLR7 agonist. 
•
Has been receiving: radiotherapy, chemotherapy, or molecularly-
targeted agents or tyrosine kinase inhibitors within 2 weeks or 5 half-
lives (whichever is longer) of the start of trial treatment; 
immunotherapy/monoclonal antibodies within 3 weeks of the start of 
trial treatment; any live vaccine within 4 weeks of the start of trial 
treatment; nitrosoureas, antibody-drug conjugates, or radioactive 
isotopes within 6 weeks of the start of trial treatment.
•
Receives concurrent systemic (oral or intravenous) steroid therapy >10 mg 
prednisone daily or its equivalent for an underlying condition.
•
Receives concurrent strong inhibitors or inducers of major cytochrome 
P450 enzymes. 
•
Has had major surgery within the 4 weeks before the first dose of 
BNT411.
•
Has ongoing or active infection requiring intravenous treatment with anti-
infective therapy that has been administered less than two weeks prior to 
first dose of trial treatment.


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•
Has side effects of any prior therapy or procedures for any medical 
condition not recovered to NCI CTCAE v.5 Grade ≤1. 
•
Has any contraindication to atezolizumab, carboplatin or etoposide as per 
USPI or SmPC in Part 1B.
Investigational 
Therapy
In Part 1A, BNT411 will be administered using a 100 mL intravenous infusion 
on Days 1, 8 and 15 of each 3-week treatment cycle (21 days) of the first 4 
cycles. In the following cycles thereafter, BNT411 will be administered every 
3 weeks on Day 1 of each 3-week treatment cycle (21 days).
In Part 1B, BNT411 will be administered using a 100 mL intravenous infusion 
on Days 2, 8 and 15 of each 3-week treatment cycle (21 days) of the first 4 
cycles. In the following cycles thereafter, BNT411 will be administered every 
3 weeks on Day 2 of each 3-week treatment cycle (21 days).
Dose reduction or termination will be based on pre-specified dose modification 
rules or stopping criteria.
In Part 1B, for combination with atezolizumab and chemotherapy, the 
administration will be in the following order:
Day 1: Atezolizumab   Carboplatin Etoposide
Day 2: BNT411  Etoposide
Day 3: Etoposide
Atezolizumab, carboplatin, and etoposide will be used in the commercially 
available formulation and at the label-recommended doses. 
For each dosing of BNT411 in Cycle 1, patients will remain in the treatment 
center and be closely monitored for immediate adverse events (AEs) for at 
least 6 hours. Hospitalization is required for the first 24 hours after the first 
BNT411 administration in Cycle 1 for clinical observation and PK sampling. 
Prolongation of the hospitalization beyond 24 hours may be performed at the 
investigator’s discretion if deemed necessary based on potential risks related to 
the trial treatment and clinical status of the patient. For each subsequent dose 
of BNT411 in all cycles, patients will be monitored for at least 6 hours.
Safety Review 
Committee
An SRC, composed of the investigators and the sponsor’s representatives will 
assess the cumulative safety data (e.g., serious AEs [SAEs], AEs, laboratory 
data and DLTs where applicable) collected during the trial to help ensure 
patient’s safety. 
The SRC will make recommendation of the RP2D at the end of both Parts 1A 
and 1B and will recommend whether to activate the expansion phase (Part 2).
Statistics
No statistical hypotheses are planned to be tested in this trial.
Descriptive statistics will be used to analyze continuous and categorical 
variables. Time-to-event-endpoints (DOR, PFS and OS) will be analyzed using 
Kaplan-Meier methodology.


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1.2
Schema
Figure 1-1:
Overall Trial Design
Key: DL, dose level; DLT, dose-limiting toxicity; ES-SCLC, extensive stage small cell lung cancer; MTD, maximal tolerated dose; RP2D, 
recommended phase 2 dose. 


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1.3
Schedule of Activities (SoA)
1.3.1
Dose Escalation Phases (Parts 1A and 1B)
Table 1-1 and Table 1-2, respectively, list all of the assessments to be performed in Parts 1A and 
1B (dose escalation phases) of the trial. Table 1-3 (Part 1A) and Table 1-4 (Part 1B) show the 
timing of the PK and electrocardiogram (ECG) assessments for dose escalation, and Table 1-6 
shows the timing for measurement of vital signs in relation to infusions. Table 1-7 (Part 1A) and 
Table 1-8 (Part 1B) list the biomarker assessments to be performed. All data obtained from these 
assessments must be reported in the patient’s source documentation. With the exception of post-
dose blood and urine sampling for PK assessments, all assessments should be performed before 
trial treatment administration (on the applicable days) or any planned intervention. On the days 
of tumor imaging, blood sampling can be before or after imaging assessments.
If non-adherence to the SoA will occur related to the COVID-19 pandemic, please review 
Addendum “Clinical trial protocol addendum related to COVID-19 pandemic Version 3.0 
04 Jun 2021”.
Information relating to COVID-19 vaccinations including a risk-benefit assessment and guidance 
for vaccination during this clinical trial is provided in Sections 10.8 and 10.9.


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Table 1-1:
Schedule of Activities – Part 1A
Treatment Cycle
Screening
Cycle 1-2
Cycle 3-4
Cycle 5–N
Treatment 
discontinuation
1
Safety 
follow-up 1
Safety 
follow-up 
2
Survival 
follow-up2
Unscheduled
Day (D)
≤21 days 
prior to 
Visit C1 
(D1)
D1
D2
D324
D8
D15
D1
D8
D15
D1
D8
D15
-
30 days 
after last 
dose
60 days 
after last 
dose
Every 
12 weeks 
Visit window
±D3
-
+D2
24
±D1
±D1
±D3
±D1
±D1
±D
3
±D1
±D1
-
+D5
±D7
±D14
Informed Consent
X
Informed Consent for genetic testing
X
Eligibility Criteria
X
Demographics
X
Medical History19
X
Height
X
Body Weight
X
X
X
X
X
X
X3
Physical Examination4
X
X
X
X
X
X
X
X
X
X
X
X
X3
Eye Examination5
X
X6
X6
X
X
X7
Vital Signs8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
ECHO or MUGA scan9
X
X3
ECG
X
Refer to Section 8.6.3 and Table 1-3 for details on ECG assessments 
CT/MRI-Scan
X10
Refer to Section 8.5.1 of the protocol for details on Imaging assessments11
ECOG Performance Status12
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
Adverse Events13
X
CONTINUOUS 
X14
X3
Prior/Concomitant Medications and 
Non-Drug Therapies21
X
CONTINUOUS
X22
X³
BNT411 Administration15
X
X
X
X
X
X
X
End of Treatment
X
New Anti-cancer Treatment
X
X
X
X
Survival Follow-up
X2
LABORATORY ASSESSMENTS (to be performed up to 3 days before administration days, unless indicated otherwise)
Hematology
X16
X17
X
X
X17
X17
X17
X17
X17
X17
X17
X17
X
X
X
X3
Biochemistry
X16
X17
X
X
X17
X17
X17
X17
X17
X17
X17
X17
X
X
X
X3
Coagulation factors
X16
X17
X17
X17
X17
X17
X17
X17
X17
X17
X
X
X
X3
Endocrine18
X16
X17
X17
X17
X
X3
Urinalysis
X16
X17
X17
X17
X17
X
X
X
X3
Pregnancy Test19
X16
X17
As indicated clinically per 
investigator’s assessment and per 
local guidelines and regulations. 
X
X
X
X3
Serology 16
X23
PK Sampling (includes blood and 
urine)
Refer to Table 1-3 for details of PK samplings
Tumor Biopsy, Biomarkers
Refer to Table 1-7 for detailed biomarker assessment schedule


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1 If the patient has to go off treatment per treatment withdrawal criteria (refer Section 7.1), the treatment discontinuation visit should be performed as soon as possible after permanent 
discontinuation of BNT411.
2 Survival follow-up starts after all other protocol required visits have been completed and may be performed as telephone, email, or clinic visit.
3 Only if relevant or clinically indicated.
4 Full physical examination should be performed at screening, thereafter a limited physical examination is performed as indicated by the patient’s symptoms, AEs, or other findings as 
determined by the investigator. Physical examination should be performed before drug administration. 
5 To be performed by an ophthalmologist. Must at least include visual acuity testing, slit-lamp examination and direct or indirect ophthalmoscopy to help diagnose cataracts, glaucoma, 
detached retina, macular degeneration, and cornea injuries. Patients who wear glasses must have their baseline visual acuity properly documented. Further examinations such as visual field 
testing, non-contact tonometry and retinal tomography can be done if required.
6 Eye examination will be done at baseline (during screening), up to 3 days before Cycle 2 and thereafter up to 3 days before every third cycle (i.e. C2, C5, C8, C11, etc.).
7 The investigator should schedule eye examination with an ophthalmologist if there is suspicion of worsening of the eyesight, or if the patient complains about decrease in visual acuity or 
ocular discomfort. Patients should be referred to an ophthalmologist at the investigator’s discretion at any time point of the trial.
8 Temperature, blood pressure, pulse rate and respiratory rate as according to Section 8.6.2 and Table 1-6 of the protocol on BNT411 administration days. On days when BNT411 is not 
administered, vital signs only need to be obtained once any time during the visit.
9 Evaluation of left ventricular function, either by echocardiogram (ECHO) or multigated acquisition (MUGA) scan, will be performed within 21 days prior to Screening and as clinically 
indicated at other time points. Note: country specific information for Germany, left ventricular function should only be assessed by an ECHO scan (see Section 12.2.1).
10 All patients will have a CT-scan with contrast agent or MRI of thorax, abdomen, and pelvis during screening. Head and neck imaging is also required for patients with squamous cell 
carcinoma of the head and neck (SCCHN). Imaging of the pelvis is not required for patients with SCCHN but is strongly recommended. If a CT scan or MRI has been performed within 21 
days before the Cycle 1 Day 1 visit as part of standard procedures, then this scan will be acceptable as a screening scan for the trial. If brain metastases/tumors are indicated, a CT-scan or 
MRI of the brain will be performed within 21 days before the Cycle 1 Day 1 visit. Scans that exceed the 21-day window may be used for trial enrollment with sponsor approval.
11 On-treatment imaging will be performed at Week 6 (+7 days), every 6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) thereafter until disease progression is assessed by the 
investigator (unless the investigator elects to continue treatment [see Section 8.5.1 for conditions of continued treatment]), withdrawal of consent, trial termination by the sponsor, or death, 
whichever occurs first, regardless of whether patients start a new anti-cancer therapy. Refer to Sections 10.5 and 10.6 of the protocol for RECIST 1.1. and iRECIST imaging and treatment 
guidelines.
12 ECOG status should be assessed before drug administration. 
13 Adverse events (AEs) and serious adverse events (SAEs) should be reported from the time of signing the informed consent to 60 days (±7 days) after the patient receives the last dose of 
BNT411.
14 Suspected BNT411-related AEs only. Furthermore, in Germany only, all SAEs that occur in the patient throughout his or her lifetime should be reported – refer to Table 1-5 and 
Section 10.3.4 for further details.
15 Patients who experience a delay in the administration of BNT411 should return to the clinic at least every 2 weeks (±3 days) and assessments listed under ‘unscheduled visit’ should be 
performed and reported in the eCRF. Unscheduled visit assessments should be performed at the investigator’s discretion. For information on COVID-19 vaccination during the trial, see 
Section 10.9.
16 All labs at the screening visit must be obtained within 7 days of Cycle 1 Day 1. All lab assessments except for PK and biomarkers are done locally.
17 Laboratory samples should be obtained up to 3 days before treatment administration.
18 TSH, free-T3 and free-T4 will only be measured at screening, Cycle 1 Day 1, Cycle 2 Day 1, and on Day 1 of every evenly numbered cycle thereafter.
19 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The frequency of testing during treatment phase may depend on 
clinical indication per investigator's assessment and may also depend on local guidelines and regulations.


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20 Medical history includes cancer history.
21 Prior/Concomitant Medications and Non-Drug Therapies include all anti-cancer pre-treatments.
22 Prior/Concomitant Medication and Non-Drug therapies only for BNT411 related AEs.
23 Country specific procedure for Germany: To confirm that a patient would be eligible to participate in the trial, an active infection with HIV/Hepatitis B or C should be ruled out by serum 
blood test of hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus 
(anti-HCV), antibody against HIV-1 and -2 (anti-HIV 1/2).
24 The visit window of +2d on Day 3 should only be used if absolutely necessary due to immune phenotyping.


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Table 1-2:
Schedule of Activities – Part 1B
Treatment Cycle
Screening
Cycle 1-2
Cycle 3- 4
Cycle 5–N
Treatment 
discon-
tinuation1
Safety 
follow-up 1 
27
Safety 
follow-up 2 
27
Survival 
follow-up2
Un-
scheduled
Day (D)
≤21 days 
prior to 
Visit C1D1
D1
D2 D328
D8
D15
D1
D2
D3
D8
D15
D1
D2
D8
D15
-
30 days 
after last 
dose
60 days 
after last 
dose
Every 
12 weeks 
Visit window
±D3
-
+D228 ±D1 ±D1 ±D3
-
+D2 ±D1
±D1 ±D3
-
±D1 ±D1
-
+D5
±D7
±D14
Informed Consent
X
Informed Consent genetic testing
X
Eligibility Criteria
X
Demographics
X
Medical History23
X
Height
X
Body weight
X
X
X
X
X
X
X3
Physical Examination4
X
X
X
X
X
X
X
X
X
X
X
X
X
X2.,3
Eye Examination5
X
X6
X6
X
X
X7
Vital Signs8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
ECHO or MUGA scan9
X
X3
ECG
X
Please refer to Section 8.6.3 and Table 1-4 for details on ECG assessments 
CT/MRI-Scan
X10
Refer to Section 8.5.1 of the protocol for details on Imaging assessments11
ECOG Performance Status12
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
Adverse Events13
X
CONTINUOUS
X14
X3
Prior/Concomitant Medications and 
Non-Drug Therapies24
X
CONTINUOUS
X25
X3
BNT411 Administration15
X
X
X
X
X
X
X
Atezolizumab Administration16
X
X
X
Carboplatin Administration17
X
X
Etoposide Administration17
X
X
X
X
X
X
Prophylactic cranial irradiation
X18
End of Treatment
X
New anti-cancer treatment
X
X
X
X
Survival follow-up
X2
LABORATORY ASSESSMENTS (to be performed up to 3 days before treatment administration , unless indicated otherwise)
Hematology
X19
X20
X
X
X20
X20
X20
X20
X20
X20
X20
X20
X
X
X
X3
Biochemistry
X19
X20
X
X
X20
X20
X20
X20
X20
X20
X20
X20
X
X
X
X3
Coagulation factors
X19
X20
X20
X20
X20
X20
X20
X20
X20
X20
X
X
X
X3
Endocrine21
X19
X20
X20
X20
X
X3
Urinalysis
X19
X20
X20
X20
X20
X
X
X
X3
Pregnancy Test22
X19
X20
As indicated clinically 
X
X
X
X3
Serology 19
X26
PK Sampling (includes blood and 
urine)
Refer to Table 1-4 for details of PK samplings


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1 If the patient has to go off treatment per treatment withdrawal criteria (refer Section 7.1), the treatment discontinuation visit should be performed as soon as possible after permanent 
discontinuation of BNT411. A separate treatment discontinuation visit should also be done after discontinuation of atezolizumab, carboplatin and etoposide, if it occurs ≥21 days later than 
BNT411 (this visit will be entered as unscheduled visit in the eCRF).
2 Survival follow-up starts after all other protocol required visits have been completed and may be performed as telephone, email, or clinic visit.
3 Only if relevant or clinically indicated.
4 Full physical examination should be performed at screening, thereafter a limited physical examination is performed as indicated by the patient’s symptoms, AEs, or other findings as 
determined by the investigator. Physical examination should be performed before drug administration.
5 To be performed by an ophthalmologist. Must at least include visual acuity testing, slit-lamp examination exam and direct or indirect ophthalmoscopy to help diagnose cataracts, glaucoma, 
detached retina, macular degeneration, and cornea injuries. Patients who wear glasses must have their baseline visual acuity properly documented. Further examinations such as visual field 
testing, non-contact tonometry and retinal tomography can be done if required.
6 Eye examination will be done at baseline (during screening), up to 3 days before Cycle 2 and thereafter up to 3 days before every third cycle (i.e. C2, C5, C8, C11, etc.)
7 The investigator should schedule an eye examination with an ophthalmologist if there is suspicion for worsening of the eyesight, or if the patient complains about decrease in visual acuity 
or ocular discomfort. Patients should be referred to an ophthalmologist at the investigator’s discretion at any time point of the trial.
8 Temperature, blood pressure, pulse rate and respiratory rate as according to Section 8.6.2 and Table 1-6 of the protocol on BNT411 administration days. On days when BNT411 is not 
administered, vital signs only need to be obtained once any time during the visit.
9 Evaluation of left ventricular function, either by echocardiogram (ECHO) or multigated acquisition (MUGA) scan, will be performed within 21 days prior to Screening and as clinically 
indicated at other time points. Note: country specific information for Germany: left ventricular function should be assessed by an ECHO scan (see Section 12.2.1).
10 All patients will have a CT-scan with contrast or MRI of thorax, abdomen, and pelvis during screening. Head and neck imaging is also required for patients with squamous cell carcinoma 
of the head and neck (SCCHN). Imaging of the pelvis is not required for patients with SCCHN but is strongly recommended. If a CT scan or MRI has been performed within 21 days prior 
to visit Cycle 1 Day 1 as part of standard procedure, it is acceptable as a screening scan for the trial. If there is suggestion of brain metastases/tumors, a CT-scan or MRI of the head and 
neck will be performed within 21 days prior to the Cycle 1 Day 1 visit. Scans that exceed the 21-day window may be used for trial enrollment with sponsor approval.
11 On-treatment imaging will be performed at Week 6 (+7 days), every 6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) thereafter until disease progression is assessed by the 
investigator (unless the investigator elects to continue treatment [see Section 8.5.1 for conditions of continued treatment]), withdrawal of consent, trial termination by the sponsor, or death, 
whichever occurs first, regardless of whether patients start a new anti-cancer therapy. Refer to Sections 10.5 and 10.6 of the protocol for RECIST 1.1. and iRECIST imaging and treatment 
guidelines.
12 ECOG status should be assessed before drug administration.
13 Adverse events (AEs) and serious adverse events (SAEs) should be reported from the time of signing the informed consent to 60 days (±7 days) after the patient receives the last dose of 
BNT411, or atezolizumab, or carboplatin, or etoposide, whichever occurs later.
Treatment Cycle
Screening
Cycle 1-2
Cycle 3- 4
Cycle 5–N
Treatment 
discon-
tinuation1
Safety 
follow-up 1 
27
Safety 
follow-up 2 
27
Survival 
follow-up2
Un-
scheduled
Day (D)
≤21 days 
prior to 
Visit C1D1
D1
D2 D328
D8
D15
D1
D2
D3
D8
D15
D1
D2
D8
D15
-
30 days 
after last 
dose
60 days 
after last 
dose
Every 
12 weeks 
Visit window
±D3
-
+D228 ±D1 ±D1 ±D3
-
+D2 ±D1
±D1 ±D3
-
±D1 ±D1
-
+D5
±D7
±D14
Tumor biopsy, biomarkers
Refer to Table 1-8 for detailed biomarker assessment schedule


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14 Suspected BNT411 related AEs only. Except for Germany and Spain, where AEs related to atezolizumab, carboplatin, and etoposide should also be reported. Furthermore, in Germany 
only, all SAEs that occur in the patient throughout his or her lifetime should be reported – refer to Table 1-5 and Section 10.3.4 for further details.
15 Patients who experience a delay in the administration of BNT411 should return to the clinic at least every 2 weeks (±3 days) and an unscheduled visit should be performed and reported in 
the eCRF. Unscheduled visit assessments should be performed at the investigator’s discretion. For information on COVID-19 vaccination during the trial, see Section 10.9.
16 After discontinuation of chemotherapy, atezolizumab will be administered in combination with BNT411.
17 The recommended number of chemotherapy cycles is 4. If the investigator decides to administer more than 4 cycles, this should be discussed with the Medical Monitor.
18 After 4 cycles, prophylactic cranial irradiation (PCI) is permitted as per local guidelines and will be reported on the Cancer Radiotherapy eCRF. No systemic anti-cancer therapies should 
be administered concurrently with PCI. A delay of ≤21 days in administering systemic anti-cancer therapies due to PCI is not considered a protocol deviation.
19 All labs at the screening visit must be obtained within 7 days of Cycle 1 Day 1. All lab assessments except for PK and biomarkers are done locally.
20 Laboratory samples should be obtained up to 3 days before treatment administration.
21 TSH, free-T3 and free-T4 will only be measured at screening, Cycle 1 Day 1, Cycle 2 Day 1, and on Day 1 of every evenly numbered cycle thereafter.
22 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The frequency of testing during treatment phase may depend on 
clinical indication per investigator's assessment and may also depend on local guidelines and regulations. Pregnancy testing should also be done after discontinuation of atezolizumab, 
carboplatin, and etoposide if it occurs ≥21 days later than BNT411.
23 Medical history includes cancer history.
24 Prior/Concomitant Medications and Non-Drug Therapies include all anti-cancer pre-treatments.
25 Prior/Concomitant Medications and Non-Drug Therapies only for BNT411 related AEs.
26 Country specific procedure for Germany: an active infection with HIV/Hepatitis B or C should be ruled out by serum blood test of hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against HIV-1 and -2 (anti-HIV 1/2).
27 A separate safety follow-up visit should also be done after discontinuation of atezolizumab, carboplatin and etoposide, if it occurs ≥21 days later than BNT411 (this visit will be entered as 
unscheduled visit in the eCRF).
28 The visit window of +2d on Day 3 should only be used if absolutely necessary due to immune phenotyping.


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Table 1-3:
PK (blood and urine) sampling and ECG assessment in Part 1A
Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 
3 - N
Treatment 
Discontinuatio
n
Safety 
follow-up 
1
Safety 
follow-up 
2
UNS
Day
≤21 days 
prior to 
Visit C1D
1
D1
D2b
D3
b
D8
D1
5
D1
D2b
D3
b
D1c, e
-
30 days 
after last 
dose
60 days 
after last 
dose
-
Before BNT411 infusion (on 
infusion days) or on day of visit
E1
X, 
E3,Ua
X, 
E3,U
a 
X,
Ua
X, 
E3 
X 
X, 
E3,Ua 
X, 
(E3),U
a
X
X, E3 
X, E1
X, E1
X, E1
X, 
E1,U
a
Start of infusion
Ud
End of infusion (+5 min)
X, E3
X, 
E3
X, E3
X,E3
Start of infusion + 1 hour (±5 min)
X
(X)
Start of infusion + 2.5 hours 
(±10 min)
X
X
X
X
Start of infusion + 4 hours (±15 min)
X
X
X
X
Start of infusion + 6 hours (±15 min)
X, 
E3a,
X
X, 
E3a
(X)
Start of infusion + 8 hours (±15 min)
X
(X)
Note: Time points for blood and urine sampling are to be followed as closely as possible but time deviations no longer than 2 hours will not be reported as 
protocol deviations as long as the exact times of sampling and dose are known.
E1 – Single ECG assessment.
E3 – Triplicate ECG assessments.
X – Blood sampling.
U – Urine sampling.
UNS – Unscheduled visit.
(X) – Blood sampling will only be performed in potential additional patients enrolled to expand the cohorts for RP2D confirmation. 
(E3) – Triplicate ECG assessment will only be performed in potential additional patients enrolled to expand the cohorts for RP2D.
a Sampling time and sample volume have to be documented.
b Time window for the Day 2 sample in the dose escalation is 24 hours ± 1 hour and for Day 3 sample is 48 hours ± 2 hours after the start of infusion on Day 1.


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c PK and ECG must be obtained in Cycle 3, Cycle 5, Cycle 7, and every 4 cycles thereafter (i.e., Cycles 3, 5, 7, 11, 15, etc.).
d 6-hour urine collection after start of BNT411 infusion and total volume collected should be documented.
e After C3D1, PBMCs (for immune phenotyping and TCR profiling) will no longer be collected. Collection of PMBCs at treatment discontinuation and/or 
unscheduled visits is only required if the patient discontinues trial treatment prior to C3D1.


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Table 1-4:
PK (blood and urine) sampling and ECG assessment in Part 1B
Treatment 
Cycle
Screening
Cycle 1
Cycle 2
Cycle 
3 - N
Treatment 
Discontinuation
Safety
follow-up 1
Safety 
follow-up 2
UNS
Day
≤21 days 
prior to 
Visit C1 
(D1)
D1
D2
D3b
D8
D15
D1
D2
D3b
D2c
-
30 days after 
last dose
60 days 
after last 
dose
-
Before BNT411 
infusion (on 
infusion days) or 
on day of visit
E1
X,E3,
Ua
X,E3,
Ua 
X,E3 
X 
X,E3,
Ua 
X,(E3)
,Ua
X,E3
X,E1
X,E1
X,E1
X,E1,
Ua
Start of infusion
Ud
End of infusion 
(+ 5 min)
X,E3
X,E3
X,E3
X,E3
Start of infusion 
+ 1 hour 
(± 5 min)
X
(X)
Start of infusion 
+ 2.5 hours 
(± 10 min)
X
X
X
X
Start of infusion 
+ 4 hours 
(± 15 min)
X
X
X
X
Start of infusion 
+ 6 hours 
(± 15 min)
X,E3a
X
X,E3a, 
(X)
Start of infusion 
+ 8 hours 
(± 15 min)
X
(X)
Note: Time points for blood and urine sampling are to be followed as closely as possible but time deviations no longer than 2 hours will not be reported as 
protocol deviations as long as the exact times of sampling and dose are known.
E1 – Single electrocardiogram (ECG) assessment. 
E3 – Triplicate ECG assessments.


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X – Blood sampling
U – Urine sampling
UNS – Unscheduled visit
(X) – Blood sampling will only be performed in potential additional patients enrolled to expand the cohorts for RP2D confirmation.
(E3) – Triplicate ECG assessment will only be performed in potential additional patients enrolled to expand the cohorts for RP2D.
a Sampling time and sample volume have to be documented.
b Time window for the Day 3 sample in the dose escalation is 24 hours ± 1 hour after the start of infusion on Day 2.
c PK and ECG must be obtained in Cycle 3, Cycle 5, Cycle 7, and every 4 cycles thereafter (i.e., Cycles 3, 5, 7, 11, 15, etc.)
d 6-hour urine collection after start of BNT411 infusion and total volume collected should be documented.
e After C3D1, PBMCs (for immune phenotyping and TCR profiling) will no longer be collected. Collection of PMBCs at treatment discontinuation and/or 
unscheduled visits is only required if the patient discontinues trial treatment prior to C3D1.


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Table 1-5:
Overview of Safety Reporting in Different Countries
Notes: If not specified otherwise, when AE is mentioned, it should also include SAE.
Trial Phase
Country
Screening
Treatment 
Phase
Safety 
Follow-up 
Phase
Survival Follow-up Phase
Beyond Trial Closure
(if patient is alive and not lost to follow-
up)
USA
All AEs
All AEs
All AEs
BNT411-related AEs 
Trial procedure-related AEs
BNT411-related SAEs
Trial procedure-related SAEs
UK
All AEs
All AEs
All AEs
BNT411-related AEs
Trial procedure-related AEs
BNT411-related SAEs
Trial procedure-related SAEs
Spain
All AEs
All AEs
All AEs
BNT411-related AEs
Atezolizumab-related AEs
Carboplatin-related AEs
Etoposide-related AEs
Trial procedure-related AEs
BNT411-related SAEs
Atezolizumab-related SAEs
Carboplatin-related SAEs
Etoposide-related SAEs
Trial procedure-related SAEs
Germany
All AEs
All AEs
All AEs
All SAEs;
if the event is not an SAE, only the 
following to be reported:
BNT411-related AEs
Atezolizumab-related AEs
Carboplatin-related AEs
Etoposide-related AEs
Trial procedure-related AEs
All SAEs


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Table 1-6:
Vital Signs during Parts 1A and 1B
Patients should be monitored for a minimum of 6 hours in the clinic after each administration of 
BNT411. 
Vital signs are measured after BNT411 infusion at the following time points (further assessments 
can be done at the discretion of the investigator):
BNT411 pre-infusion (up to 30 min before infusion)
15 min after start of infusion (±5 min)* 
30 min after end of infusion (±5 min) 
60 min after end of infusion (±10 min) 
120 min after end of infusion (±15 min) 
*If infusion lasts for more than 60 minutes, vital signs should be assessed every 15 minutes (± 5 minutes) for the remaining duration of the 
infusion.


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Table 1-7:
Biomarker table – in Part 1A
Treatment Cycle
Screening
Cycle 1-2
Cycle 
3-N
Treatment 
discontinuation
Unscheduled
Day/Week
≤21 days prior 
to Visit C1 (D1)
D1
D2
D
3
D8
D15
D16
-
-
Visit window
-
1h
2h
±D1
±D1
±D3
-
-
Tissue compartment
Tumor FFPE sample 
X1
Tumor biopsy 
X2
X2
X2
X2
Blood compartment
Cytokines
X3
X3
X3
Immune Phenotyping
X4
X4
X4
X4
X4
X4
X4
X4
TCR profiling
X5
X5
X5
X5
1 A formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (for e.g., immunohistochemistry, tumor mutational burden) must be 
obtained from each patient from the latest available archival tumor tissue. If such tissue cannot be provided, the sponsor approval of 
enrollment is needed. Details regarding the preparation of slides and number of slides to be prepared will be described in the lab manual.
2 An optional fresh tumor biopsy (aspirates are not acceptable) which is collected before Cycle 1, Day 1, preferably derived from 
advanced stage disease. This biopsy needs to contain tumor tissue and is taken after failure/stop of last prior treatment at screening or 
before first administration of BNT411. Additionally, biopsies should be collected at Week 6 ([+7 days], i.e., after 2 cycles of BNT411) 
and at disease progression or treatment discontinuation if it is considered feasible without a risk of complications for the patient. If 
deemed necessary by the investigator, the patient may be called in for an unscheduled visit, optional additional tumor biopsies may be 
collected if patients have unscheduled biopsies or tumor tissue resection during the course of the trial. Details to the preparation of fresh 
tumor biopsies will be described in the lab manual.
3 Cytokine samples will be taken at the same time points given for PK sampling with the exception of “end of infusion”– please refer to 
Table 1-3. Furthermore, cytokine samples will be taken at disease progression or treatment discontinuation. If an adverse event (AE) of 
cytokine release syndrome (CRS) is suspected, cytokines should be obtained at an unscheduled visit to confirm diagnosis.
4 Immune phenotyping samples are requested at Day 1 (pre-dose), 24 hours / Day 2 (±1 hours) and 48 hours / Day 3 (±2 hours) after start 
of infusion in Cycles 1 and 2. Furthermore, immune phenotyping samples will be taken pre-dose in Cycles 1 and 2 at Day 8 and Day 15 
and pre-dose for every second cycle starting from Cycle 3 (e.g., Cycle 3, 5, 7, etc.) including time of disease progression or treatment 
discontinuation. Samples can also be taken at an unscheduled visit.
5 T-cell receptor (TCR) profiling (blood) samples are requested at Cycle 1 Day 1 (pre-dose), and at Cycle 3 Day 1 (pre-dose) and at time 
of disease progression or treatment discontinuation. Samples can also be taken at an unscheduled visit.
6 After C3D1, PBMCs (for immune phenotyping and TCR profiling) will no longer be collected. Collection of PMBCs at treatment 
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Table 1-8:
Biomarker table – in Part 1B
Treatment Cycle
Screening
Cycle 1-2
Cycle 3-N
Treatment 
discontinuation 
Unscheduled
Day/Week
≤21 days 
prior to 
Visit C1 
(D1)
D1
D2
D3
D8
D15
D16
-
-
Visit window
-
1h
±D1
±D1
±D3
-
-
Tissue compartment
Tumor FFPE sample 
X1
Tumor biopsy 
X2
X2
X2
X2
Blood compartment
Cytokines
X3
X3
X3
Immune Phenotyping
X4
X4
X4
X4
X4
X4
X4
TCR profiling
X5
X5
X5
X5
1 A formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (for e.g., immunohistochemistry, tumor mutational burden) must be 
obtained from each patient from the latest available archival tumor tissue. If such tissue cannot be provided, the sponsor approval of 
enrollment is needed. Details regarding the preparation of slides and number of slides to be prepared will be described in the lab manual.
2 An optional fresh tumor biopsy (aspirates are not acceptable), which is collected before Cycle 1 Day 1, preferably derived from 
advanced stage disease. This biopsy needs to contain tumor tissue and is taken after failure/stop of last prior treatment at screening or 
before first administration of BNT411. Additionally, biopsies should be collected at Week 6 ([+7 days], i.e., after 2 cycles of BNT411) 
and at disease progression or treatment discontinuation if it is considered feasible without a risk of complications for the patient. If 
deemed necessary by the investigator, the patient may be called in for an unscheduled visit, optional additional tumor biopsies may be 
collected if patients have unscheduled biopsies or tumor tissue resection during the course of the trial. Details to the preparation of fresh 
tumor biopsies will be described in the lab manual.
3 Cytokine samples will be taken at the same time points given for PK sampling with the exception of “end of infusion”– please refer to 
Table 1-4. Furthermore, cytokine samples will be taken at disease progression or treatment discontinuation. If an adverse event (AE) of 
cytokine release syndrome (CRS) is suspected, cytokines should be obtained at an unscheduled visit to confirm diagnosis.
4 Immune phenotyping samples are requested at D1 (pre-dose) and at D3 i.e. 48 hours (±2 hours) after start of infusion of BNT411 in 
Cycles 1 and 2. Furthermore, immune phenotyping samples will be taken pre-dose in Cycles 1 and 2 at Day 8 and Day 15 and pre-dose 
(D1) for every second cycle starting from Cycle 3 (e.g. Cycle 3, 5, 7, etc.) including time of disease progression or treatment 
discontinuation. Samples can also be taken at an unscheduled visit.
5 T-cell receptor (TCR) profiling (blood) samples are requested at Cycle 1 Day 1 (pre-dose), and at Cycle 3 Day 1 (pre-dose) and at time 
of disease progression or treatment discontinuation. Samples can also be taken at an unscheduled visit.
6 After C3D1, PBMCs (for immune phenotyping and TCR profiling) will no longer be collected. Collection of PMBCs at treatment 
discontinuation and/or unscheduled visits is only required if the patient discontinues trial treatment prior to C3D1.


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2
Introduction
2.1
Background
2.1.1
Overview of the Disease 
Cancer is the second leading cause of death globally and is expected to be responsible for an 
estimated 9.6 million deaths in 2018 (Center for Disease Control and Prevention 2017; 
International Agency for Research on Cancer 2017). Refinements in conventional therapies such 
as chemotherapy, radiotherapy, surgery, and targeted therapies and recent advances in 
immunotherapies have improved outcomes in patients with advanced cancers. However, many 
immunotherapy treatments have demonstrated efficacy in only a selected group of cancers 
(Ventola et al, 2017; Yang et al, 2015). There is an unmet medical need for more effective and 
less toxic therapies with cures remaining scarce in patients with advanced solid tumors.
Small cell lung cancer (SCLC) accounts for approximately 15% of bronchogenic carcinomas. At 
the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to 
the ipsilateral hemithorax, which can be safely encompassed within a radiation field. These 
patients are designated as having limited-stage disease (LS-SCLC) (Murray et al, 1993). Patients 
with tumors beyond the ipsilateral hemithorax, including malignant pleural or pericardial 
effusion or hematogenous metastases are said to have extensive-stage disease (ES-SCLC).
SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung 
cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely 
disseminated by the time of diagnosis and to recur. ES-SCLC was chosen as the indication to 
escalate the doses of BNT411 with atezolizumab, carboplatin and etoposide. 
2.1.1.1 Incidence and Mortality
The overall incidence of SCLC in the United States and in the United Kingdom has decreased 
during the past few decades (Govindan et al, 2006; Riaz et al, 2012). The following table shows 
the estimated number of new cases of lung cancer and deaths from lung cancer (SCLC and non-
small cell lung cancer [NSCLC] combined) in the United States in 2018 (American Cancer 
Society 2019) and in Europe in 2012 (Ferlay et al, 2013).
Lung Cancer
United States, 2018
Europe, 2012
New Cases
234,030
410,000
Deaths
154,050
353,000
Separate worldwide data for SCLC are not available. The incidence of lung cancer started to 
decline among men in the early 1980s and has continued to do so over the past 20 years. In 
contrast, the incidence in women started to increase in the late 1970s and did not begin to decline 
until the mid-2000s (American Cancer Society 2019; Siegel et al, 2019).


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2.1.1.2 Clinical Features
Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms 
and signs may result from the location of the primary local invasion or compression of adjacent 
thoracic structures, distant metastases or paraneoplastic phenomena. The most common 
symptoms at presentation are worsening cough, shortness of breath and dyspnea. Symptoms 
from distant metastases may also be present and include neurological defect or personality 
change from brain metastases or pain from bone metastases. Infrequently, patients with SCLC 
may present with symptoms and signs of the paraneoplastic syndromes.
2.1.1.3 Diagnosis
Treatment options for patients are determined by histology, stage, and general health and 
comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming 
the diagnosis and determining the extent of the disease. The procedures used to determine the 
presence of cancer include the following: history, physical examination, routine laboratory 
evaluations, chest X-ray, chest computed tomography (CT) scan with infusion of contrast 
material and biopsy.
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must 
review the pathologic material. This is critical because SCLC, which responds well to 
chemotherapy and is generally not treated surgically, can be confused on microscopic 
examination with NSCLC (Travis et al, 1999).
2.1.1.4 Prognosis and Survival
Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite 
improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC 
has the most aggressive clinical course of any type of pulmonary tumor, with median survival 
from diagnosis of only 2 months to 4 months. About 10% of the total population of SCLC 
patients remain free of disease during the 2 years from the start of therapy, which is the time 
period during which most relapses occur. Even these patients, however, are at risk of dying from 
lung cancer (both small and non-small cell types) (Johnson et al, 1990). The overall survival 
(OS) at 5 years is 5% to 10% (Fry et al, 1996; Johnson et al, 1990; Lassen et al, 1995; Murray et 
al, 1993).
An important prognostic factor for SCLC is the extent of disease. Patients with LS-SCLC have a 
better prognosis than patients with ES-SCLC. For patients with LS-SCLC, median survival of 16 
months to 24 months and 5-year survival of 14% with current forms of treatment have been 
reported (Fry et al, 1996; Janne et al, 2002; Murray et al, 1993; Turrisi et al, 1999). In patients 
with ES-SCLC, median survival of 6 months to 12 months is reported with currently available 
therapy, but long-term disease-free survival is rare. Prophylactic cranial radiation prevents 
central nervous system recurrence and can improve survival in patients with good performance 
status who have had a complete response or a very good partial response to chemoradiation in 
LS-SCLC or chemotherapy in ES-SCLC (Auperin et al, 1999; Slotman et al, 2007).
2.1.2
Standard Treatment Options for Patients with ES-SCLC
Standard treatment options for patients with ES-SCLC include the following:


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1. Combination chemotherapy.
2. Radiation therapy.
3. Immunotherapy.
4. Thoracic radiation therapy for patients who respond to chemotherapy.
5. Prophylactic cranial irradiation (PCI).
2.1.2.1 Combination Chemotherapy
Chemotherapy for patients with ES-SCLC is commonly given as a two-drug combination of 
platinum and etoposide in doses associated with at least moderate toxic effects (as in LS-SCLC) 
(Okamoto et al, 2007). Cisplatin is associated with significant toxic effects and requires fluid 
hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is 
active in SCLC, is dosed according to renal function, and is associated with less non-
hematological toxic effects.
Other regimens appear to produce similar survival outcomes but have been studied less 
extensively or are in less common use. Doses and schedules used in current programs yield 
overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with 
ES-SCLC (Pujol et al, 2000; Roth et al, 1992). Intracranial metastases from small cell carcinoma 
may respond to chemotherapy as readily as metastases in other organs (Nugent et al, 1979; 
Twelves et al, 1990).
2.1.2.2 Combination Chemotherapy and Radiation Therapy
Combination chemotherapy plus chest radiation therapy does not appear to improve survival 
compared with chemotherapy alone in patients with ES-SCLC.
2.1.2.3 Immunotherapy
Atezolizumab is a humanized, engineered monoclonal antibody against the protein programmed 
cell death-ligand 1 (PD-L1). On March 18, 2019, the Food and Drug Administration approved 
atezolizumab in combination with carboplatin and etoposide, for the first-line treatment of adult 
patients with ES-SCLC. This has marked the first systemic therapy approval for ES-SCLC after 
almost 30 years.
Approval was based on IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-
blind, placebo-controlled trial in 403 patients with ES-SCLC who had received no prior 
chemotherapy for extensive stage disease and had Eastern Cooperative Oncology Group (ECOG) 
performance status 0 or 1.
Major efficacy outcome measures were OS and progression-free survival (PFS) as assessed by 
investigator per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in the intent-to-
treat (ITT) population. Median OS was 12.3 months (range: 10.8–15.9 months) for patients 
receiving atezolizumab with chemotherapy and 10.3 months (range: 9.3–11.3 months) for those 
receiving placebo with chemotherapy (hazard ratio 0.70; 95% confidence interval [CI]: 0.54, 
0.91; p=0.0069). Median PFS was 5.2 months (range: 4.4–5.6 months) compared with 4.3 
months (range: 4.2–4.5 months) in the atezolizumab and placebo arms, respectively (HR 0.77; 
95% CI: 0.62, 0.96; p=0.0170).


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2.1.3
High Unmet Medical Need in ES-SCLC
As stated above, median survival of 6–12 months is reported in ES-SCLC with currently 
available therapy. There is still a very high unmet medical need to develop new therapies in ES-
SCLC, especially an innovative combination therapy to improve outcomes. The combination of 
immunotherapy and chemotherapy has proven effective, but the outcomes are still unsatisfactory 
compared to other malignant diseases (i.e., 2-month OS benefit and 0.9-month PFS benefit; 
IMpower133). Therefore, and in the light of the intended mode of action the development of a 
combined Toll-like receptor (TLR) 7 agonist with atezolizumab, carboplatin and etoposide to 
increase efficacy outcomes in ES-SCLC is fully justified.
2.1.4
Introduction to the Investigational Treatment
A promising approach in cancer immunotherapy involves Toll-like receptors (TLR), a group of 
receptors belonging to the innate immune system. Members of the TLR family are largely 
expressed by several immune and nonimmune cells, each cell type expressing a different 
combination of TLRs. Their function is to sense pathogen structures from different origins, such 
as bacteria, viruses, fungi, or protozoan parasites (Medzhitov et al, 2001; Holldack et al, 2014).
In particular, TLR7 is known to contribute to antitumor responses by affecting immune cells, 
tumor cells, and the tumor microenvironment (Smits et al., 2008). Recognition by TLR7 
activates intracellular pathways that culminate in the induction of type I interferons (IFNs), 
proinflammatory cytokines, chemokines and in the upregulation of costimulatory molecules. 
This boost can restore and support the anti-tumoral immunity of the innate and adaptive immune 
system. 
BNT411 is a highly potent and selective small molecule TLR7 agonist of the imidazoquinoline 
family which comprises other TLR ligands such as imiquimod (CAS-No.99011-02-6), 
resiquimod (CAS-No. 144875-48-9) and 852A (Cas-No. 532959-63-0). 
Imiquimod, resiquimod and 852A are being studied as immunotherapy drugs and show strong 
anti-tumoral activity; however, only imiquimod has been approved for human use so far. 
Repetitive intravenous administrations of imiquimod at a systemically effective IFNα-inducing 
dose level is associated with dose-limiting adverse reactions (Holldack et al, 2014; Witt et al, 
1993). As a consequence, imiquimod is registered for topical use only in localized diseases such 
as basal cell carcinoma, genital warts and bladder cancer (Edwards et al, 2000; Spencer et al, 
2006; Stanley et al, 2002; Vacchelli et al, 2012). Similarly, repeat-dose intravenous regimens of 
resiquimod and 852A are not well tolerated, limiting the clinical use of these compounds again to 
the treatment of localized disease (Lubong Sabado et al, 2015; Rook et al, 2015; Dudek et al, 
2007; Dummer et al, 2008; Geller et al, 2010; Spaner et al, 2010; Weigel et al, 2012). This 
unfavorable safety profile of imiquimod, resiquimod and 852A for intravenous administration 
may be attributable to the release of a broader array of proinflammatory cytokines (Gorden et al, 
2005; Hamm et al, 2009). 
BNT411 has been benchmarked in human whole blood preparations and been designed to 
mediate in this in vitro setting at concentrations corresponding to anticipated therapeutic doses 
primarily IFNα-release, as opposed to a broader array of cytokines to optimize the safety profile 
(study reports R-19-0027, R-19-0028). Further preclinical studies support this hypothesis and 


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show a broad safety window in different animal species (see Section 2.1.4.3) in association with 
an anti-tumoral activity in mouse models (study reports R-19-0011, R-19-0013). 
2.1.4.1 Structure
Figure 2-1:
Structure of BNT411
Nomenclature
BNT411
Laboratory code
SC100745, SC1.2, Ago1.2
Compound IUPAC Name
N-(4-(4-amino-2-(2-methoxyethyl)-1H-
imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-
2H-pyran-4-yl)acetamide
CAS 
2296821-50-4
Molecular weight
439.5579
Exact molecular weight
439.25834
Formula
C24H33N5O3
2.1.4.2 Mode of action
BNT411 is a selective TLR7 agonist, which activates signaling via the TLR7 pathway. TLR7 is 
expressed in dendritic cells (DC), primarily plasmacytoid DC, B-cells, and 
monocytes/macrophages. It is a key sensor for pathogen-associated molecular patterns (PAMPs) 
expressed on infectious agents (Medzhitov et al, 2001). Signaling through TLR7 initiates a 
cascade of effects. One is activation of plasmacytoid dendritic cells (pDC) for secretion of 
interferon alpha (IFNα). IFNα is a critical cytokine, which via pleiotropic mechanisms (direct 
mediation of tumor cell death; anti-angiogenesis; inhibition of suppressive regulatory T-cells; 
activation of immune cells, Th1 response), promotes anti-tumoral effects (Smits et al, 2008). 
TLR7 also activates DCs to efficiently process and present antigens released from dying tumor 
cells. This results in expansion of cytotoxic T-lymphocytes (CTLs). Expanded and activated T-
cells migrate into the tumor tissue, recognize tumor specific antigens and lyse tumor cells 


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(Vascotto et al, 2019). In addition, TLR7 signaling activates the innate immune system including 
natural killer (NK) cells and macrophages (Wiedemann et al., 2016; Williams et al, 2016). NK 
cells are capable of recognizing and lysing tumor cells which have down regulated their human 
leucocyte antigen (HLA) molecules in order to evade the adaptive immune system. 
In aggregate, these effects of TLR7-signaling are strong promoters of an efficient activation of 
innate and adaptive immunity against cancer cells. Synthetic compounds such as BNT411, which 
mimic the binding specificity of PAMPs, are considered promising drug candidates, which may 
overcome cancer-associated immune suppression and promote tumor cell killing. One of the 
challenges of known TLR7 agonists is the induction of a broader spectrum of pro-inflammatory 
cytokines beyond INF , including pyrogenic ones. This effect is hypothesized to be caused by 
TLR8 cross-signaling and made responsible for dose-limiting side effects upon systemic 
administration (Gorden et al, 2005; Hamm et al, 2009).
At therapeutic doses in human whole blood assays, BNT411 mediates primarily IFN-release, 
whereas release of pyrogenic pro-inflammatory cytokines requires 1-2 orders of magnitude 
higher doses (study reports R-19-0027, R-19-0028). An in vitro benchmarking experiment with 
other TLR7 agonists has shown that BNT411 induces IFN at a 10-30-fold lower concentration 
and causes the secretion of twice the amount of IFN   Cmax  than the most active tested 
comparator compound resiquimod (study report R-19-0028). In line with these observations, 
proof-of concept studies with BNT411 in mouse and monkey models demonstrated in vivo 
release of high levels of therapeutically relevant IFN. In addition, at those applied dose ranges 
anti-tumoral activity was demonstrated in mouse colorectal cancer tumor models (study reports 
R-19-0011, R-19-0013). 
2.1.4.3 Summary of non-clinical studies
Proof of principle for BNT411’s mode of action (MoA) has been obtained in animal models and 
in in vitro human whole blood assays. With respect to nonclinical safety, as specified in the ICH 
S9 guidance, the required non-clinical program was conducted to enable the proposed first-in-
human trial. Pivotal toxicology studies followed GLP regulations and were conducted in rats and 
cynomolgus monkeys. 
Note: More details on the non-clinical studies can be found in the investigator’s Brochure.
Primary Pharmacodynamics
IFNα as the driver cytokine of the MoA was observed to be the earliest pharmacodynamic 
marker in human whole blood preparations. Furthermore, upon BNT411 exposure in this in vitro 
setting, IFNα release was more pronounced and occurred at lower concentrations compared with 
other TLR7 agonist benchmarks. In addition, proinflammatory cytokines like TNFα or IL6 were 
observed only with significantly higher BNT411 concentrations than needed for a strong IFNα 
secretion. Due to this primarily release of IFNα at therapeutic doses as opposed to a broader 
array of cytokines, it is expected that BNT411 can potentially reduce dose-limiting side effects 
upon systemic administration.
Anti-tumor efficacy of BNT411 in monotherapy could be demonstrated in vivo in CT26, a 
syngeneic colon cancer mouse model. Of note, mice in the treatment group displayed increased 
frequencies of gp70+ T cells indicating that adaptive immunity contributes to the anti-tumor 
effect; in line with an elevated IFNα serum level. The combination of BNT411 with oxaliplatin 


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in the CT26 model resulted in higher reduction of tumor volume as compared to either treatment 
alone.
Secondary Pharmacodynamics
A receptor screening test evaluated the selectivity and specificity of BNT411 on 55 human 
receptors, transporters, and ion channels. No inhibition was observed on any of these unrelated 
targets, demonstrating that BNT411 did not engage with them. Only the human recombinant M1 
muscarinic acetylcholine receptor was partly inhibited at concentrations corresponding to non-
therapeutic doses. 
Safety Pharmacology
In vitro activity of BNT411 on the hERG ion channel was only seen at concentrations 
approximately 200-fold greater than the anticipated maximally administered dose in humans. 
Thus, interference with hERG activity is highly unlikely.
Based on the pharmacology of BNT411, a slight but transient increase in body temperature was 
seen in monkeys shortly after treatment. Further potential cardiovascular effects of BNT411 
were monitored in monkeys, as well as effects on the nervous system and on respiratory 
parameters in rats. However, in the dose range proposed for clinical testing, BNT411 is not 
anticipated to interfere with the function of these major organ systems.
Pharmacokinetics
Pharmacokinetics of BNT411 was evaluated across different animal species. No accumulation or 
sex-related differences in exposure were observed with weekly dosing in either rat or monkey. 
Exposure increases with dose showed a minor non-linearity which was more pronounced in rats 
than in cynomolgus monkeys.
In vitro plasma protein binding of BNT411 was similar across all tested species and was 64% for 
human plasma proteins.
In vitro studies on induction/inhibition of drug-metabolizing enzymes did not indicate potential 
interactions based on the low systemic exposure levels calculated for the proposed clinical dose 
levels. A study with human liver microsomes and recombinant CYP enzymes revealed that 
BNT411 was predominantly metabolized by CYP3A4 and CYP3A5.
Toxicology
Toxicological studies included single-dose toxicity in mice, rats, dogs and cynomolgus monkeys; 
29-day (once weekly) repeat-dose toxicity studies in rat and cynomolgus; mutagenicity (Ames 
test); and an in vitro phototoxicity test. 
Repeat-dose studies in rat and cynomolgus demonstrated effects of BNT411 that are consistent 
with the pharmacology of the compound. At high toxicological doses observations included 
changes to the eye in cynomolgus monkeys due to immune cell infiltration and in both species 
exaggerated pharmacological effects in spleen and lymph nodes. Overall, critical findings were 
made at toxicological dose levels in vast (200 – 1,000-fold) excess of the highest planned clinical 
dose. 


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2.2
Trial Rationale
2.2.1
Rationale for Testing BNT411 in Combination with Chemotherapy and Checkpoint 
Inhibitors
There is a strong unmet medical need to develop new efficacious therapies for patients with 
advanced malignancies whose disease no longer responds to standard therapy, but also for 
patients where current standard of care results in only marginal long-term disease-free survival 
(e.g., ES-SCLC). 
It is meanwhile accepted that a dysfunction of the immune system contributes to cancer disease. 
This paradigm, reflected by the so called “cancer immunity cycle” Figure 2-2 (Chen and 
Mellman, 2013), stipulates that tumor cell breakdown and release of tumor antigens results in 
priming of antigen-specific cytotoxic T cells but an efficient immune response to counteract the 
tumor is prevented by various physiological immune suppressive mechanisms. 
The compounds used in the standard of care first-line treatment of ES-SCLC do act in this 
regard. Chemotherapy (carboplatin, etoposide) induces immunogenic cell death (ICD) (Emens 
and Middleton, 2015), which is a prerequisite for inducing T cell specificities against a broad 
diversity of tumor antigens. This involves the release of tumor antigens and the emission of 
danger-associated molecular patterns (DAMPs) in the tumor microenvironment (TME). The 
anti-PDL1 antibody atezolizumab counteracts immunosuppressive signals produced by cancer 
cells or cells in the TME), directed specifically against PD1-positive and thus robustly primed 
effectors. As SCLC is a high mutational burden cancer, these mechanisms of efficient immune 
response are further promoted (George et al, 2015; Goodman et al, 2017; Peifer et al, 2012; 
Rudin et al, 2012). Finally, TLR7 agonists, which have immune effects synergizing with and 
complementing the ones of chemotherapy and anti-PDL1 blockade, can help to tip the balance 
towards robust cancer immunity.
In this regard, TLR7 signaling induced by BNT411 is expected to contribute on various levels, 
e.g. by improving the priming of antigen-specific T cells in the lymph node, and by recruiting 
additional cellular effectors such as NK cells and by reshaping the TME.


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Figure 2-2:
Modified Cancer Immunity Cycle from Chen & Mellman, Immunity, 2013. 
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment 
As this trial is the first to test BNT411 in humans, all precautions indicated when testing a new 
systemically active compound in a FIH trial will be taken, including choosing a high medical 
need patient population. The trial will be conducted at centers experienced in FIH trials, and 
trial-related procedures will only be performed by qualified physicians and trained nurses. The 
sponsor also prepares and trains the investigator to closely monitor, dose-delay, dose-reduce or 
withdraw patients based on adverse events that may occur with BNT411. Furthermore, there will 
be regular safety data review by the sponsor and the Safety Review Committee (SRC) for 
identification and evaluation of potential safety concerns. All patients enrolled in this trial will be 
monitored by qualified health care professionals who will provide care and evaluate the patient’s 
response to the trial drug, in terms of its safety and efficacy.
Beyond that, the sponsor went through a diligent exercise to identify and assess risks specific to 
BNT411 based on (i) the preclinical data package obtained for BNT411 and its predecessor 
compound SC1; and (ii) non-clinical and (iii) clinical literature data on other TLR7 agonists. 
This group of compounds encompasses, for example, 852A, resiquimod, and imiquimod, which 
are based on the same imidazoquinoline core structure as BNT411. 852A is structurally most 
closely related to BNT411 and has been extensively tested as an intravenously administered 
TLR7 agonist in several clinical trials (Astry et al, 2008; Dudek et al, 2007; Dummer et al, 2008; 
Geller et al, 2010; Harrison et al, 2007; Spaner et al, 2010; Weigel et al, 2012).
One risk, based on preclinical data with BNT411, is ocular toxicity. In one non-clinical, single-
dose toxicity study (Study SD_17_001) in monkeys, at doses 200-fold higher than the highest 
dose to be administered in humans (allometrically scaled to the HED), ocular toxicity occurred 


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due to infiltration of immune cells into the eyes. For TLR8 agonist motolimod (VTX-2337) 
ocular inflammation in monkeys has also been described at doses (allometrically scaled to the 
HED) approximately 170-fold higher than the highest dose applied to humans in a clinical 
phase 1 study, and ocular AEs were not observed (Northfelt et al. 2015). Taking into account this 
broad safety window, the risk of BNT411-induced ocular toxicity is considered low.
2.3.1.1 Important identified risks
Cytokine release syndrome
Cytokine release syndrome (CRS) has been recognized as an identified risk for BNT411. It is 
classified as an important identified risk. CRS is associated with the intended MoA of BNT411 
to modulate the immune system via a TLR7-signaling mediated release of a distinct type 1 IFN 
dominated spectrum of cytokines. The compound has been specifically developed not to activate 
a broad range of pyrogenic cytokines in the biologically active dose range.
In monkeys (studies SD_18_006 and SD_18_007), slight increase in body temperature was 
observed at doses (allometrically scaled to the human equivalent dose) corresponding to the two 
highest dose levels that will be applied in humans. In rats (studies SD_18_003 and SD_18_004), 
decreased motility and increased respiratory parameters were detected at doses (allometrically 
scaled to the human equivalent dose) which are 100-fold higher than the highest dose which will 
be administered in humans. 
The sponsor expects elevation of serum levels of indicator cytokines in the majority of patients at 
biologically active dose levels of BNT411. Systemic effects caused by those cytokines are 
pharmacodynamic surrogates. Correlating with such laboratory changes, adverse events (AEs) 
such as mild-to-moderate, transient and manageable flu-like symptoms (e.g. arthralgia, body 
temperature increased, chills, dehydration, dizziness, fatigue, feeling cold, headache, hot flush, 
hyperhidrosis, influenza-like illness, myalgia, nausea, pyrexia, tachycardia, and vomiting) are 
expected to occur. For these clinical manifestations of cytokine elevation, the trial protocol 
implements management with analgesics or anti-pyretics at recommended commonly used doses.
As BNT411 was developed to release cytokines such as IFN at an EC50 range lower than the 
EC50 required for release of cytokines such as TNF, IL-6, and IL-10, the sponsor gauges the 
risk of higher grade clinically relevant and unmanageable manifestations of elevated cytokines as 
low and this protocol addresses the probability of such risks with a risk management plan. Upon 
stimulation, it has been described for TLR7 agonists that lymphocytes egress to the periphery 
and return within 24 to 48 hours. This sequestration effect has been attributed to the secretion of 
IFN (Perkins et al, 2012) and may present as transient lymphopenia due to redistribution rather 
than cytotoxicity. Frequent laboratory monitoring is planned to observe this expected effect.
2.3.1.2 Important potential risks
Currently, no important potential risks have been identified for BNT411.
2.3.2
Potential Risks Associated with BNT411 in Combination with Atezolizumab, 
Carboplatin, and Etoposide
As this is the first trial in humans, the risk of synergistic and/or potentiating toxicities when 
BNT411 is combined with atezolizumab, carboplatin and etoposide cannot be completely ruled 


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out. Therefore, the trial seeks to mitigate this risk by implementing a bifurcated trial design to 
start combination dose escalation. The combination dose escalation will only occur after 
reasonable data for BNT411 are generated in monotherapy dose escalation. Additionally, the 
dose level to start the combination dose level and at any given time thereafter will always be one 
dose level lower than in monotherapy dose escalation. This should mitigate such a potential risk 
for unknown synergistic and/or potentiating toxicities. Supporting data from preclinical studies 
of BNT411 in combination with cytotoxic agents also do not suggest any other risks seen in 
BNT411 monotherapy. The sponsor is also currently performing further preclinical experiments 
of BNT411 in combination with more chemotherapy agents and anti-PD-L1 antibody.
No indications of organ-specific autoimmunity have been identified for BNT411, or for any 
other imidazoquinoline compounds. In this trial (Part 1B, Part 2) BNT411 is combined with 
atezolizumab, which is known in line with its mode of action to be associated with organ-specific 
autoimmunity and consequently with immune-related adverse events (irAEs). Therefore, irAEs 
and their management are specifically addressed by this trial protocol, even though the risk of 
them induced by single agent BNT411 is considered as very low. 
In conclusion, the non-clinical and literature data collected so far do not show any potential 
unacceptable toxicities that cannot be mitigated or managed in the clinical setting. The 
anticipated benefits of BNT411 in patient populations with high unmet medical needs outweigh 
the potential risks with the compound.
2.3.3
Benefit Assessment
BNT411 is expected to be beneficial even when used as a monotherapy anticancer agent as 
shown by preclinical data. The TLR7 agonist could potentially invigorate a systemic immune 
reaction to confer antitumor immune response. In monotherapy dose escalation, patients have 
exhausted all available standard-of-care therapies and those patients could potentially benefit 
from the use of BNT411 monotherapy as the last alternative given the current preclinical 
pharmacological data generated. There is still a high unmet medical need in patients with 
advanced or metastatic solid tumors and it is planned to evaluate BNT411 in various suitable 
tumor indications and settings.
2.3.4
Potential Benefits Associated with BNT411 in Combination with Atezolizumab, 
Carboplatin and Etoposide
BNT411 is expected to mount tumor-targeted, integrated innate and adaptive immune reactions 
in combination with cytotoxic therapies and PD1/PDL1 blockade in particular in settings with 
large tumor load. 
The focus of development on ES-SCLC is justified based on its poor prognosis even in the early 
setting. In IMPower133, atezolizumab in combination with chemotherapy prolonged the median 
overall survival by 2 months and PFS by 0.9 month, meaning that the medical need is still very 
high. ES-SCLC is an ideal setting for BNT411 because there is extensive disease and it is highly 
sensitive to the standard of care, thereby providing an efficient tumor cell death and high 
-volume release of tumor antigens. As SCLC is a high mutational load tumor type it is expected 
that it is a rich source for neo-epitopes which would be adjuvanticized by BNT411. Therefore, 
BNT411 is postulated to enhance the chemo-immunotherapy backbone with atezolizumab, 
carboplatin and etoposide in ES-SCLC. It could potentially prolong a durable immune response 


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in a low-tumor-burden environment that should benefit the patients in terms of longer overall 
survival. Further potential benefits and rationale for the combination are described in 
Section 2.2.1.
2.3.5
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to patients participating in this trial, the 
potential risks identified in association with BNT411 are justified by the anticipated benefits that 
may be afforded to patients with advanced or metastatic solid tumors.


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3
Objectives and Endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1:
Objectives and Endpoints
OBJECTIVES
ENDPOINTS
Primary
• For Parts 1 and 2: Assess safety profile 
• Occurrence of DLTs within a patient 
during the DLT evaluation period
• Occurrence of TEAEs within a patient 
including grade ≥3, serious, fatal TEAE by 
relationship 
• Occurrence of dose reduction and 
discontinuation of BNT411 within a 
patient due to TEAEs 
• For Part 1: Determine MTD and/or RP2D 
• MTD defined as the highest tolerated dose
• RP2D based on integrated evaluation of 
safety, tolerability, clinical benefit, PK, and 
pharmacodynamic data, for all dose levels 
tested
Secondary
• For Parts 1 and 2: Establish PK profile 
• PK parameters (AUC, CL and VD, Cmax, 
Tmax, Ctrough, and T1/2) 
• For Part 2: Evaluate anti-tumor activity 
according to RECIST 1.1
• ORR defined as the proportion of patients 
in whom a CR or PR is observed as best 
overall response. 
• DCR defined as the proportion of patients 
in whom a CR or PR or SD (assessed at 
least 6 weeks after first dose) is observed 
as best overall response.
• DOR defined as the time from first 
objective response (CR or PR) to the date 
of the first occurrence of objective tumor 
progression or death from any cause, 
whichever occurs first.


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OBJECTIVES
ENDPOINTS
Exploratory
• For Part 2: Evaluate anti-tumor activity 
according to iRECIST
• iORR defined as the proportion of patients 
in whom a iCR or iPR is observed as best 
overall response. 
• iDCR defined as the proportion of patients 
in whom a iCR or iPR or iSD (assessed at 
least 6 weeks after first dose) is observed 
as best overall response.
• iDOR defined as the time from first 
objective response (iCR or iPR) to the date 
of the first occurrence of objective tumor 
progression (iCPD) or death from any 
cause, whichever occurs first.
• For Part 2: Evaluate preliminary efficacy
• PFS defined as the time from first dose of 
BNT411 to first occurrence of objective 
tumor progression (per RECIST 1.1), or 
death from any cause, whichever occurs 
first. 
• OS defined as the time from first dose of 
BNT411 to death from any cause.
• For Parts 1 and 2: Preliminary assessment 
of biomarkers that might act as 
pharmacodynamics, anti-tumor, and safety 
indicators of activity of BNT411 
monotherapy and in combination with 
chemotherapy and atezolizumab
• Changes in selected cytokines and other 
activation markers compared to baseline
• Changes in systemic and intra-tumoral 
immune response in blood and tumor 
tissue compared to baseline (e.g. 
immunophenotyping of immune cells in 
peripheral blood, absolute and relative 
changes compared to baseline in tissues 
and/or PBMCs)
AUC, area-under-the-concentration-time curve; CL, clearance; Cmax, maximum concentration; (i)CR, (immune) 
complete response; Ctrough, trough concentration; (i)DCR, (immune) disease control rate; DLTs, dose-limiting 
toxicities; DOR, duration of response; iCPD, immune confirmed progressive disease; iRECIST, immune RECIST; 
MTD, maximal tolerated dose; (i)ORR, (immune) objective response rate; OS, overall survival; PBMCs, peripheral 
blood mononuclear cells; PFS, progression-free survival; PK, pharmacokinetic; (i)PR, (immune) partial response; 
RECIST, Response Evaluation Criteria in Solid Tumors; RP2D, recommended Phase 2 dose; (i)SD, (immune) stable 
disease; T1/2, terminal half-life; TEAEs, treatment emergent AEs; Tmax, time to Cmax; VD, volume of distribution. 


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4
Trial Design
4.1
Overall Design
This is an open-label, multicenter Phase 1/2a dose escalation, safety, PK and pharmacodynamic 
trial of BNT411 with expansion cohorts in a mixed population of patients with solid tumors. The 
trial consists of three parts: 
•
Part 1A will be a monotherapy dose escalation in patients with advanced solid cancers until 
the MTD and/or RP2D of BNT411 as monotherapy are defined.
•
Part 1B will be a combination dose escalation in patients with chemotherapy-naïve ES-
SCLC until the MTD and/or RP2D of BNT411 in combination with atezolizumab, 
carboplatin and etoposide are defined.
•
Part 2 will consist of expansion cohorts in solid cancers based on data generated in Part 1A 
and Part 1B. 
Part 1B is planned to start before the MTD/RP2D is reached in Part 1A using a bifurcated trial 
design. Bifurcation is planned to start when Part 1A monotherapy dose level 5 (2.4 µg/kg) 
evaluation is completed and deemed safe. At this point, Part 1B would start with one dose level 
below (i.e. dose level 4 [1.2 µg/kg]). Based on nonclinical data, this dose level is considered to 
be the anticipated minimally efficacious dose. Atezolizumab, carboplatin and etoposide will be 
administered at fixed doses approved for the indication of ES-SCLC.
In case the MTD for monotherapy is identified prior to dose level 5, the bifurcation will start one 
dose level below the monotherapy MTD dose level. The sponsor together with the Safety 
Review Committee (SRC) may explore intermediate dose levels to bifurcate from monotherapy 
to combination dose escalation based on safety, PK, pharmacodynamics and preliminary efficacy 
data generated. 
The dose level of BNT411 in Part 1B at any given time will always be one dose level below that 
in Part 1A. This approach will allow for rapid and safe triggering of the combination dose 
escalation. This will lead to the timely optimization of the combination schedule that will be 
taken to the Phase 2 trial. At the same time, patient safety is safeguarded by generating enough 
monotherapy data before bifurcation, and clear rules for parallel dose escalations are outlined.
In Part 2, once a dose level is deemed safe and endorsed by the SRC, additional patients can be 
included at a given dose level of either monotherapy or combination in order to explore, for 
example, early efficacy in other indications and/or pharmacodynamic signals. Furthermore, 
different doses and schedules might be explored during the dose escalation and/or expansion 
based on the data generated in the dose escalation. Additional indication-specific solid cancer 
cohorts are implemented by protocol amendment. 
In Parts 1A and 1B, patients will receive one infusion of BNT411 every week in a 3-week cycle 
for the first 4 cycles. In the following cycles thereafter, BNT411 will be administered every 3 
weeks. In Part 1B of Cycle 5 onwards, instead of receiving BNT411 on Day 1, patients will 
receive the BNT411 infusion on Day 2 of each cycle. Treatment will continue until protocol-
defined treatment discontinuation criteria are met (refer to Section 7.1). 
Efficacy will be assessed by on-treatment imaging at Week 6 (+7 days), every 6 weeks (±7 days) 
for 48 weeks, and every 12 weeks (±7 days) thereafter until disease progression is assessed by 


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the investigator (unless the investigator elects to continue treatment [see Section 8.5.1 for 
conditions of continued treatment]), withdrawal of consent, trial termination by the sponsor, or 
death, whichever occurs first, regardless of whether patients start a new anti-cancer therapy. The 
RECIST 1.1 criteria will be used for secondary endpoint response evaluation including PFS 
(Eisenhauer et al, 2009); iRECIST will be used for exploratory endpoint response evaluation 
(Seymour et al, 2017). All images obtained must be submitted to the central imaging vendor. The 
design of the trial is shown in Figure 4-1.
Figure 4-1:
Overall Trial Design
4.1.1
Dose Escalation (Part 1A and 1B)
4.1.1.1 Dose Escalation in Part 1A
The dose escalation starts with an accelerated phase consisting of single patient cohorts followed 
by larger patient cohorts informed by a classical 3+3 design. The single patient cohorts in the 
first 3 dose levels will be expanded to 3+3-patient cohorts in case of occurrence of Grade ≥2 
toxicities, or the occurrence of DLTs, or based on the decision of the sponsor’s SRC based on 
safety data generated. In addition, in the single-patient cohort phase, the next cohort can only 
start once the DLT period for the previous dose level has been assessed and the next dose level is 
proposed by the SRC and endorsed by the sponsor. Once a single-patient cohort has been 
expanded, all future cohorts will follow the 3+3 design. Additional details regarding the SRC can 
be found in Section 9.6. The DLT period is defined as one cycle (i.e. 21 days).
During the 3+3 phase, at every dose level to be tested, staggered enrollment will be employed as 
described below. In each dose level cohort, the 3 patients will be dosed successively with a 
safety monitoring interval of at least 48 hours between the intravenous administration of 
BNT411 in the first and the second patient, and between the second and the third patient. The 
safety monitoring period is reduced to at least 24 hours when expanding a dose level which has 
already been declared safe.


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Hospitalization is required for the first 24 hours after the first BNT411 administration in Cycle 1 
for clinical observation and PK sampling. Prolongation of the hospitalization beyond 24 hours 
may be performed at the investigator’s discretion if deemed necessary based on potential risks 
related to the trial treatment and clinical status of the patient. For the assessments of each cohort, 
the dose limiting toxicities will be collected for the first treatment cycle, i.e., a DLT evaluation 
period of 21 days.
Dose escalation will follow a classical 3+3 design and continue until DLTs are observed in 2/3 or 
2/6 patients as described in the following dose escalation table (Table 4-1).
Table 4-1:
Dose escalation table
Number of evaluable patients 
with DLT at a given dose level 
after the first treatment cycle
Escalation decision rule
0 out of 3
OR
1 out of 6 
Enter patients at the next higher dose level 
1 out of 3 
Enter more patients at this dose level to a total of at least 6 
evaluable patients or 2 patients with DLT 
2 out of 3 
OR 
at least 2 out of 6
Dose escalation will be stopped, the MTD will be 
considered to be reached at the one before the last dose level 
explored. The sponsor will decide, based on a discussion 
between the investigators and the sponsor at a dose 
escalation meeting, if additional patients need to be enrolled 
and at which dose to finalize the trial
Any condition which would 
require further clarification of 
safety
A cohort of 6 patients can eventually be extended and more 
patients can be enrolled in a cohort if decided by the sponsor 
based on a discussion between the investigators and the 
sponsor at a dose escalation meeting
DLT = dose-limiting toxicity; MTD = maximal tolerated dose.
The dose escalation will potentially (dependent on data collected during the trial) evaluate 
BNT411 at eight main dose levels as shown in Table 4-2.


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Table 4-2:
BNT411 dose increments
Dose Level
Dose of BNT411*
(μg/kg/administration)
Dose Increment*
1**
0.05
Starting dose
2**
0.15
200%
3**
0.45
200%
4
1.2
166%
5
2.4
100%
6
4.8
100%
7
9.6
100%
8
16.0
66%
* Can be reduced or increased as a function of the observed biologic activity and based on other data generated 
during the trial for dose optimization.
** Accelerated titration (single patient cohorts). Will be expanded to 3+3-patient cohorts in case of occurrence of 
Grade ≥2 toxicities, or the occurrence of DLTs, or based on the decision of the sponsor’s SRC based on safety data 
generated.
Based on the nonclinical toxicology profile, which does not suggest a steep dose- or exposure-
response curve and showed no severe toxicity findings, an initial dose tripling is proposed. 
Subsequently, standard dose doubling is proposed starting from dose level 4 in line with the FDA 
Guidance for Industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. Based on 
nonclinical data, dose level 4 is the anticipated minimal efficacious dose. Furthermore, the 
sponsor proposes seven optional, intermediate dose levels at 0.075, 0.225, 0.9, 1.8, 3.6, 7.2 and 
12.8 µg/kg.
To be eligible for DLT assessment, patients should receive all three infusions of BNT411 during 
Cycle 1 (DLT assessment period). Patients who will not be able to fulfil the criteria for the DLT 
assessment will be replaced and this only applies to patients who do not experience a DLT. As 
long as patients do not experience a DLT, patients who have been replaced can continue with 
BNT411 treatment and follow the same trial procedures until unacceptable toxicity, documented 
disease progression, and/or the onset of a new anti-cancer therapy (palliative radiotherapy of, for 
example, painful bone metastases not defined as target lesions will be allowed).
After completion of the DLT period for each cohort, the SRC will review the data from the DLT 
period – including but not limited to all relevant safety and clinical data – to propose a dose level 
for the next cohort of patients; PK and pharmacodynamics data, if available, will also be taken 
into consideration. 
The sponsor can backfill a certain dose level cohort to explore and generate more safety, PK, 
pharmacodynamics, and anti-tumor data up to a total of 14 patients in a given cohort. Staggering 
would not be implemented as backfilling would occur once the dose level is declared safe by the 
SRC.


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4.1.1.2 MTD and RP2D Definitions
The MTD is defined as the highest tolerated dose.
The RP2D will be determined based on integrated evaluation of safety, tolerability, clinical 
benefit, PK and pharmacodynamics data, for all dose levels tested. The RP2D will be determined 
based on aggregate data including, but not limited to, the following rules and considerations: 
1. The RP2D will not exceed the MTD. 
2. Consideration will be given to toxicities other than DLTs, specifically adverse events (AEs) 
assessed as related to BNT411 treatment, the nature and frequency of toxicities, and the 
emergence of any specific category of toxicities. 
3. Evidence of clinical activity, as available. 
4. Available pharmacodynamics data.
If the RP2D cannot be distinguished using the criteria above, cohort expansion for optimized 
RP2D determination may take place at up to two dose levels to obtain data for up to six 
additional patients per dose level. Selection of RP2D will then be based on this larger dataset. If 
serious related toxicities are observed in later cycles beyond Cycle 1, a reduction of the MTD 
and/or adjustment of RP2D may be considered. This determination will be made by dose-
expansion cohort (DEC) and endorsed by the SRC.
4.1.1.3 Dose Escalation in Part 1B
The rules and details on the bifurcated design are outlined in Section 4.1.
The dose escalation in Part 1B follows the classical 3+3 design as described above in 
Section 4.1.1.1. However, in the case that any dose level in Part 1B is declared as MTD, dosing 
in Part 1B should stop. The monotherapy dose escalation in Part 1A can proceed independently 
of Part 1B until MTD and/or RP2D of BNT411 monotherapy are established. Refer to 
Section 6.6.5 for safety stopping criteria.
After 4 cycles of treatment, PCI is permitted as per local guidelines and will be reported on the 
electronic Case Report Form (eCRF). No systemic anti-cancer therapies should be administered 
concurrently with PCI. A delay of ≤21 days in administering systemic anti-cancer therapies due 
to PCI is not considered a protocol deviation. Thoracic radiation with curative intent or the intent 
to eliminate residual disease is not permitted. Palliative thoracic radiation and other palliative 
radiotherapies are allowed.
4.1.2
Expansion Phase (Part 2)
As described in Section 4.1, expansion cohorts can be implemented by protocol amendment. The 
decision to expand is based on the totality of data generated in both Part 1A and Part 1B. The 
expansion cohort can be a single-arm cohort or a randomized cohort. All decisions for expansion 
should be endorsed by the SRC.
4.1.3
Adaptive Trial Design Elements
•
In order to account for potential interpatient variability with an immunotherapy 
compound such as a TLR7 agonist, a recommended Phase 2 dose range (RP2DR) instead 


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of a recommended dose for BNT411 can be implemented based on data generated in dose 
escalation. The dose range will not exceed the MTD established in the trial and will not 
exceed more than 3 dose levels. 
•
Bifurcation is planned to start when Part 1A monotherapy dose level 5 (2.4 µg/kg) 
evaluation is completed and considered safe. At this point, Part 1B would start with one 
dose level below (i.e., dose level 4 [1.2 µg/kg]). Based on nonclinical data, this dose level 
is considered to be the anticipated minimally efficacious dose. If minimal 
pharmacodynamics activity is not reached when monotherapy dose level 5 is completed, 
bifurcation to Part 1B may happen at a higher dose level. Bifurcation can also start at a 
lower dose level than dose level 5, if pharmacodynamics activity is seen earlier. 
However, the following rule always applies: the dose level of BNT411 in Part 1B at any 
given time will always be one dose level below that in Part 1A. Decision to bifurcate at 
any given dose level will be discussed and agreed by the SRC.
•
Addition or removal of PK time points depending on emerging data on BNT411 can be 
performed. Samples at various time points post-injection may be added based on 
emerging data from this trial. If the PK data are uninformative, one or more time points 
may be removed.
•
The sponsor can backfill a certain dose level cohort to explore and generate more safety, 
PK, pharmacodynamics, and anti-tumor data up to a total of 14 patients in a given cohort.  
Staggering would not be implemented as backfilling would occur once the dose level is 
declared safe by the SRC.  
4.2
Planned Number of Patients
•
Between 6 to 60 DLT evaluable patients are planned to be enrolled in Part 1A. 
•
Between 6 to 30 DLT evaluable patients are planned to be enrolled in Part 1B.
•
For the dose escalation (Parts 1A and 1B), approximately 12 sites will be opened in North 
America and Europe. 
•
For possible expansion, approximately 25 to 35 sites will be opened in North America, 
Europe and potentially the rest of the World.
4.2.1
Replacement of Patients
Patients will be replaced in the following scenarios:
•
Patient is not evaluable for DLTs (only applies to patients who do not experience a DLT).
•
Patient was enrolled in the trial but did not receive a dose of BNT411.
4.3
Trial Design Rationale
The first part of this trial is a FIH, open-label, dose-escalation trial studying BNT411 
monotherapy in patients with different types of malignant solid tumors in order to determine the 
safety profile of BNT411. The second part aims to determine further the safety profile of 
BNT411 in combination with atezolizumab, carboplatin and etoposide in patients with 
ES-SCLC. The third part is the expansion phase to explore BNT411 further as a monotherapy or 
in combination with atezolizumab, carboplatin and etoposide in select tumor indications. 
Different treatment schedules and other indications may also be explored in Part 2.


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In order to address the trial objectives in this FIH trial, a dose-escalation using an accelerated 
titration (i.e. single-patient cohort) followed by a 3+3 design was selected. The first three dose 
levels are assumed to induce no or minimal biological effects in humans and are included to 
safeguard patient’s safety while introducing a novel compound in humans. In case of occurrence 
of Grade ≥2 toxicities, or the occurrence of DLTs, or based on the decision of the sponsor’s SRC 
based on safety data generated, the single-patient cohorts will be expanded to 3+3-patient 
cohorts. The single-patient cohorts will accelerate safely to start dosing patients with doses 
expected to induce minimal biological effects with BNT411. The classical 3+3 design is 
appropriate for a FIH dose-escalation trial in oncology; however, this trial will consider all data 
generated to decide on the RP2D. 
The safety, PK, pharmacodynamics, and clinical efficacy data combined provide both more 
flexibility and better accuracy of the estimated RP2D while safeguarding the patient’s safety. 
The MoA of BNT411, a TLR7 agonist stimulating the innate immune system, which further 
activates the adaptive immune system, allows the trial to be driven by pharmacodynamics. 
Selected biomarkers, such as type-1 interferons and other cytokines can potentially be used to 
guide the dose escalation in both Part 1A and Part 1B. 
4.3.1
Rationale for Bifurcated Design
One cornerstone of the development rationale is to have a setting with fast and high volume 
release of tumor antigens from a high-mutational load tumor (see Section 2.1.4.2 and Section 2.2 
for details). This is to be achieved by combining with an already efficient but not durable 
cytotoxic treatment. Therefore, rapid triggering of combination testing is desired. One of the 
common approaches to integrate the combination assessment in clinical development is by using 
a bifurcated design, which is pursued in this trial. 
In Part 1A, monotherapy dose escalation will be executed through several dose levels and if 
safety is acceptable and no DLTs are identified, the trial will “bifurcate” to two distinct paths for 
subsequent escalation. This will allow safety, tolerability, PK and pharmacodynamics of 
BNT411 in combination with the approved therapy of atezolizumab, carboplatin and etoposide to 
be assessed and optimized at an early stage. This approach will potentially accelerate further 
clinical development for early access in areas of high unmet medical need.
4.3.2
Rationale for Body Weight-Based Dosing
Thus far, the development of most of the intravenously applied drugs employs either 
body-weight-based or body-surface-area-based dosing in the FIH setting. Once clinical PK data 
are generated, population PK modeling is applied to explore the effect of body weight (BW) and 
body surface area (BSA) on variability and the dosing is adapted, where applicable. The 
development of BNT411 follows the same paradigm. 
Non-clinical experiments with BNT411 in various animal species (mouse, rat, cynomolgus 
monkey, dog) have yielded PK data to support BW-based dosing as they have shown similar 
plasma concentrations and exposure to BNT411 within the respective species. Simulation of 
human PK parameters based on these non-clinical PK data supports this observation. Therefore, 
BW-based dosing will be applied in the trial in order to ensure similar plasma concentration 
(exposure) within dosing cohorts. A cap on dosing for patients weighing 120 kg and more will be 
implemented in the proposed clinical trial.


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4.4
Dose and Schedule Rationale 
Administration of TLR7 agonists results in the activation of pDCs followed by their transient 
depletion. Consequently, the pool of excitable pDCs has to be replenished by expanding and 
maturing precursor cells from the bone marrow (Markov et al, 2016), a process which takes 
about 7 days (Bourquin et al, 2011; Tsitoura et al, 2015). It has been described for other TLR7 
agonists that this may result in tachyphylaxis, meaning that within this time period, additional 
administrations will not result in further secretion of IFNα (Bourquin et al, 2011; Tsitoura et al, 
2015). To avoid this mechanism and yet ensure frequent stimulation of the immune system, 
BNT411 will be administered once weekly in the first 4 cycles. These 4 cycles are considered to 
induce a sufficient immune response. Consequently, BNT411 is applied every 3 weeks as a 
maintenance therapy after the first 4 cycles instead of every week.
BNT411 will be administered as a 30-minute infusion in the clinic. Preclinical experiments 
revealed acute adverse effects at lower doses when administered as bolus injection but not as 
infusion, while pharmacodynamic parameters remained comparable, irrespectively of the 
duration of compound administration. 
The BNT411 starting dose of 0.05 µg/kg is calculated based on a minimally anticipated biologic 
effect level (MABEL) approach with an additional safety factor of 25:
•
Upon BNT411 exposure, IFN-secretion is the earliest detectable pharmacodynamics 
marker in human whole blood preparations.
•
4 nM is the minimal effective concentration (MEC) of BNT411 needed to induce IFN 
in this in vitro setting (Studies R-19-0027 and R-19-0028), which equals approximately a 
human plasma Cmax of 2 ng/mL.
•
To reach this target plasma concentration, an intravenously applied dose of 1.25 µg/kg is 
required (based on human pharmacokinetic modeling with animal data; Study 
BNSM2018002). This dose equals approximately dose level 4 (1.2 µg/kg).
•
A safety factor of 25 is applied, resulting in the proposed human starting dose of 
0.05 µg/kg.
Based on the nonclinical toxicological profile, which does not indicate a steep dose- or exposure-
response curve and does not show any severe toxicity findings, an initial dose tripling for the 
accelerated titration design in the dose escalation phase Part 1A is suggested. Following this, 
standard dose doubling is suggested starting from dose level 4 in line with the FDA Guidance for 
Industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. Based on nonclinical data 
and as described in the MABEL approach, dose level 4 (1.2 µg/kg) is the anticipated minimal 
efficacious dose.
Information relating to COVID-19 vaccinations including a risk-benefit assessment and guidance 
for vaccination during this clinical trial is provided in Sections 10.8 and 10.9.
More details on the dose and schedule rationale can be found in the Investigator’s Brochure.


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4.5
End of Trial Definition
The trial will be considered completed once all patients have completed treatment and safety 
follow-ups. After the sponsor considers the data collection is completed, patients will continue to 
follow the SoA defined by the protocol unless the medical monitor gives approval not to do so.
5
Trial Population
5.1
Inclusion Criteria
Each patient who meets all of the following criteria is eligible to enroll in the trial.
For Part 1A:
1. Histologically confirmed solid tumor (cytology is allowed for NSCLC, SCLC and pancreatic 
cancer) that is metastatic or unresectable and for which there is no available standard therapy 
likely to confer clinical benefit, or patients who are not candidates for such available therapy.
For Part 1B:
2. Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung 
Study Group [VALG] staging system) who received no prior chemotherapy for extensive stage 
disease.
3. Those treated with prior chemo/radiotherapy with curative intent for LS-SCLC should be 
treatment-free for at least 6 months since last chemo/radiotherapy.
4.
No interstitial lung disease or active, non-infectious pneumonitis.
For Both Part 1A and Part 1B
5. Male and female ≥18 years of age.
6. Must sign an informed consent form (ICF) indicating that he or she understands the purpose 
of and procedures required for the trial and are willing to participate in the trial prior to any 
trial related assessments or procedures. 
7. ECOG performance status of 0 to 1.
8. Measurable disease according to RECIST 1.1. 
9. Albumin level at screening ≥30 g/L.
10. Adequate coagulation function at Screening as determined by:
a.
International normalized ratio (INR) or prothrombin time ≤1.5 x upper limit normal 
(ULN; unless on therapeutic anticoagulants with values within therapeutic window), 
b. Activated partial thromboplastin time (aPTT) ≤1.5 x ULN (unless on therapeutic 
anticoagulants with values within therapeutic window).
11. Adequate hematologic function at Screening as determined by:
a.
White blood count (WBC) ≥3 x 109/L,
b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (patient may not use granulocyte-colony 
stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-
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c.
Platelet count ≥100 x 109/L,
d. Hemoglobin (Hgb) ≥9.0 g/dL. 
12. Adequate hepatic function at Screening as determined by:
a.
Total bilirubin ≤1.5 mg/dL (or ≤2.0 mg/dL for patients with known Gilbert’s syndrome),
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN; or 
≤5 x ULN in patients with metastatic liver disease.
13. Adequate renal function at Screening as determined by:
a.
Glomerular filtration rate (GFR)  60 mL/min/1.73 m²– e.g. according to the abbreviated 
Modification of Diet in Renal Disease (MDRD) equation:
GFR = 186 × (SCr-1.154) × (age-0.203) 
(where SCr, the serum creatinine level, is expressed in mg/dL; multiplied by 0.742 if the 
patient is female; multiplied by 1.212, if the patient is African-American (Levey et al, 
1999).
14. Able to attend trial visits as required by the protocol.
15. Women of childbearing potential (WOCBP) must have a negative serum (beta-human 
chorionic gonadotropin [beta-hCG]) test/value at Screening. Patients who are 
postmenopausal or permanently sterilized as defined in Section 10.4 can be considered as not 
having reproductive potential. Further guidance on contraceptive measures for female 
patients can be found in Section 10.4.
16. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the entire trial, until 6 months after last BNT411 treatment.
17. A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control, e.g. either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also 
not donate sperm during the trial and for 6 months after receiving the last dose of BNT411 
(refer Section 10.4 for further recommendations).
18. All patients must provide an FFPE (Formalin Fixed Paraffin Embedded) from the latest 
available archival tumor tissue. If such tissue cannot be provided, the sponsor’s approval of 
enrollment is needed.
5.2
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from trial participation. 
Prior and Concomitant Therapy
1. Has received prior systemic therapy with a TLR7 agonist.
2. Has been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or tyrosine 
kinase inhibitors within 2 weeks or 5 half-lives (whichever is longer) of the start of trial 
treatment; immunotherapy/monoclonal antibodies within 3 weeks of the start of trial 


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treatment; any live vaccine within 4 weeks of the start of trial treatment; nitrosoureas, 
antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of trial 
treatment.
3. Receives concurrent systemic (oral or intravenous) steroid therapy >10 mg prednisone daily 
or its equivalent for an underlying condition.
4. Receives concurrent strong inhibitors or inducers of the cytochrome P450 enzymes. 
5. Has had major surgery within the 4 weeks before the first dose of BNT411.
6. Has ongoing or active infection requiring intravenous treatment with anti-infective therapy 
that has been administered less than two weeks prior to first dose of trial treatment.
7. Has side effects of any prior therapy or procedures for any medical condition not recovered 
to NCI CTCAE v.5 Grade ≤1.
Notes: peripheral neuropathy Grade ≤2 is allowed; alopecia of any grade is allowed.
Medical Conditions
8. Current evidence of new or growing brain or leptomeningeal metastases during screening. 
Patients with known brain or leptomeningeal metastases may be eligible if they: 
a.
had radiotherapy, surgery or stereotactic surgery for the brain or leptomeningeal 
metastases, 
b. have no neurological symptoms (excluding Grade ≤2 neuropathy),
c.
have stable brain or leptomeningeal disease on the CT or MRI scan within 4 weeks 
before signing the informed consent,
d. are not undergoing acute corticosteroid therapy or steroid taper.
Notes: Subjects with central nervous system symptoms should undergo a CT scan or 
Magnetic Resonance Imaging (MRI) of the brain to exclude new or progressive brain 
metastases. Spinal bone metastases are allowed, unless imminent fracture with cord 
compression is anticipated.
9. Has history of seizures other than isolated febrile seizure in childhood; has a history of a 
cerebrovascular accident or transient ischemic attack less than 6 months ago.
10. Has effusions (pleural, pericardial, or ascites) requiring drainage.
11. Has eye pathology likely to confound observation of potential ocular AEs (refer to 
Ophthalmologic Manual).
12. Has a fever ≥38°C within 3 days before signing the ICF.
13. Has a history of autoimmune disease active or past including but not limited to 
inflammatory bowel disease, systemic lupus erythematosus (SLE), ankylosing spondylitis, 
scleroderma, or multiple sclerosis. Has any active immunologic disorder requiring 
immunosuppression with steroids or other immunosuppressive agents (e.g. azathioprine, 
cyclosporine A) with the exception of patients with isolated vitiligo, resolved childhood 
asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and euthyroid 
patients with a history of Grave's disease. Patients with controlled hyperthyroidism must be 


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negative for thyroglobulin, thyroid peroxidase antibodies, and thyroid-stimulating 
immunoglobulin prior to trial drug administration.
14. Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-
cell (CD4+) counts <350 cells/uL and with a history of acquired immunodeficiency 
syndrome (AIDS)-defining opportunistic infections.
15. Known history/positive serology for hepatitis B requiring active anti-viral therapy (unless 
immune due to vaccination or resolved natural infection or unless passive immunization 
due to immunoglobulin therapy). Patients with positive serology must have Hepatitis B 
virus (HBV) viral load below the limit of quantification.
16. Active Hepatitis C virus (HCV) infection; patients who have completed curative antiviral 
treatment with HCV viral load below the limit of quantification are allowed.
Notes: Country specific criteria for Germany - To confirm that a patient would be eligible, 
an active infection with HIV/Hepatitis B or C should be ruled out by serum blood test at 
screening (see Section 12.2.1).
17. Has a known hypersensitivity to a component of BNT411 drug product, or another similar 
compound.
18. Has another primary malignancy that has not been in remission for at least 2 years, with the 
exception of those with a negligible risk of metastasis or death (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, 
or ductal carcinoma in situ).
Note: should be discussed with Medical Monitor in case of uncertainties.
Other Comorbidities
19. Has abnormal electrocardiograms (ECGs) that are clinically significant, such as 
Framingham-corrected QT interval >480 ms.
20. In the opinion of the treating investigator, has any concurrent conditions that could pose an 
undue medical hazard or interfere with the interpretation of the trial results; these conditions 
include, but are not limited to: 
a.
ongoing or active infection requiring antibiotic/antiviral/antifungal therapy,
b. concurrent congestive heart failure (New York Heart Association [NYHA] Functional 
Classification Class III or IV),
c.
concurrent unstable angina,
d. concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial 
fibrillation),
e.
acute coronary syndrome within the previous 6 months,
f.
significant pulmonary disease (shortness of breath at rest or on mild exertion) for 
example due to concurrent severe obstructive pulmonary disease.
21. Has a cognitive, psychological or psychosocial impediment that would impair the ability of 
the patient to receive therapy according to the protocol or adversely affect the ability of the 


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patient to comply with the informed consent process, protocol, or protocol-required visits 
and procedures.
22. Is pregnant or breastfeeding. 
Exclusion criteria added with amended protocol version 3.0 (Prior and Concomitant 
Therapy)
23.  Has any contraindication to atezolizumab, carboplatin or etoposide as per USPI or SmPC 
in Part 1B.
5.3
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently entered in the trial. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, the reason(s) for screen failures, 
eligibility criteria, and any serious adverse event (SAE).
Patients who fail their first screening for trial eligibility may qualify for two re-screening 
opportunities (a total of three screenings per patient) at the investigator’s discretion. Patients 
must re-sign the informed consent form prior to re-screening. Results of standard-of-care tests or 
examinations performed prior to obtaining informed consent and within 28 days prior to the 
treatment may be used; such tests do not need to be repeated for screening or re-screening.


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6
Trial Treatment
6.1
Trial Treatment(s) Administered
Trial treatment may refer to the following compounds, either:
1. BNT411, and/or
2. Atezolizumab, and/or
3. Carboplatin, and/or
4. Etoposide.
BNT411 is a highly potent and selective small molecule TLR7 agonist of the imidazoquinoline 
family being developed by BioNTech and is a new investigational agent to be tested clinically in 
this trial. In all countries participating in the trial, BNT411 is considered as investigational 
medicinal product (IMP).
Atezolizumab is a PD-L1 blocking antibody indicated for the treatment of patients with various 
cancer diagnoses at different stages. Atezolizumab was first approved by FDA on May 18, 2016 
to treat urothelial carcinoma, and similar positive opinion by European Medicines Agency 
(EMA) followed in July 2017. Carboplatin is a platinum coordination compound and etoposide is 
a topoisomerase inhibitor. They are both cytotoxic agents used in various chemotherapy 
regimens to treat many cancer indications. On March 18, 2019, the FDA approved atezolizumab 
in combination with carboplatin and etoposide, for the first-line treatment of adult patients with 
ES-SCLC. Since then, it has become a standard-of-care treatment in the US. In October 2019, 
EMA issued similar positive opinion for the combination. For the purpose of this trial, in the 
USA and UK, atezolizumab, carboplatin and etoposide are considered as non-investigational 
medicinal products (NIMPs). However, the individual drugs are considered as IMPs in Spain and 
Germany at the request of the competent authorities due to their use in combination with 
BNT411.
Information relating to COVID-19 vaccinations including a risk-benefit assessment and guidance 
for vaccination during this clinical trial is provided in Sections 10.8 and 10.9.
6.1.1
BNT411
In Part 1A, BNT411 will be administered using a 100 mL intravenous infusion on Days 1, 8 and 
15 of each 3-week treatment cycle (21 days) of the first 4 cycles after all required procedures and 
assessments have been completed. In the following cycles thereafter, BNT411 will be 
administered every 3 weeks on Day 1 of each 3-week treatment cycle (21 days) after all required 
procedures and assessments have been completed.
In Part 1B, BNT411 will be administered using a 100 mL intravenous infusion on Days 2, 8 and 
15 of each 3-week treatment cycle (21 days) of the first 4 cycles after all required procedures and 
assessments have been completed. In the following cycles thereafter, BNT411 will be 
administered every 3 weeks on Day 2 of each 3-week treatment cycle (21 days) after all required 
procedures and assessments have been completed.
In both Part 1A and Part 1B, patients will be administered BNT411 according to dose levels 
outlined in Table 4-2. BNT411 will be administered as a body weight-based dosing. A cap on 
dosing for patients weighing 120 kg and more will be implemented in the proposed clinical trial.


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In Part 1B, for combination with atezolizumab and chemotherapy, the administration will be in 
the following order:
Day 1: Atezolizumab  Carboplatin  Etoposide
Day 2: BNT411  Etoposide
Day 3: Etoposide
For each dosing of BNT411 in Cycle 1, patients will remain in the treatment center and be 
closely monitored for immediate AEs for at least 6 hours. Hospitalization is required for the first 
24 hours after the first BNT411 administration in Cycle 1 for clinical observation and PK 
sampling. Prolongation of the hospitalization beyond 24 hours may be performed at the 
investigator’s discretion if deemed necessary based on potential risks related to the trial 
treatment and clinical status of the patient. For each subsequent dose of BNT411 in all cycles, 
patients will be monitored for at least 6 hours. 
6.1.2
Atezolizumab, Carboplatin, and Etoposide
Atezolizumab, carboplatin, and etoposide will be used in the commercially available 
formulation.
For information on the formulation, packaging, and handling of atezolizumab, carboplatin, and 
etoposide, see the prescribing information for each drug.
The recommended dosage of atezolizumab is 1200 mg intravenously over 60 minutes every 
3 weeks. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be 
delivered over 30 minutes. 
Carboplatin should be administered after completion of atezolizumab by intravenous infusion 
over 30−60 minutes to achieve an initial target AUC of 5 mg/mL/min (Calvert formula dosing) 
with standard anti-emetics per local practice guidelines. Because of their immune-suppressive 
effect, premedication with corticosteroids should be minimized to the extent that is clinically 
feasible.
On Day 1 of each cycle, etoposide (100 mg/m2) should be administered intravenously over 
60 minutes following carboplatin administration. The dose will be calculated using the Mosteller 
formula (BSA [m2] = square root((height [cm] x weight [kg])/3600))
On Day 2 and Day 3 of each cycle, etoposide (100 mg/m2) should be administered intravenously 
over 60 minutes. Premedication should be administered according to local standard-of-care. 
Because of their immune-suppressive effect, premedication with corticosteroids should be 
minimized to the extent that is clinically feasible.
After the DLT-observation period, if the patient tolerates the combination of 
atezolizumab+carboplatin+etoposide+BNT411, chemotherapy should continue for a total of 
4 cycles; further chemotherapy cycles at the investigator’s discretion should be discussed with 
the Medical Monitor. After completion of chemotherapy, atezolizumab+BNT411 combination 
should continue until one of the protocol-defined treatment discontinuation criteria is met 
(Section 7.1).
For the dosing schedule, refer to the Schedule of Activities (SoA), Section 1.3.


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6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all trial treatment received and any discrepancies are 
reported and resolved before use of the trial treatment.
2. Only patients enrolled in the trial may receive trial treatment and only authorized site 
staff are allowed to supply or administer trial treatment. All trial treatment must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
3. Details regarding trial medication preparation are provided in the Pharmacy Manual.
4. The investigator or designee, institution, or the head of the medical institution (where 
applicable) is responsible for trial treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation, and final disposition records).
5. Further guidance and information for the final disposition of unused trial treatments are 
provided in the Pharmacy Manual.
6.3
Measures to Minimize Bias: Randomization and Blinding
Not applicable as this is a non-randomized, open-label trial.
6.4
Trial Treatment Compliance
When patients are dosed at the site, they will receive trial treatment directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and the eCRF. The dose of trial treatment and trial 
patient identification will be confirmed at the time of dosing by a member of the trial site staff 
other than the person administering the trial treatment.
6.5
Concomitant Therapy and Procedures
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or procedure that the patient is receiving or undergoing at the time of 
signing the Informed Consent Form, or receives or undergoes during the trial must be recorded 
along with, as applicable:
•
reason for use
•
dates of administration including start and end dates
•
dosage information including dose and frequency.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Concomitant anti-emetics, anti-diarrheal agents, intravenous fluids, or electrolyte replacement 
based on clinical or laboratory assessments and blood transfusions while on treatment based on 
individual institutional guidelines will be allowed.


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Radiotherapy should be documented in the eCRF including total dose, fractionation and location.
The prohibited medications while on trial treatment are as follows:
•
Other anti-cancer therapy not included under trial treatment in a given part of the trial 
(e.g. Part 1A, Part 1B and Part 2).
•
Other prohibited concomitant medications as listed in inclusion and exclusion criteria 
(Section 5.1 and Section 5.2).
•
No systemic anti-cancer therapies should be administered concurrently with PCI. A delay 
of ≤21 days in administering systemic anti-cancer therapies due to PCI is not considered 
a protocol deviation.
•
For further guidance on prohibited and restricted medications, please refer to the IB for 
BNT411, and USPI or SmPCs for atezolizumab, carboplatin and etoposide.
6.5.1
Premedication
As part of its intended mode of action, BNT411 is expected to induce a discrete spectrum of 
cytokines. These may be associated with flu-like symptoms within the first hours after 
administration.
Routine premedication with analgesics or anti-pyretics such as acetaminophen/paracetamol, 
ibuprofen, naproxen, or aspirin at established doses and schedules can be given at the 
investigator’s discretion and patients can be appropriately prehydrated prior to treatment. 
Because of their immune-suppressive effect, premedication with corticosteroids should be 
minimized to the extent that is clinically feasible. The use of corticosteroids as anti-emetics or 
for any other purposes may be substituted with other drugs from different classes per 
investigator’s discretion. All premedication must be reported on the concomitant medication 
page in the eCRF.
6.5.2
Rescue Medication
Not applicable.
6.6
Dose Modifications
Dose Limiting Toxicity
In general, a DLT for a drug or other treatment is defined as an adverse event that prevents an 
increase of the dose level of that treatment (for details on reporting see Section 8.7.8).
For the purpose of dose escalation, the DLT monitoring period will be 21 days. The occurrence 
of any of the toxicities outlined in this section will be considered a DLT, excluding toxicities 
clearly related to disease progression or intercurrent illness. 
SAEs, non-serious (NS) Grade ≥3 AEs and clinically significant abnormal laboratory values 
Grade ≥3 will be collected and assessed for DLTs (for each dose level during the first cycle). 
NCI CTCAE v.5.0 will be used to grade the intensity of AEs.
No indications of organ-specific autoimmunity have been identified for BNT411, or for any 
other imidazoquinoline compounds. Therefore, the risk of immune-related AEs (irAEs) with 
BNT411 alone is regarded as low. BNT411 will be combined with atezolizumab in Part 1B of 


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the dose escalation. Atezolizumab in line with its mode-of-action is associated with organ-
specific autoimmunity and consequently with immune-related adverse events. 
Therefore, definitions of DLT will be categorized as non-immune-related AEs and immune-
related AEs (irAEs).
Other clinically significant toxicities, including a single event or multiple occurrences of the 
same event, may be considered as DLTs.
AEs occurring after treatment Cycle 1 may be considered DLTs upon discussion between the 
investigator(s) and the sponsor(s) medical monitor.
Any other toxicity assessed as related to BNT411 treatment, and which in the opinion of the trial 
investigator(s) and the sponsor(s) medical monitor constitutes a DLT.
Dose-escalation:
Patients experiencing a DLT (an AE fulfilling the DLT criteria within the DLT period of 
21 days) should discontinue trial drug immediately. If requested by the investigator, the sponsor 
may allow a patient with a DLT to continue in the trial and consider a reduced dose. For this 
decision, a thorough benefit-risk assessment of the individual patient is required and consultation 
with the SRC needs to be considered.
6.6.1
Dose Limiting Toxicity for Part 1A
Non-immune-related AEs that are considered DLTs:
During the first treatment cycle, any toxicity that is of Grade 3 and that does not resolve to 
Grade 1 or lower within a week despite the use of medical intervention, or that is of Grade 4, but 
with exceptions as follows:
•
The following events occurring during the DLT period ARE also considered a DLT:
o
Arrhythmia: Grade >2 newly developed arrhythmia of any kind.
o
Absolute leucocyte count ≥50×109/L sustained for 14 days.
o
Hypotension of Grade 3 that persists for >4 hours and requires hospitalization. 
•
The following events occurring during the DLT period ARE NOT considered a DLT:
o
Grade ≤3 nausea or vomiting controllable with anti-emetics within 72 hours.
o
Hypotension (systolic pressure <90 mm Hg) of Grade <3 that is of limited duration 
(less than 72 hours) or can be managed with hydration measures.
o
Hypotension that requires a precautionary admission for observation after Grade 3 
hypotension that persists for ≤4 hours.
o
Grade 3 amylase and lipase elevations that are not accompanied by clinical 
signs/symptoms of pancreatitis.
Immune-related AEs that are considered DLTs:
•
Any Grade 4 irAEs regardless of duration. 
•
Grade 3 colitis that does not downgrade to Grade ≤2 within 3 days after onset of the event 
despite maximal supportive care including systemic corticosteroids or downgrade to 
Grade ≤1 or baseline within 14 days.
•
Any Grade 3 or Grade 4 non-infectious pneumonitis regardless of duration.


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•
Any Grade 3 irAE, excluding colitis and pneumonitis, that does not downgrade to Grade ≤2 
within 3 days after onset of the event despite maximal supportive care including systemic 
corticosteroids or downgrade to Grade ≤1 or baseline within 14 days. 
•
Any Grade 2 pneumonitis that does not resolve to Grade ≤1 within 3 days of the initiation 
of maximal supportive care. 
•
Liver transaminase elevation higher than 8×ULN or total bilirubin higher than 3×ULN. 
•
Any other toxicity that is greater than baseline grade, is clinically significant and/or 
unacceptable, and is judged to be a DLT by the investigator and the sponsor.
•
The definition excludes the following conditions: 
o
Grade ≤4 lymphopenia which is not considered clinically significant by the 
investigator.
o
Grade 3 endocrinopathy that is managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the patient is asymptomatic. 
o
Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g. 
inflammatory reaction at sites of metastatic disease, lymph nodes) that resolves to 
Grade ≤1 within 3 weeks. 
o
Concurrent vitiligo or alopecia of any AE grade.
6.6.2
Dose Limiting Toxicity for Part 1B
Non-immune-related AEs that are considered DLTs:
During the first treatment cycle, any toxicity that is of Grade 3 and that does not resolve to 
Grade 1 or lower within a week despite the use of medical intervention, or that is of Grade 4, but 
with exceptions as follows:
•
The following events occurring during the DLT period ARE also considered a DLT:
o
Arrhythmia: Grade >2 newly developed arrhythmia of any kind.
o
Absolute leucocyte count ≥50×109/L sustained for 14 days.
o
Hypotension of Grade 3 that persists for >4 hours and requires hospitalization. 
•
The following events occurring during the DLT period ARE NOT considered a DLT:
o
Any Grade 3 or 4 neutropenia, leucopenia, anemia and thrombocytopenia that can be 
solely attributed to chemotherapy compounds.
o
Grade ≤3 nausea or vomiting controllable with anti-emetics within 72 hours.
o
Hypotension (systolic pressure <90 mm Hg) of Grade <3 that is of limited duration 
(less than 72 hours) or can be managed with hydration measures.
o
Hypotension that requires a precautionary admission for observation after Grade 3 
hypotension that persists for ≤4 hours.
o
Grade 3 amylase and lipase elevations that are not accompanied by clinical 
signs/symptoms of pancreatitis.
Immune-related AEs that are considered DLTs:
•
Any Grade 4 irAEs regardless of duration. 
•
Grade 3 colitis that does not downgrade to Grade ≤2 within 3 days after onset of the 
event despite maximal supportive care including systemic corticosteroids or downgrade 
to Grade ≤1 or baseline within 14 days.
•
Any Grade 3 or Grade 4 non-infectious pneumonitis regardless of duration.


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•
Any Grade 3 irAEs, excluding colitis and pneumonitis, that does not downgrade to 
Grade ≤2 within 3 days after onset of the event despite maximal supportive care 
including systemic corticosteroids or downgrade to Grade ≤1 or baseline within 14 days. 
•
Any Grade 2 pneumonitis that does not resolve to Grade ≤1 within 3 days of the initiation 
of maximal supportive care. 
•
Liver transaminase elevation higher than 8×ULN or total bilirubin higher than 3×ULN. 
•
Any other toxicity that is greater than baseline grade, is clinically significant and/or 
unacceptable, and is judged to be a DLT by the investigator and the sponsor.
•
The definition excludes the following conditions: 
o
Grade ≤4 lymphopenia which is not considered clinically significant by the 
investigator.
o
Grade 3 endocrinopathy that is managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the patient is asymptomatic. 
o
Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g. 
inflammatory reaction at sites of metastatic disease, lymph nodes) that resolves to 
Grade ≤1 within 3 weeks. 
o
Concurrent vitiligo or alopecia of any AE grade.
6.6.3
Dose Modification Guidance
6.6.3.1 Handling of Adverse Events Fulfilling the DLT Criteria after the DLT Period has 
ended in Part 1A
AEs that fulfill the DLT criteria after the DLT period has ended in the dose-escalation phase of 
Part 1A of the trial (i.e. from Cycle 2 Day 1 and beyond) or during the expansion phase (i.e. from 
Cycle 1 Day 1 and beyond) should be handled as shown in Figure 6-1.
Please Note: Patients must complete the DLT monitoring period prior to implementing the dose 
modification criteria outlined in this section.
Figure 6-1:
Handling of adverse events fulfilling the DLT criteria after the DLT-observation 
period has ended – Part 1A
DL, dose level
*Dose delay: Next dose of BNT411 can maximally be delayed 21 days unless approved otherwise by the sponsor 
medical monitor.


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# No delay for recovery from Grade ≥2 allowed
## Unless grade at baseline was Grade ≥2 and AE has resolved to baseline grade.
Note: Grade 4 AEs fulfilling DLT criteria will always lead to BNT411 discontinuation.
First occurrence of AE fulfilling DLT criteria Grade 3:
•
As a first measure, administration of BNT411 needs to be withheld.
•
Investigator must contact sponsor for thorough discussion in order to decide 
whether the patient should be withdrawn from BNT411 treatment or next dosing 
should be delayed.
•
Administration of BNT411 can be delayed for up to 21 days (i.e. one cycle) 
unless otherwise approved by the sponsor’s medical monitor. If the intensity 
resolves to Grade ≤1 or baseline within this period, re-treatment may be 
considered under the following circumstances:
o
Sponsor and investigator will discuss any safety concerns in order to 
decide whether the next dose of BNT411 should be administered at the 
same dose level or one dose level lower (DL-1). Intermediate dose levels 
defined in the protocol may also be considered. The sponsor may also 
consult the SRC.
Second occurrence of an identical AE Grade 3 after re-exposure to BNT411:
•
As a first measure, administration of BNT411 needs to be withheld.
•
If re-treatment leads to an identical AE with the same intensity, the next 
administration of BNT411 can be delayed for up to 21 days unless otherwise 
approved by the sponsor’s medical monitor. If the intensity of the AE resolves to 
Grade ≤1 or baseline within this period, re-treatment may be considered under the 
following conditions:
• The next dose of BNT411 should be administered at one dose level lower 
(DL-1 or DL-2) than the dose level causing the recurrence of the AE. 
Intermediate dose levels defined in the protocol may be considered.
Third occurrence of an identical AE Grade ≥2 after re-exposure to BNT411:
•
As a first measure, administration of BNT411 needs to be withheld.
•
If re-treatment at a lower dose leads to a third identical AE with intensity 
Grade ≥2, the patient must permanently discontinue trial drug. No dose delay is 
allowed. However, if the AE is Grade ≤1 or baseline, re-treatment may be 
considered under the following condition:
• The next dose of BNT411 should be administered at the same reduced 
dose level (DL-1 or DL-2).
Please note:
•
Re-escalation of BNT411 dose is not allowed for patients who previously have 
been dose-reduced.


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•
BNT411 must be permanently discontinued if the patient experiences an AE 
fulfilling the DLT criteria (after the DLT period has ended for the dose escalation 
or during the expansion) that fails to resolve to Grade  1 within 21 days after the 
planned dosing date unless otherwise approved by the sponsor’s medical monitor.
•
BNT411 must be permanently discontinued if more than 2 dose reductions are 
required.
•
BNT411 must be permanently discontinued in the case of a dose delay of more 
than 21 days due to toxicity possibly related to BNT411 unless otherwise 
approved by the sponsor’s medical monitor.
•
The investigators are encouraged to contact the sponsor in the case of any safety 
concerns that need thorough discussion and evaluation.
6.6.3.2 Handling of Adverse Events Fulfilling the DLT Criteria after the DLT Period has 
ended in Part 1B
AEs that fulfill the DLT criteria after the DLT period has ended in the dose-escalation phase of 
Part 1B of the trial (i.e. from Cycle 2 Day 1 and beyond) or during the expansion (i.e. from 
Cycle 1 Day 1 and beyond) should be handled as shown in Figure 6-2.
Please Note: Patients must complete the DLT monitoring period prior to implementing the dose 
modification criteria outlined in this section.
Figure 6-2:
Handling of adverse events fulfilling the DLT criteria after the DLT-observation 
period has ended – Part 1B
DL, dose level
*Dose delay: Next dose of BNT411 can maximally be delayed 21 days unless approved otherwise by the sponsor 
medical monitor.
# No delay for recovery from Grade ≥2 allowed
## Unless grade at baseline was Grade ≥2 and AE has resolved to baseline grade.


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Note: Grade 4 AEs fulfilling DLT criteria will always lead to BNT411 discontinuation.
First occurrence of AE fulfilling DLT criteria Grade 3:
•
As a first measure, administration of BNT411 needs to be withheld.
•
Investigator must contact sponsor for thorough discussion in order to decide 
whether the patient should be withdrawn from BNT411 treatment or next dosing 
should be delayed.
•
Administration of BNT411 can be delayed for up to 21 days (i.e. one cycle) 
unless otherwise approved by the sponsor’s medical monitor. If the intensity 
resolves to Grade ≤1 or baseline within this period, re-treatment may be 
considered under the following circumstances:
o
Sponsor and investigator will discuss any safety concerns in order to 
decide whether the next dose of BNT411 should be administered at the 
same dose level or one dose level lower (DL-1). Intermediate dose levels 
defined in the protocol may also be considered. The sponsor may also 
consult the SRC.
Second occurrence of an identical AE Grade 3 after re-exposure to BNT411:
•
As a first measure, administration of BNT411 needs to be withheld.
•
If re-treatment leads to an identical AE with the same intensity, the next 
administration of BNT411 can be delayed for up to 21 days unless otherwise 
approved by the sponsor’s medical monitor. If the intensity of the AE resolves to 
Grade ≤1 or baseline within this period, re-treatment may be considered under the 
following conditions:
o
The next dose of BNT411 should be administered at one dose level lower 
(DL-1 or DL-2) than the dose level causing the recurrence of the AE. 
Intermediate dose levels defined in the protocol may be considered.
Third occurrence of an identical AE Grade ≥2 after re-exposure to BNT411:
•
As a first measure, administration of BNT411 needs to be withheld.
•
If re-treatment at a lower dose leads to a third identical AE with intensity 
Grade ≥2, the patient must permanently discontinue trial drug. No dose delay is 
allowed. However, if the AE is Grade ≤1 or baseline, re-treatment may be 
considered under the following condition:
o
Next dose of BNT411 should be administered at the same reduced dose 
level (DL-1 or DL-2).
Please note:
•
Re-escalation of BNT411 dose is not allowed for patients who previously have 
been dose-reduced.
•
BNT411 must be permanently discontinued if the patient experiences an AE 
fulfilling the DLT criteria (after the DLT period has ended for the dose escalation 


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or during the expansion) that fails to resolve to Grade 1 within 21 days after the 
planned dosing date unless otherwise approved by the sponsor medical monitor.
•
BNT411 must be permanently discontinued if more than 2 dose reductions are 
required.
•
BNT411 must be permanently discontinued in the case of a dose delay of more 
than 21 days due to toxicity possibly related to BNT411 unless otherwise 
approved by the sponsor’s medical monitor.
•
The investigators are encouraged to contact the sponsor in the case of any safety 
concerns that need thorough discussion and evaluation.
•
If the causal relationship of AE cannot be attributed to either BNT411, 
atezolizumab, carboplatin and etoposide, BNT411 should be discontinued; 
atezolizumab, carboplatin and etoposide should be dose modified as per the US 
Prescribing Information or the Summary of Product Characteristics.
6.6.4
Dose Modification for Specific Adverse Events
6.6.4.1 Immune-related Adverse Events (irAEs) – For Part 1B Only
Guidance for BNT411 dose modification and management of irAEs is provided in the Table 6-1 
below. For Grade 1 irAEs, trial treatment should be continued with close monitoring. 
Corticosteroids taper should be initiated over the course of at least 4 to 6 weeks when the irAE 
improves to Grade ≤1. Permanent discontinuation of trial treatment is recommended with 
Grade 4 toxicities with the exception of endocrinopathies that have been controlled by hormone 
replacement. Trial treatment should also be permanently discontinued for any Grade 3 irAE that 
recurs and for any life-threatening irAE. For additional guidance on the recommended 
management of irAEs, please refer to the Management of Immune-Related Adverse Events in 
Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical 
Oncology Practice Guideline (Brahmer et al, 2018). Furthermore, guidelines for the monitoring 
and management of potential cytokine release syndrome (CRS) can be found in Attachment 12.1.


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Table 6-1:
BNT411 Dose Modification and Management of irAEs
Immune-related AEs
Toxicity Grade (CTCAE v5.0)
Dose Modification
Guidance for Management of irAEs
Grade 1-2
1st occurrence
If there is radiographic evidence of 
pneumonitis progression, hold treatment until 
there is evidence of improvement/ resolution to 
Grade 1 or less1
2nd occurrence: Permanently discontinue
Pneumonitis 
Grade 3 or 4
Permanently discontinue
Monitor for signs and symptoms of pneumonitis
Evaluate for pneumonitis with radiographic imaging
For Grade ≥2:
Consider initiation of corticosteroid treatment (initial dose of 
1-2 mg/kg prednisone or equivalent followed by taper). 
Corticosteroid taper should be initiated when the irAE 
improves to Grade ≤1
Grade 2
Hold treatment until resolved to baseline1
Grade 3 
Refer to Sections 6.6.3.1 and 6.6.3.2 
Colitis 
Grade 4
Permanently discontinue
Monitor for signs and symptoms of colitis. Consider 
gastroenterology consultation and confirm diagnosis of colitis
Consider administration of corticosteroids (initial dose of 1-2 
mg/kg prednisone or equivalent) followed by taper 
Corticosteroid taper should be initiated when the irAE 
improves to Grade ≤1
T1DM or Hyperglycemia
Newly diagnosed T1DM or 
Grade 3-4 hyperglycemia
Refer to Sections 6.6.3.1 and 6.6.3.2 
Monitor for hyperglycemia or other signs and symptoms of 
diabetes 
Consider endocrinology consultation 
Consider administration of insulin for type 1 diabetes
Consider administration of anti-hyperglycemic medication in 
patients with hyperglycemia
Grade 2
Continue treatment at the discretion of the 
investigator
Hypophysitis
Grade 3 or 4
Refer to Sections 6.6.3.1 and 6.6.3.2
Monitor for signs and symptoms of hypophysitis. 
Consider endocrinology consultation
Consider administration of corticosteroids and initiate 
hormonal replacements as clinically indicated. Corticosteroid 
taper should be initiated upon irAE improving to Grade ≤1
Grade 2
Continue treatment at the discretion of the 
investigator
Hyperthyroidism 
Grade 3-4 
Refer to Sections 6.6.3.1 and 6.6.3.2
Monitor for signs and symptoms of thyroid disorders 
Consider management with thionamides and beta-blockers as 
appropriate
Grade 2
Continue treatment at the discretion of the 
investigator
Hypothyroidism
Grade 3-4
Refer to Sections 6.6.3.1 and 6.6.3.2 
Monitor for signs and symptoms of thyroid disorders. 
Consider endocrinology consultation
Consider initiation of thyroid replacement hormones per 
standard of care


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Immune-related AEs
Toxicity Grade (CTCAE v5.0)
Dose Modification
Guidance for Management of irAEs
Grade 1
Consider temporary hold pending 
consideration of baseline renal function and to 
confirm etiology1
Grade 2
Hold treatment until resolved to baseline1
Nephritis and Renal 
Dysfunction
Grade 3-4 
Permanently discontinue
Monitor for changes in creatinine levels
For Grade ≥2:
–
If worsening or no improvement, consider 
administration of corticosteroids (prednisone 1-2 
mg/kg or equivalent) followed by taper
–
Corticosteroid taper should be initiated upon irAE 
improving to Grade ≤1
Grade 1-2
Continue treatment at the discretion of the 
investigator
Grade 3
Refer to Sections 6.6.3.1 and 6.6.3.2
Skin Adverse Reactions
Grade 4
Permanently discontinue
Based on the severity of the adverse reaction, consider 
administration of corticosteroids. Corticosteroid taper should 
be initiated upon irAE improving to Grade ≤1
For signs or symptoms of SJS or TEN, withhold and refer the 
patients for specialized care. If SJS or TEN is confirmed, 
permanently discontinue
Grade 2
Continue treatment at the discretion of the 
investigator
Grade 3
Refer to Sections 6.6.3.1 and 6.6.3.2 and or 
discontinue based on the type of event.
All other immune-related 
AEs
Grade 4 
Permanently discontinue
Based on type and severity of AE, consider administration of 
corticosteroids. Permanently discontinue for any Grade 3 irAE 
that recurs and for any life-threatening irAEs
1 The next dose of BNT411 can maximally be delayed for 21 days unless approved otherwise by the sponsor’s medical monitor. If irAE resolves within 21 days 
to baseline, restart treatment at the same dose level after consultation with the sponsor’s medical monitor.
AE, adverse event; irAEs, immune-related AEs; CTCAE, Common Terminology Criteria for Adverse Events; T1DM, type 1 diabetes mellitus; SJS, Steven 
Johnsons Syndrome; TEN, toxic epidermal necrolysis


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6.6.4.2 Infusion-Related Reactions (IRRs) 
IRR is a general risk to be considered for any new compound administered intravenously 
irrelevant of its MoA. IRR is typically of immediate onset after the compound’s administration. 
We cannot exclude the risk of IRR with BNT411 due to the given limited experience with 
BNT411.
The following treatment guidelines are provided below for patients who experience an IRR 
associated with administration of BNT411 treatment.
•
Grade 1- If an IRR Grade 1 occurs, the infusion does not need to be interrupted and can 
be continued at the investigator’s discretion at half the infusion rate under close medical 
supervision.
•
Grade 2-3- If an IRR Grade 2 or Grade 3 occurs, the infusion should be interrupted and 
appropriate medical management instituted. The infusion may be re-started at the 
investigator’s discretion at half the infusion rate under close medical supervision if 
symptoms have resolved to Grade ≤1 within an hour.
o
Patients who have experienced prior infusion related Grade 2 or Grade 3 reactions 
in the trial should be premedicated. Premedication to prevent IRR in subsequent 
infusions may be administered at the investigator's discretion according to local 
guidelines but preferably includes an antihistamine (e.g., diphenhydramine 50 mg 
orally twice daily [po] or equivalent antihistamine), acetaminophen/paracetamol 
(e.g. acetaminophen 500-1000 mg po or equivalent), and if considered necessary, 
patients should receive corticosteroids at a suggested maximum dose of 100 mg 
prednisone or equivalent.
o
If the patient has a second Grade 3 IRR despite premedication, the infusion should 
be stopped and the patient should be withdrawn from treatment.
•
Grade 4- If anaphylaxis or Grade 4 IRR occurs, administration of BNT411 should be 
discontinued immediately and permanently, and appropriate medical therapy should be 
administered.
Please note:
•
At all times during BNT411 infusion, immediate emergency treatment of an anaphylactic 
reaction according to institutional standards must be assured. In order to treat possible 
anaphylactic reactions, for instance, dexamethasone 10 mg and epinephrine in a 1:1000 
dilution or equivalents should always be available along with equipment for assisted 
ventilation.
•
All premedication must be reported on the concomitant medication page in the eCRF.
6.6.5
Safety Stopping Criteria
Across all patients in both Part 1A and Part 1B, the following rules apply:
1. The trial will be paused for:
a.
Any death possibly related to BNT411
b. Two Grade 4 AEs that are considered possibly, probably, or definitely related to 
BNT411


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If a suspected DLT occurs, a SRC meeting will be held as rapidly as possible. In the meantime, 
dosing of the ongoing patients in that cohort will continue unless there is reason to suspect there 
is an unacceptable safety risk based on the nature and/or severity of the observed DLT. 
The SRC will decide whether and when the trial can be restarted after approval of a substantial 
amendment by the regulatory authorities and EC; or with the sponsor’s concurrence, whether the 
trial should be stopped. Further information on the SRC is described in Section 9.6 and in the 
SRC Charter.
In individual patients, treatment with BNT411 should be discontinued due to safety 
concerns under the following conditions:
1. If the patient experiences an AE fulfilling the DLT criteria.
2. If the patient experiences an AE that fulfils the DLT criteria after the DLT period has ended 
in the dose-escalation or during the expansion phase, but that fails to resolve to Grade 1 
within 21 days after the planned dosing date or any other dose delay of more than 21 days 
due to toxicity possibly related to BNT411, unless otherwise approved by the sponsor’s 
medical monitor.
3. In case of a drug-related or life-threatening Grade 4 AE that does not fulfill the DLT criteria 
(excluding asymptomatic Grade 4 elevations in non-hematological laboratory values that 
resolve to Grade ≤2 within 14 days [± medical intervention]) unless otherwise approved by 
the sponsor’s medical monitor.
4. If more than two dose reductions are required.
5. Patients with any eye disorders Grade ≥3, especially the occurrence of retinal detachment and 
marked decrease in visual acuity.
6. In case of cytokine release syndrome (CRS) Grade 4, the patient should be discontinued from 
treatment.
7. Second occurrence of an IRR of Grade ≥3 despite premedication prior to second infusion.
8. First occurrence of anaphylaxis or Grade 4 IRR.
Please note:
Patients should, whenever possible, irrespective of the reason for discontinuation, be examined 
as soon as possible.
6.6.6
Safety Alert Communication Plan
Safety data such as DLTs, SAEs, SUSARs, or safety-relevant protocol deviations which may 
impact all patients in the trial will be communicated by the medical monitor through “Safety 
Alert Email” to the investigators and site staff to inform them about abovementioned safety 
issues. If recruitment has to be suspended, or dosing to be withheld in all patients, this 
countermeasure will be detailed in the safety alert email. If necessary, the email will also give 
guidance to the Investigators to promptly contact the patients and inform about any safety issue 
which may require patients to come for unplanned visit or any other measures as appropriate. If 
the email is not acknowledged, the site will be telephoned until contact is made with appropriate 
site staff. Furthermore, a SRC meeting will be held as rapidly as possible. Investigators and site 


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staff who do not attend SRC meetings will be provided with an email update of all SRC 
decisions within 24 hours of each meeting.
6.6.7
Atezolizumab Dose Modification and Management of Specific Adverse Events
Dose modifications for atezolizumab are permitted according to the atezolizumab Prescribing 
Information valid in a given country and local standard-of-care. Management of specific adverse 
events should be done according to the atezolizumab Prescribing Information and local standard 
of care.
6.6.8
Carboplatin Dose Modification and Management of Specific Adverse Events
Dose modifications for carboplatin are permitted according to the carboplatin Prescribing 
Information valid in a given country and local standard-of-care. Management of specific adverse 
events should be done according to the carboplatin Prescribing Information and local standard of 
care.
6.6.9
Etoposide Dose Modification and Management of Specific Adverse Events
Dose modifications for etoposide are permitted according to the etoposide Prescribing 
Information valid in a given country and local standard-of-care. Management of specific adverse 
events should be done according to the etoposide Prescribing Information and local standard of 
care.
6.7
Treatment after the End of the Trial
Patients who show some level of clinical benefit during the trial may be permitted to receive 
further cycles of treatment if discussed with the sponsor.


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7
Discontinuation of Trial Treatment and Patient 
Discontinuation/Withdrawal
7.1
Discontinuation of Trial Treatment
Patients will receive BNT411 treatment until one of the predefined discontinuation of treatment 
criteria has been met:
•
Radiographic disease progression per RECIST 1.1 (Section 8.5.1) or confirmed 
radiographic disease progression by iRECIST (if applicable),
•
Death,
•
Unacceptable AEs requiring BNT411 discontinuation (refer to Safety Stopping Criteria –
Section 6.6.5),
•
Investigator believes that it is in the best interest of the patient to stop BNT411 treatment,
•
Withdrawal of consent,
•
Pregnancy
•
Lost to follow-up
If BNT411 treatment is permanently discontinued for other reasons than radiographic disease 
progression, every effort should be made to continue tumor assessments.
Further information on discontinuation of atezolizumab, carboplatin and etoposide should be 
referred to the respective SmPC or USPI.
Patients should, whenever possible, irrespective of the reason for discontinuation, be examined 
as soon as possible and the treatment discontinuation visit should be performed (Section 8.3). 
7.1.1
Temporary Discontinuation
See Section 6.6.5.
7.1.2
Rechallenge
For instructions/considerations regarding re-treatment of patients who have experienced a DLT 
see Sections 6.6.3.1 (Part 1A) and 6.6.3.2 (Part 1B), and for those who have experienced an IRR, 
see Section 6.6.4.2.
7.2
Withdrawal from the Trial
Patients will be withdrawn from the trial (dose escalation or expansion) for the following 
reasons:
•
A patient may withdraw from the trial at any time at his or her own request,
•
At the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons,
•
Lost to follow-up, 
•
Patient died,
•
Trial closure.


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If the patient withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the trial, he or she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site trial records.
The sponsor will make any effort to ensure patients are followed up for completion of safety 
assessment in the trial. See Table 1-1 and Table 1-2 for data to be collected at the 
time of trial discontinuation and follow-up and for any further evaluations that 
need to be completed.
When a patient withdraws consent, the reason for withdrawal is to be documented in the eCRF 
and in the source document. Trial drug assigned to the withdrawn patient may not be assigned to 
another patient. 
7.2.1
Withdrawal from the Use of Research Samples
The patient may withdraw their consent for future use of research samples at any time. To 
initiate the sample destruction process, the investigator must notify the sponsor of withdrawal of 
consent for the research samples and to request sample destruction. The sponsor will then initiate 
the process for sample destruction. If requested, the investigator will receive written 
confirmation from the sponsor that the samples have been destroyed. If the patient withdraws 
consent for research samples, the sponsor may retain and continue to use any data from samples 
already analyzed before such a withdrawal of consent. Samples will be destroyed after they are 
no longer needed for the clinical trial.
7.2.2
Safety Follow-up Evaluations
Patients discontinuing from treatment for any reason will have safety follow-up visits 30 days 
(+5 days) and 60 days (±7 days) after the patient receives the last dose of BNT411. Separate 
safety follow-up visits should also be done after discontinuation of atezolizumab, carboplatin and 
etoposide, if it occurs ≥21 days later than BNT411. If the patient initiates new anti-cancer 
treatment within 60 days of the last dose of trial treatment, the safety follow-up visit should be 
performed prior to starting new anti-cancer treatment. Once new anti-cancer treatment is 
initiated, the patient will move into survival follow-up.
7.3
Lost to Follow up
For patients whose status is unclear because they fail to appear for trial visits without stating an 
intention to withdraw consent, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent form and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, registered 
letters, etc. A patient should not be considered lost to follow-up until due diligence has been 
completed (where possible, three telephone calls and, if necessary, a certified letter to the 
patient’s last known mailing address or local equivalent methods). Patients lost to follow-up 
should be recorded as such on the appropriate disposition eCRF.


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8
Trial Assessments and Procedures
•
Trial procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
•
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue trial 
treatment.
•
Adherence to the trial design requirements, including those specified in the SoA, is 
essential and required for trial conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the patient’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
•
In case the COVID-19 pandemic creates challenges that may interfere with the conduct 
of this clinical trial, the addendum “Clinical trial protocol addendum related to 
COVID-19 pandemic Version 3.0 04 Jun 2021” gives guidance and outlines assistance 
on protocol procedures, patient enrollment and requirements within the established 
protocol. 
•
Information relating to COVID-19 vaccinations including a risk-benefit assessment and 
guidance for vaccination during this clinical trial is provided in Sections 10.8 and 10.9. 
The schedule of assessments to be performed in Parts 1A and 1B of the trial are summarized in 
Table 1-1 to Table 1-8 in Section 1.3.1. With the exception of post-dose blood and urine 
sampling for PK assessments, all assessments should be performed before trial treatment 
administration (on the applicable days) or any planned intervention. On the days of tumor 
imaging, blood sampling can be before or after imaging assessments.
8.1
Screening Procedures
Informed consent must be obtained within 21 days before Day 1 of Cycle 1 of Part 1 (A or B). 
Patients must provide written informed consent before any other screening-specific assessments 
are performed. Trial sites must maintain a log of all consenting patients which will include date 
and time of consent. 
Consenting patients who meet eligibility criteria will be enrolled in the trial and will be assigned 
a patient number. 
Screening assessments will be performed as summarized in Table 1-1 and Table 1-2. Screening 
will be initiated and completed within 21 days before Day 1 of Cycle 1 for Parts A and B.


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Women of child-bearing potential must have a negative serum pregnancy test conducted at 
screening. 
Vital signs and ECG will be performed as described in Sections 8.6.2 and 8.6.3. 
Laboratory safety tests (hematology, biochemistry, coagulation, endocrine [thyroid stimulating 
hormone (TSH), triiodothyronine (T3) and thyroxine (T4) and urinalysis) will be assessed as 
described in Section 8.6.4.
All patients will have a CT-scan with contrast or MRI of thorax, abdomen, and pelvis during 
screening. Evaluation of left ventricular function, either by echocardiogram (ECHO) or 
multigated acquisition (MUGA) scan, will be performed at Screening (or within 21 days of 
screening) and as clinically indicated at other time points.1 Head and neck imaging is also 
required for patients with squamous cell carcinoma of the head and neck (SCCHN). Imaging of 
the pelvis is not required for patients with SCCHN but is strongly recommended. If a CT scan or 
MRI has been performed within 21 days before visit Cycle 1 Day 1 as part of standard 
procedure, it is acceptable as a screening scan for the trial. If there is suggestion of brain 
metastases/tumors, a CT-scan or MRI of the head and neck will be performed within 21 days 
before the Cycle 1 Day 1 visit. Scans that exceed the 21-day window may be used for trial 
enrollment with sponsor approval.
Note: country specific information for Germany.2
8.2
Procedures During Treatment Visits for Cycles 1-N 
The assessments to be performed are shown in Table 1-1 and Table 1-2.
Details about these assessments are provided in Sections 8.5 to 8.12.
8.3
Treatment Discontinuation
The evaluations to be performed are detailed in Table 1-1 and Table 1-2. If the treatment 
discontinuation visit coincides with a regularly scheduled cycle visit, the treatment 
discontinuation evaluations will supersede those of the regularly scheduled cycle visit.
8.4
Other Visits 
8.4.1
Safety Follow-up
The evaluations to be performed are detailed in Table 1-1 and Table 1-2. 
8.4.2
Survival Follow-up
The evaluations to be performed are detailed in Table 1-1 and Table 1-2. 
1 Note: country specific information for Germany: left ventricular function should only be assessed by an ECHO 
scan (see Section 12.2.1).
2 Country specific information for Germany: to confirm that a patient would be eligible to participate in the trial, an 
active infection with HIV/Hepatitis B or C should be ruled out by serum blood test (see Section 12.2.1).


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8.4.3
Unscheduled Visits
The evaluations that may be performed are detailed in Table 1-1 and Table 1-2. 
8.5
Efficacy Assessments
8.5.1
Anti-tumor Activity Assessment – CT/MRI Imaging
Anti-tumor activity will be evaluated according to RECIST 1.1 (Eisenhauer et al, 2009) and 
iRECIST criteria (Seymour et al, 2017) (see Sections 10.5 and 10.6). Efficacy will be assessed 
by on-treatment imaging at Week 6 (+7 days), every 6 weeks (±7 days) for 48 weeks, and every 
12 weeks (±7 days) thereafter until disease progression is assessed by the investigator (unless the 
investigator elects to continue treatment [see below]), withdrawal of consent, trial termination by 
the sponsor, or death, whichever occurs first, regardless of whether patients start a new 
anti-cancer therapy.
In all parts of the trial, treatment should be discontinued in all patients who exhibit evidence of 
progressive disease by RECIST 1.1. However, to better accommodate standard clinical practice 
which is guided by the fact that these patients have, in general, limited treatment options and 
such options have limited efficacy and significant toxicity, patients may be considered for 
treatment beyond progression at the discretion of the investigator and after appropriate 
discussion with the patient and obtaining informed consent, only if all of the following criteria 
are met:
•
Absence of clinical symptoms or signs indicating clinically significant disease progression
•
No decline in performance status
•
Absence of rapid disease progression or threat to vital organs or critical anatomical sites [e.g. 
central nervous system (CNS) metastasis, respiratory failure due to tumor compression, 
spinal cord compression] requiring urgent alternative medical intervention
•
No significant, unacceptable or irreversible toxicities related to trial treatment
•
Patients must provide written consent to acknowledge deferring alternative treatment options 
including other clinical trials in favor of continuing trial treatment at the time of initial 
progression.
Patients who continue treatment beyond radiographic disease progression per RECIST 1.1 
should be closely monitored clinically and with a follow-up scan in 6 weeks or sooner if 
symptomatic deterioration occurs. Treatment should be discontinued if clinical deterioration due 
to disease progression occurs at any time, or if persistent disease growth is confirmed in a 
follow-up scan. In addition, patients should be discontinued for unacceptable toxicity or for any 
other signs or symptoms of deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data and clinical status.
Patients who discontinue treatment for reasons other than radiographic disease progression (e.g. 
toxicity) will continue scheduled tumor assessments at the same frequency as would have been 
followed if the patient had remained on trial treatment.
Patients whose treatment schedule has been changed (e.g., delay due to toxicity) still should 
follow the original tumor assessment schedule (every 6 weeks [±7 days] for 48 weeks, and every 
12 weeks [±7 days] thereafter).


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8.6
Safety Assessments
Safety assessments are described in Sections 8.6.1 to 8.6.8, with the exception of AEs, which are 
described in Section 8.7. Planned time points for all safety assessments are provided in the SoA. 
More frequent assessments may be performed at the investigator’s discretion, if medically 
indicated.
8.6.1
Physical Examination
Physical examinations will be performed (by inspection, palpation, and auscultation) by a 
physician at the trial site according to the SoA (Table 1-1 and Table 1-2).
A complete physical examination will be performed at screening, up to 21 days prior to first 
administration of IMP. The complete physical examination includes evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Abnormalities (clinical significant 
findings) observed at screening will be recorded on the general Medical History/Concomitant 
Diseases page of the eCRF, if started before signing the ICF. New or worsened clinically 
significant abnormalities after signing the ICF have to be recorded on the AE page of the eCRF.
A limited, system-directed physical examination will be performed at the other times noted in the 
SoA and as clinically indicated at other time points. New or worsened clinically significant 
abnormalities will be recorded on the AE page of the eCRF.
Height and weight will be assessed at screening. Weight will be assessed at additional time 
points as indicated in the SoA. Assessment of weight should be repeated at any time if there are 
apparent weight changes.
8.6.2
Vital Signs
Vital signs will be assessed by the appropriate trial personnel at the time points listed in the SoA 
(Table 1-1 and Table 1-2).
During dose escalation, body temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed as summarized in Table 1-6 on BNT411 administration days. On days when BNT411 is 
not administered, vital signs only need to be obtained once, at any time during the visit.
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the patient in a quiet setting without distractions (e.g. television, cell phones).
•
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 3 blood pressure measurements (3 consecutive blood pressure readings will 
be recorded at intervals of at least 1 minute). The average of the 3 blood pressure 
readings will be recorded on the eCRF.
8.6.3
Electrocardiograms
Triplicate (during trial treatment) or single (at other time points) 12-lead ECG will be obtained as 
outlined in the SoA (see Section 1.3, Table 1-3 and Table 1-4) using an ECG machine that 


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automatically calculates the pulse rate and measures PR, QRS, QT, and corrected QT (QTc) 
intervals. For the assessment the subjects will be in the supine position, lying still and quietly 
until the assessment has been done. 
In general, increases in QT/QTc to >500 ms or of >60 ms over baseline are commonly used as 
thresholds for potentially discontinuing trial treatment; consultation with a cardiologist should be 
considered for any such increases to determine whether they are clinically significant.
At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 5 minutes.
8.6.4
Clinical Safety Laboratory Assessments
The following laboratory assessments will be performed as summarized in the SoA: hematology, 
biochemistry, endocrine parameters (TSH, T3 and T4), coagulation profile, and urinalysis (see 
Section 10.2 for details).
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the trial in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the patient's condition.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the trial or within 60 days after the last dose of trial treatment should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified, and the sponsor notified.
All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the investigator (e.g. SAE or AE or dose modification), then the results must be 
recorded in the eCRF.
8.6.5
Eye Examination
Eye examinations are to be performed by an ophthalmologist and should include at least visual 
acuity testing and slit-lamp exam to help diagnose cataracts, glaucoma, detached retina, macular 
degeneration, and cornea injuries. Patients who wear glasses must have their baseline visual 
acuity properly documented. Further examinations such as visual field testing, non-contact 
tonometry and retinal tomography can be done if required. Eye examination will be done at 
baseline (during screening), up to 3 days before Cycle 2 and thereafter up to 3 days before every 
third cycle (i.e., C2, C5, C8, C11, etc.). 
The investigator should perform an unscheduled eye examination with a direct ophthalmoscope 
if there is suspicion of worsening of the eyesight. Patients should be referred to an 


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ophthalmologist at the investigator’s discretion even before the performance of indirect 
ophthalmoscopy, and at any time point of the trial.


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8.6.6
ECOG Performance Status
ECOG performance status will be assessed at the time points indicated in Table 1-1 and 
Table 1-2 using the following scale:
Grade
ECOG Description
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
Death
8.6.7
Pregnancy Testing
In this trial, patients are considered to have reproductive potential, unless they are 
postmenopausal or permanently sterile. Details and definitions are provided in Section 10.4. See 
Table 1-1 and Table 1-2 for the time points when pregnancy tests should be performed for 
women of childbearing potential. A serum pregnancy test is performed at screening. Thereafter, 
urine pregnancy test is sufficient unless indicated otherwise. A serum pregnancy test is warranted 
to confirm a positive urine pregnancy test.
See Section 8.7.5 for details of reporting pregnancies.
8.6.8
Echocardiogram or multigated acquisition scan
Evaluation of left ventricular function, either by echocardiogram (ECHO) or multigated 
acquisition (MUGA) scan, will be performed at Screening (or within 21 days of screening) and as 
clinically indicated at other time points.1
8.7
Adverse Events and Serious Adverse Events
The definitions of AEs and SAEs can be found in Section 10.3. 
1 Note: country specific information for Germany: left ventricular function should only be assessed by an ECHO 
scan (see Section 12.2.1).


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AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the trial treatment or trial procedures, or that 
caused the patient to discontinue the trial or trial treatment (see Section 7).
8.7.1
Time Period and Frequency for Collecting AE and SAE Information
All SAEs and AEs will be collected from the signing of the ICF until the safety follow-up visit at 
the time points specified in the SoA (Section 1.3, Table 1-5).
All SAEs will be recorded and reported by the investigator to the sponsor or designee 
immediately and no later than 24 hours after becoming aware of the event, as indicated in 
Section 10.3. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
trial participation. However, if the investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the trial, and he/she considers the event to be reasonably 
related to the trial treatment or trial participation, the investigator must promptly notify the 
sponsor.
Safety-related information / paper-based SAE reports (initial and follow-up reports) are to be 
sent to the safety contact details outlined in Section 10.3.4.
8.7.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.7.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3.
8.7.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a trial 
treatment under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial treatment under clinical investigation. The sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), 


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and investigators. The execution of expedited reporting to the different entities may be delegated 
as detailed in the trial-specific Safety Management Plan. Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. An investigator 
who receives an investigator safety report describing an SAE or other specific safety information 
(e.g. summary or listing of SAEs) from the sponsor will review and then file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.7.5
Pregnancy
Any female participant who becomes pregnant while participating in the trial will discontinue the 
IMP. Details of all pregnancies in female patients and, if indicated, female partners of male 
patients will be collected (procedures described in Section 10.4.1). 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Section 10.4.1.
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs (details defined in Section 10.4.1).
8.7.6
Death Events
AEs leading to death will be recorded and analyzed (for details see Section 10.3.3). Deaths will 
also be followed up during survival follow-up. After treatment discontinuation, information on 
survival follow-up and new anti-cancer therapy (including but not limited to targeted therapy and 
immunotherapy) will be collected via phone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent for survival 
follow-up or the sponsor terminates the trial). If a patient requests to be withdrawn from survival 
follow-up, this request must be documented in the source documents and signed by the 
investigator. 
Deaths clearly related to the progression of the disease will not be documented and reported as 
AEs or SAEs. These deaths must be collected on the death page of the eCRF.
In Germany only: Any death, irrespective whether causally related to disease progression or not, 
will be documented as AE and reported as SAE.
8.7.7
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs
The progression of underlying disease (e.g., new metastases) during trial participation is not 
considered as an AE. 
Because disease progression is common for patients with cancer, it will not be reported 
according to the standard process for expedited reporting of an SAE even though the event may 
meet the definition of a SAE. These events will be recorded on the corresponding page in the 
patient’s eCRF. 


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NOTE: symptoms resulting from the progression and clearly stated as related to the progressive 
disease (PD) and fatal cases clearly related to the progression will not be documented and 
reported as AEs and SAEs. However, specific symptoms at time of progression that are 
considered to be caused by other reason, and fatal cases where other reason rather than the PD 
may not be discarded, will have to be documented as AEs and reported as SAEs if applicable.
In Germany only: deaths related to disease progression will be reported as AEs or SAEs.
8.7.8
Dose Limiting Toxicity
See Sections 6.6.1 and 6.6.2 for the definition of DLTs in this trial. 
A DLT has to be documented on an SAE report form and forwarded to the safety contacts as 
described later in this document. DLT reporting needs to be carried out in the same way as SAE 
reporting (i.e., no more than 24 hours after learning of the event) as described in Section 10.3.4. 
8.8
Treatment of Overdose
For this trial, an overdose is defined as a patient receiving a dose of BNT411 15% in excess of 
the intended dose specified in this protocol. Guidance on overdose for atezolizumab, carboplatin 
and etoposide should be referred to SmPC and USPI.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient.
Medication errors include infusion rate errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product. 
All events of overdose and/or medication errors with BNT411 must be reported from the 
investigational site to the sponsor within 24 hours of awareness whether associated with an AE 
or not.
In addition, overdose and/or medication errors with BNT411 must also be recorded in the AE 
page of the eCRF when associated with signs, symptoms or clinical sequelae (see 
Section 10.3.1).
Overdose, medication errors, misuse and abuse do not automatically make an AE serious, but if 
the consequences are serious, for example death or hospitalizations, the event is serious and must 
be reported as an SAE.
Rescue medication to reverse the action of BNT411 is not available. In case of overdose, 
medication errors, misuse, and/or abuse of trial drug, patients should receive supportive care 
according to local guidelines and potential side effects of BNT411 should be treated 
symptomatically.
In the event of an overdose, the investigator should:
i.
Contact the Medical Monitor immediately.
ii.
Closely monitor the patient for any AE/SAE and laboratory abnormalities until BNT411 
can no longer be detected systemically.


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iii.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis).
iv.
Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
8.9
Pharmacokinetics
Plasma and urine samples will be collected for measuring concentrations of BNT411 and its 
major metabolites. Table 1-3 and Table 1-4 describe the timing of collection of samples for PK 
assessments during dose escalation. For urine sampling, the exact time of sampling and the 
volume (mL) excreted at each time point before infusion of BNT411 must be documented. Total 
amount of urine has to be collected within the first 6 hours following start of the infusion and 
total volume excreted should be documented on C1D1. Full pharmacokinetic profiles will be 
documented in additional patients enrolled to confirm the RP2D. The actual date and time (24-
hour clock time) of each sample will be recorded, except for the 6-hour urine collection.
The following PK parameters will be determined when appropriate (including but not limited to): 
area-under-the-concentration-time curve [AUC], clearance [CL] and volume of distribution [VD], 
maximum concentration [Cmax], time to Cmax [Tmax], pre-dose trough concentrations [Ctrough], 
terminal half-life [T1/2], and accumulation ratio [RA].
Further details are provided in the laboratory manual.
8.10 Pharmacodynamic Biomarkers
The trial will include pharmacodynamic assessments based on changes in selected cytokines and 
other activation markers. Cytokine samples will be taken at the same time points as for PK 
sampling – see Table 1-3 and Table 1-4. 
Furthermore, cytokine samples will be taken at disease progression or treatment discontinuation. 
If an adverse event of CRS is suspected, cytokines should be obtained at an unscheduled visit to 
support the diagnosis.
Table 1-7 (Part 1A) and Table 1-8 (Part 1B) provide details of biomarker assessments to be 
performed during dose escalation. Samples will be collected from all patients. Biomarker 
assessments will include tumor biopsy, blood sampling for cytokine analysis, and further 
analysis, that may include immune phenotyping, tumor mutational burden and TCR profiling. 
Further details regarding sample types, volumes etc. are provided in the laboratory manual.
Samples may be analyzed to monitor pharmacodynamics by evaluating changes in systemic and 
intratumoral immune response (e.g. immunophenotyping of immune cells in peripheral blood, 
absolute and relative changes compared to baseline in tissues and/or peripheral blood 
mononuclear cells [PBMCs]) in blood and tumor tissue compared to baseline. Additionally, 
targeted sequencing may be performed for profiling of T-cell receptors (TCR profiling) in order 
to identify potential markers that may predict clinical response (see Section 8.11). 
Samples for biomarker analysis can be used up to 5 years after the end of the trial. Biomarker 
analyses may be deferred or not performed, if during or at the end of the trial, it becomes clear 
that the analysis will not have sufficient scientific value for biomarker evaluation, or if there is 


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not enough sample to allow adequate evaluation. In the event that the trial is terminated early or 
shows poor clinical efficacy, completion of biomarker assessments is based on justification and 
intended utility of the data.
8.11 Genetics
Where required by local or country specific regulations, each patient must sign a separate 
informed consent form if he or she agrees to genetic testing (DNA and RNA) of the collected 
samples. 
These analyses may include the following:
i. Identification of tumor specific mutations on a DNA level to evaluate tumor 
mutational burden (TMB) as a potential predictive marker
ii. Identification of mRNA expression pattern of immune-relevant genes in the 
tumor as a potential predictive marker
iii. Profiling of T-cell receptors (TCRs) in the periphery and tumor as a potential 
predictive marker as well as a surrogate for pharmacodynamics
If a patient refuses to consent to DNA and RNA research in these specific regions, the patient is 
still eligible to participate in the trial.
8.12 Immunogenicity Assessments
Immunogenicity is not being evaluated in this trial.
8.13 24/7 Coverage for Urgent Protocol-related Medical Questions 
In a trial-related health emergency, when the assigned Medical Monitor for the trial cannot be 
reached by a caller, for discussion of urgent protocol Medical-related questions an on-call 
physician can be reached 24 hours per day, 7 days per week via an ICON Call-Centre: 
To reach the ICON HelpDesk for 24/7 Coverage of Urgent Protocol-related Medical Questions, 
dial the local number found here: https://icophone.iconplc.com/24-7-Medical.pdf


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9
Statistics 
9.1
Statistical Hypotheses
No statistical hypotheses are planned to be tested in this trial. 
9.2
Sample Size Determination
The sample size for Parts 1A and 1B is driven by the 3+3 trial design and will range from three 
to six DLT evaluable patients per cohort depending on the number of DLTs which may occur. In 
total, between 6 to 60 DLT evaluable patients are planned to be enrolled in the Part 1A, and 
between 6 to 30 DLT evaluable patients are planned to be enrolled in the Part 1B.
9.3
Analysis Sets
Modified Intent to Treat Set
The modified ITT (mITT) set is defined as all patients who are assigned to BNT411 and have a 
baseline and at least one on-treatment/post-treatment tumor response assessment.
Safety Set
The safety set is defined as all patients who received BNT411 (i.e. at least one dose of BNT411).
DLT Evaluation Set
The DLT evaluation set includes all patients from the safety set who either have completed the 
DLT evaluation period and meet the minimum exposure criterion or have experienced a DLT 
during the DLT evaluation period (Cycle 1). 
Patients who do not experience any DLT during the DLT evaluation period are considered to be 
evaluable if they have been observed for minimum 21 days following the first dose and are 
considered to have sufficient safety data to conclude that a DLT did not occur. A patient is 
considered to have met the minimum exposure criterion if the relative dose intensity (RDI) of 
BNT411 in Cycle 1 is 100%. 
Patients who are excluded from the DLT evaluation set will be replaced.
The DLT evaluation set will be used for the evaluation of DLTs in order to assess the MTD and 
the RP2D. The safety set will be used for all other safety analyses, while the mITT set will be 
used for efficacy analyses (Part 2 only).
9.4
Statistical Analyses
Statistical analyses will be performed by the BioNTech or a designated CRO. All statistical 
analyses will be carried out using SAS®, Version 9.4 or higher, and/or other statistical software 
as required. 
The statistical analysis plan will be finalized prior to database snapshot for the main statistical 
analysis, it will include a more technical, and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.


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9.4.1
General Considerations
Continuous variables will be summarized by cohort using the following descriptive statistics: 
number of patients (n), mean, standard deviation, median, minimum and maximum. 
Categorical variables will be summarized by cohort presenting absolute and relative frequencies 
(n and %) of patients in each category. 
Time-to-event-endpoints (DOR, PFS and OS) will be analyzed using Kaplan-Meier methodology 
by cohort and censored in accordance with the FDA Guidance: “Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics” and the EMA guidance “Guideline on the evaluation 
of anti-cancer medicinal products in man”. Censoring rules will be defined in the SAP. 
The median survival time (including 95% confidence limits according to Brookmeyer and 
Crowley) and the first and third quartile will be presented. Survival rates (including 95% 
confidence interval based on Greenwood's formula) as well as the number and percentage of 
patients with events, censored and under risk will be displayed for selected time points (e.g. at 3, 
6, 12 months). The time-to-event analysis will be illustrated using Kaplan-Meier plots.
Baseline is defined as last available value prior to first dose of trial treatment (i.e. BNT411, or 
atezolizumab, carboplatin, and etoposide).
9.4.2
Primary Endpoint(s)
The primary objective of the trial is to assess the safety profile of the regimen based on the 
following endpoints:
•
Occurrence of dose limiting toxicities (DLTs) within a patient during the DLT evaluation 
period
•
Occurrence of treatment-emergent adverse events (TEAE) within a patient including 
grade ≥3, serious, fatal TEAE by relationship
•
Occurrence of dose reduction and discontinuation of BNT411 within a patient due to 
treatment-emergent adverse events (TEAE)
And to determine the MTD and/or RP2D defined as follows:
•
MTD – the highest tolerated dose
•
RP2D based on integrated evaluation of safety, tolerability, clinical benefit, PK, and 
pharmacodynamics data, for all dose levels tested.
A treatment emergent AE is defined as any AE with an onset date on or after the first 
administration of trial treatment (if the AE was absent before the first administration of trial 
treatment) or worsened after the first administration of trial treatment (if the AE was present 
before the first administration of trial treatment). AEs with an onset date more than 60 days after 
the last administration of trial treatment will be considered as treatment emergent only if 
assessed as related to trial treatment by the investigator. Treatment-emergent AEs will be 
summarized overall and by treatment arm. The trial treatment includes BNT411, atezolizumab, 
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AEs will be coded using the most recent version of Medical Dictionary for Regulatory Activities 
(MedDRA®) coding system to get a System Organ Class (SOC) and Preferred Term (PT) for 
each AE and graded for severity using NCI CTCAE v5.0. 
The number and percentage of patients reporting at least one AE will be summarized by PT 
nested within SOC for each of the following AE types: 
•
any AE
•
related AE
•
Grade ≥3 AE
•
related Grade ≥3 AE
•
any SAE
•
related SAE
•
SAE leading to death
•
AE leading to dose reduction
•
AE leading to permanent discontinuation of treatment
•
DLT.
Moreover, the number and percentage of patients with any AE will be summarized by worst NCI 
CTCAE grade by PT nested within SOC.
DLTs will be presented in terms of listings presenting the reported term and MedDRA PT and 
SOC term, its time of onset, duration, and outcome, relationship, NCI CTCAE grade, and 
seriousness including dose exposure data. 
9.4.3
Secondary Endpoint(s)
For Parts 1 and 2:
•
Establish the PK profile, including estimating the following parameters: AUC, CL and 
VD, Cmax, Tmax, Ctrough, and T1/2
For Part 2:
•
Evaluate anti-tumor activity according to RECIST 1.1 (Eisenhauer et al, 2009), including 
the following:
o
ORR defined as the proportion of patients in whom a CR or PR is observed as 
best overall response.
o
DCR defined as the proportion of patients in whom a CR or PR or SD (assessed at 
least 6 weeks after first dose) is observed as best overall response.
o
DOR defined as the time from first objective response (CR or PR) to the first 
occurrence of objective tumor progression (PD) or death from any cause, 
whichever occurs first.
The ORR and DCR will be summarized with absolute and relative frequencies along with two-
sided 95% Clopper-Pearson confidence intervals by cohort. Patients not meeting the criteria for 
CR or PR for ORR (CR or PR or SD for DCR), including those without any post-baseline tumor 
assessments, will be considered as non-responders.
DOR will be analyzed using Kaplan-Meier methodology as described in Section 9.4.1.


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9.4.4
Exploratory Endpoint(s)
For Part 2:
Exploratory endpoints include evaluation of anti-tumor activity according to iRECIST:
•
iORR defined as the proportion of patients in whom a iCR or iPR is observed as best overall 
response.
•
iDCR defined as the proportion of patients in whom a iCR or iPR or iSD (assessed at least 
6 weeks after first dose) is observed as best overall response.
•
iDOR defined as the time from first objective response (iCR or iPR) to the first occurrence 
of objective tumor progression (iCPD) or death from any cause, whichever occurs first.
The iORR and iDCR will be summarized with absolute and relative frequencies along with two-
sided 95% Clopper-Pearson confidence intervals by cohort. Patients not meeting the criteria for 
iCR or iPR for iORR (iCR or iPR or iSD for iDCR), including those without any post-baseline 
tumor assessments, will be considered as non-responders.
iDOR will be analyzed using Kaplan-Meier methodology as described in Section 9.4.1.
If too few responders are observed, this exploratory analysis may be omitted.
A preliminary assessment of efficacy will also be included based on evaluation of:
•
PFS defined as the time from first dose of BNT411 to first occurrence of objective tumor 
progression, or death from any cause, whichever occurs first. 
•
OS defined as the time from first dose of BNT411 to death from any cause. 
PFS and OS will be analyzed using Kaplan-Meier methodology as described in Section 9.4.1.
For Parts 1 and 2:
A preliminary assessment of biomarkers that might act as pharmacodynamics, anti-tumor, and 
safety indicators will also be included:
•
assess the pharmacodynamics based on immune system activation as shown by changes in 
select cytokines and other activation markers.
9.4.5
Other Safety Analyses
Other safety analyses will be detailed in the statistical analysis plan (SAP).
9.4.6
Other Analyses 
Other analyses will be detailed in the SAP.
9.5
Interim Analyses 
No formal interim analysis is planned. However, data will be reviewed by the SRC after each 
cohort. The main statistical analysis will be performed once all patients have completed 
treatment and safety follow-up.


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9.6
Safety Review Committee (SRC)
A Safety Review Committee (SRC), composed of the investigators and the sponsor’s 
representatives will assess the cumulative safety data (e.g. SAEs, AEs, laboratory data and DLTs 
where applicable) collected during the trial to help ensure patient’s safety. 
The SRC will make recommendations for the RP2D at the end of both Parts 1A and 1B and will 
recommend whether to activate the expansion phase (Part 2).
Meetings with the SRC will take place at the time points outlined in the latest version of the 
signed SRC charter.
If a toxic dose is reached, the Medical Monitor will email the investigators and site staff to 
inform them that recruitment has been suspended pending review by the SRC. If the email is not 
acknowledged, the site will be telephoned until contact with the appropriate site staff is made. 
Investigators and site staff who do not attend SRC meetings will be provided with an email 
update of all SRC decisions within 24 hours of each meeting.


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10 Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations
10.1.1 Regulatory and Ethical Considerations
•
This trial will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations
•
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the trial is initiated.
•
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the trial design, except for changes necessary to eliminate an 
immediate hazard to trial patients.
•
The investigator will be responsible for the following:
o
Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
10.1.2 Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial.
10.1.3 Informed Consent Process
•
The investigator or his/her representative will explain the nature of the trial to the 
patient or his/her legally authorized representative and answer all questions regarding 
the trial.
•
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 


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Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or trial center.
•
The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the trial and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
•
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the trial.
•
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.
•
Patients who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorized designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a patient's agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this optional research will not provide this separate signature.
10.1.4 Data Protection
•
Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred.
•
The patient must be informed that his/her personal trial-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the patient who will be required to give consent for their data to be used 
as described in the informed consent 
•
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5 Data Quality Assurance
•
All patient data relating to the trial will be recorded on electronic CRF (eCRF) unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.
•
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
•
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.


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•
Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.
•
The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data.
•
The sponsor assumes accountability for actions delegated to other patients (e.g. 
Contract Research Organizations).
•
Trial monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are being 
protected; and that the trial is being conducted in accordance with the currently 
approved protocol and any other trial agreements, ICH GCP, and all applicable 
regulatory requirements.
•
Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the investigator for 25 years after trial completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to 
the sponsor.
10.1.6 Source Documents
•
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
•
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the 
trial. Also, current medical records must be available.
•
Definition of what constitutes source data can be found in the ICH Guideline for Good 
Clinical Practice.
10.1.7 Trial and Site Start and Closure
The trial start date is the date on which the clinical trial will be open for recruitment of patients.
The first act of recruitment is the signing of the ICF by the first patient and will be the trial start 
date.
The sponsor designee reserves the right to close the trial site or terminate the trial at any time for 
any reason at the sole discretion of the sponsor. Trial sites will be closed upon trial completion. 
A trial site is considered closed when all required documents and trial supplies have been 
collected and a trial-site closure visit has been performed.


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The investigator may initiate trial-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a trial site by the sponsor or investigator may include but are not 
limited to:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
•
Inadequate recruitment of patients by the investigator
•
Discontinuation of further trial treatment development
If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the trial of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up.
10.1.8 Publication Policy
•
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.
•
The sponsor will comply with the requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement.
•
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
•
The overall publication policy for the trial data is addressed in the clinical agreement for 
each investigator site.
10.1.9 Dissemination of Clinical Trial Data
A final ICH E3 conform report integrating all trial results will be prepared by the sponsor.
In all cases, trial results will be reported in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the trial or the country in which the trial 
was conducted.
Clinical trial data and documentation will be disseminated as required per applicable laws and 
regulations, e.g., the European Union (EU) Regulation No 536/2014, EU Regulation 1049/2001, 
and the US Final Rule, which implements Section 801 of the Food and Drug Administration 
Amendments Act (FDAAA 801). Clinical documents under such laws includes protocols and 
protocol amendments, SAPs, ICH E3 clinical study reports.
This trial will be registered, and trial results be publicly posted, on publicly accessible trial 
registries (e.g., ClinicalTrials.gov, EU Clinical Trials Register, etc.) as required per applicable 
laws and regulations.


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If this clinical trial is used to support marketing authorization packages/submissions, the sponsor 
will comply with the EU Policy 0070, the proactive publication of clinical data on the EMA 
website. Clinical data, under Phase 1 of this policy, includes clinical overviews, clinical 
summaries, ICH E3 clinical study reports, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. under Phase 2 of this policy, “clinical data” 
includes the publishing of individual patient data.
Even if not required by applicable laws and regulations, this trial will be registered, and trial 
results be publicly posted on ClinicalTrials.gov. 
The results for all primary and secondary outcome measures, irrespective of outcome, will be 
submitted for publication in academic journals (for further details, see Section 10.1.8).


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10.2 Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10-1 will be performed by either local or central laboratories as 
detailed in the relevant footnotes to Table 1-1 and Table 1-2.
•
If a sample is required for local and central assessment/ analysis, it is important that the 
sample for central analysis is obtained at the same time as the local 
sample. Additionally, if the local laboratory results are used to make either a trial 
treatment decision or response evaluation, the results must be entered into the eCRF.
•
Protocol-specific requirements for inclusion of patients, including pregnancy testing, 
are detailed in Section 5.1 of the protocol.
•
Additional tests may be performed at any time during the trial as determined necessary 
by the investigator or required by local regulations.


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Table 10-1:
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular volume 
(MCV)
Mean corpuscular 
hemoglobin (MCH)
White blood cell (WBC) count 
with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) 
Count
Hemoglobin
Hematocrit
Biochemistry
Blood urea nitrogen 
(BUN)
Potassium,
Magnesium
Chloride,
Phosphate (inorg.)
Lactate 
dehydrogenase 
(LDH),
Amylase
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (non-fasting)
Calcium
Alkaline 
phosphatase
Albumin
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilirubinogen, nitrite and leukocyte 
esterase 
•
Microscopic examination (if blood or protein is abnormal)
Coagulation 
Factors
•
Prothrombin time 
•
Activated partial thromboplastin time (aPTT)
•
International normalized ratio (INR)
Endocrine Tests
•
TSH, free T3 and free T4
Pharmacodynamics 
and biomarkers
•
Blood sampling for cytokine analysis, immune phenotyping
Serology
•
Country specific procedure for Germany: To confirm trial eligibility, an active 
infection with HIV/Hepatitis B or C should be ruled out by serum blood test of 
hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), 
antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus 
(anti-HCV), antibody against HIV-1 and -2 (anti-HIV 1/2).
Other Screening 
Tests
•
Highly sensitive serum human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)
Investigators must document their review of each laboratory safety report.
The results of each test must be entered into the eCRF.


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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1 Definition of AE
AE Definition
•
An AE is any untoward medical occurrence in a patient or clinical trial patient, 
temporally associated with the use of trial treatment, whether or not considered related 
to the trial treatment.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of trial treatment.
•
A treatment-emergent AE (TEAE) is defined as any AE with an onset date on or 
after the first administration of trial treatment (if the AE was absent before the first 
administration of trial treatment) or worsened after the first administration of trial 
treatment (if the AE was present before the first administration of trial treatment). AEs 
occurring after the period of observation (60 days after last treatment dose) will be 
considered as treatment-emergent only if assessed as related to the trial treatment by 
the investigator.
Events Meeting the AE Definition
•
New conditions or worsening of pre-existing conditions detected or diagnosed after 
signing patient informed consent 
•
Any abnormal laboratory test results (hematology, biochemistry, endocrine parameters, 
coagulation profile or urinalysis) or other safety assessments (e.g. ECGs, radiological 
scans, vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the 
investigator (i.e. medical conditions that have medical consequences for the subject) or 
laboratory value or other clinical test that is associated with symptoms or leads to a 
change in trial treatment or concomitant treatment or discontinuation from trial 
treatment.
•
Any exacerbation of pre-existing medical condition (a worsening in the character, 
frequency, or severity of a known medical condition). This includes any condition 
resulting from concomitant illnesses, reactions to concomitant medications, or 
progression of concomitant disease states.
•
Recurrence of a previous medical condition not present at baseline or exacerbation of a 
chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.


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Events Meeting the AE Definition
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
•
Trial procedure related AEs (caused by a protocol-mandated intervention, including 
those that occur prior to assignment of trial treatment, such as tumor biopsies).
•
Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE or SAE if they fulfil the definition of an AE or SAE.
Events NOT Meeting the AE Definition
•
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than anticipated for the patient’s condition.
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition. However, specific symptoms at time of progression that are considered to be 
caused by other reason, and fatal cases where other reason rather than the PD may not 
be discarded and will have to be documented as AEs and reported as SAEs if 
applicable. In Germany only: Deaths related to disease progression will be 
documented as AEs and reported as SAEs.
•
Any abnormal laboratory findings which are evaluated and documented in the source 
data as not clinically significant (e.g., an abnormal laboratory value without any 
clinical manifestation, such as transient lymphopenia after infusion of BNT411 due to 
redistribution), should not be documented as an AE.
•
The disease/disorder being studied, or anticipated progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than anticipated for the patient’s 
condition.
•
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the trial that do not worsen.


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10.3.2 Definition of SAE
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
patient was 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.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
•
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is considered medically important:
•
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical treatment to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
•
Examples of such events include invasive or malignant cancers, 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.


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The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(e.g. rated as mild, moderate, or severe); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
SAE exemptions are defined in Section 10.3.3 of this appendix.
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event that is 
considered to have a positive causal relationship to the IMP and is classified as unexpected by 
the sponsor. A related adverse event is classified as unexpected when the nature or severity (= 
intensity) is not consistent with the applicable product information (reference safety information, 
i.e. the Investigator’s Brochure (IB) for an unauthorized IMP or summary of product 
characteristics for an authorized product). SUSARs are subject to expedited reporting by the 
sponsor to the appropriate regulatory authorities, ethics committees and participating 
investigators.
10.3.3 Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
•
The investigator will then record all relevant AE/SAE information in the eCRF, i.e.
• intensity according to NCI CTCAE v5.0,
• seriousness,
• action taken (with trial treatment and other actions),
• outcome, and
• causal relationship/causality.
•
All assessments as well as the AE term (diagnosis/description), start date and time of 
onset, and end date and time must be documented in the source data and the eCRF. To 
avoid colloquial expressions, the AE should be documented in standard medical 
terminology. The AE should be evaluated and documented as a diagnosis rather than 
individual signs or symptoms. If a definite diagnosis is not possible, the individual 
signs and symptoms should be documented (each as a single AE).
•
Data pertaining to AEs will be collected during each trial visit. Based on the subject's 
spontaneous description, or the investigator's inquiry or examination during each visit, 


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AE and SAE Recording
the clinical significance of any sign or symptom will be evaluated by the investigator.
•
The definition of clinical significance includes medical conditions that have medical 
consequences for the subject. Examples of medical consequences are as follows (list is 
not exhaustive):
o
Ongoing treatment or (re)start of a treatment (includes drug and non-drug 
therapies)
o
Further investigations within a narrow time-frame (e.g. ultrasound testing, 
gastroscopy, coloscopy)
o
Impact on upcoming trial treatment (e.g., treatment with a reduced dose, delay 
of treatment start, cancellation of treatment)
•
Clinically significant findings must be documented as AEs in the source data and 
eCRF. Findings that are evaluated and documented in the source data as not clinically 
significant (e.g., an abnormal laboratory value without any clinical manifestation) 
should not be documented as an AE. All clinically significant symptoms, diseases, and 
syndromes present at the baseline visit should not be documented as an AE but as 
medical history/concomitant disease
•
It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the sponsor or any involved clinical research organization in lieu of 
completion of the AE/SAE eCRF page.
•
Whenever copies of medical records for certain cases are requested by the sponsor, all 
patient identifiers, with the exception of the patient number, need to be redacted on the 
copies of the medical records before submission to the sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Period of observation:
•
The period of observation starts after informed consent has been obtained. After 
informed consent, all AEs and SAEs should be reported until 60 days after the last dose 
of trial treatment. 
•
AEs occurring later than 60 days after the last trial treatment must only be documented 
if a relationship to trial treatment or trial procedure is suspected. 


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AE and SAE Recording
•
SAEs will continue to be reported until 60 days after the last dose of IMP. All SAEs 
for which the investigator suspects a relationship to IMP or trial procedure have to be 
reported to the safety contact (given in Section 10.3.4), even if they occur after the end 
of the period of observation. In Germany, all SAEs, regardless of relatedness, that 
occur in a patient throughout his or her lifetime should be reported (Section 12.2.1).
•
Investigators will seek information on AEs at each subject contact. All AEs, whether 
reported by the subject or noted by trial personnel, will be recorded in the subject’s 
medical record and on the AE eCRF.
•
The investigator should follow each AE until the event has resolved to baseline grade 
or better, the event is assessed as stable by the investigator, the subject is lost to follow-
up, or the subject withdraws consent. Every effort should be made to follow all SAEs 
considered to be related to trial treatment or trial-related procedures until a final 
outcome can be reported.
SAE exemptions: 
•
Hospitalizations for respite care or solely for coordination of care (including hospice 
arrangements) will not be considered as reportable SAEs.
•
Visits to a hospital by ambulance or to the emergency room without admission will not 
be regarded as hospitalization unless the event fulfills any other of the seriousness 
criteria.
•
Hospitalizations that were necessary solely because of subject requirement for 
outpatient care outside of normal outpatient clinic operating hours will not be 
considered as reportable SAEs.
•
Planned hospitalizations required by the protocol (e.g., for trial treatment 
administration or insertion of access device for trial treatment administration) will not 
be considered as reportable SAEs. 
•
Hospitalizations for procedures or interventions of a pre-existing condition of the 
subject (elective surgery = planned, non-emergency surgical procedure) will not be 
considered as reportable SAEs:
o
if it was planned and documented in the subject record before the trial-specific 
subject informed consent was signed, or
o
if it was scheduled during the trial when elective surgery became necessary and 
the subject has not experienced an AE.


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AE and SAE Recording
NOTE: Hospitalization of this type should be avoided during trial treatment. 
•
Routine treatment or monitoring of the underlying disease not associated with any 
deterioration in the subject’s condition.
•
Hospitalization of a subject for monitoring and symptomatic treatment for up to 24 
hours due to a transient inflammatory reaction of Grade 1 or 2 will not be considered 
an SAE (but needs to be documented as an AE).
•
Deaths clearly related to the progression of the disease will not be documented and 
reported as AEs or SAEs. These deaths must be collected on the death page of the 
eCRF. 
In Germany only: Deaths related to disease progression will be documented as AE and 
reported as SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the trial and assign it to 1 of the intensity categories according to NCI CTCAE v.5.0.
AEs that are not listed in NCI CTCAE v5.0 should be classified according to the investigator’s 
discretion as close as possible to NCI CTCAE v5.0, based on the comparison with the most 
severe case encountered in past training and clinical experience. 
Each AE must be classified in one of the following 5 categories: 
•
Grade 1 - Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
•
Grade 2 - Moderate: Minimal, local, or non-invasive intervention indicated; limiting 
age appropriate instrumental Activities of Daily Living (ADL)*. 
•
Grade 3 - Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
•
Grade 4 - Life-threatening consequences: urgent intervention indicated.
•
Grade 5 - Death related to AE.
* Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money etc.
** Self-care ADL refers to bathing, dressing and undressing, feeding oneself, using the toilet, 
taking medications, and not bedridden.
With regards to the intensity of an AE, the following must be documented in the source data 
and eCRF:


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Assessment of Intensity
•
Initial intensity of the AE 
•
Maximum intensity of the AE
•
For each change of intensity*** 
o
new grade of intensity
o
date of change (= start of new grade of intensity)
***A change of intensity only needs to be documented if there is a clearly definable change in 
grading of the AE (e.g. a laboratory result changes from severe to moderate according to NCI 
CTCAE criteria).
NOTE: The NCI CTCAE grading does not automatically correspond to the seriousness 
criteria, i.e. the term ‘severe’ describes the intensity of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This is not the same as ‘serious’, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.
Assessment of Causality
•
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration 
will be considered and investigated.
•
The following table can be taken as guidance:
Causality Assessment:
Causality Term
Assessment Criteria
Assessed as
Certain
­
Event or laboratory test abnormality, with plausible 
time relationship to drug intake 
­
Cannot be explained by disease or other drugs 
­
Response to withdrawal plausible (pharmacologically, 
pathologically) 
­
Event definitive pharmacologically or 
phenomenologically (i.e. an objective and specific 
medical disorder or a recognized pharmacological 
phenomenon) 
­
Rechallenge satisfactory, if necessary 
Related
Probable/
Likely
­
Event or laboratory test abnormality, with reasonable 
time relationship to drug intake 
­
Unlikely to be attributed to disease or other drugs 
­
Response to withdrawal clinically reasonable 
­
Rechallenge not required 
Related


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Assessment of Causality
Possible
­
Event or laboratory test abnormality, with reasonable 
time relationship to drug intake 
­
Could also be explained by disease or other drugs 
­
Information on drug withdrawal may be lacking or 
unclear 
Related
Unlikely
­
Event or laboratory test abnormality, with a time to 
drug intake that makes a relationship improbable (but 
not impossible) 
­
Disease or other drugs provide plausible explanations 
not related
Nevertheless, it is sufficient to document the causality in the source data and eCRF as
•
related,
•
not related
For an event considered “related to trial treatment” there is a reasonable possibility of a causal 
relationship (there are facts, evidence, and/or arguments to suggest a causal relationship, rather 
than a relationship cannot be ruled out).
For an event considered “not related to trial treatment” there is no reasonable possibility of a 
causal relationship.
•
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
•
Events caused by the procedure of trial treatment administration should be 
differentiated from events caused by the trial treatment itself. Only events suspected to 
be caused by the trial treatment itself should be documented as related to trial treatment, 
but not events caused by the procedure of trial treatment administration (e.g. reactions 
at the injection site of trial treatment likely to be caused by the procedure of trial 
treatment administration, discomfort after blood drawing). Such AEs need to be 
documented as “related to trial procedure” with the causing procedure specified.


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Action taken by the investigator to trial treatment
Action(s) taken by the investigator as a result of an AE must be documented. 
Action(s) taken with trial treatment by the investigator can be:
•
Dose not changed (= continuation of trial treatment administration according to the 
trial protocol)
•
Dose reduced 
•
Trial treatment withdrawn temporarily (= interruption and resumption):
o
Delayed start of the next vaccination 
o
Cancellation of administration at a given visit
o
Interruption of trial treatment administration during a given visit 
•
Trial treatment permanently withdrawn (= discontinuation)
•
Unknown (e.g., in case the subject is lost to follow-up)
•
Not applicable (e.g., in case treatment with trial treatment has not yet started or event 
starts after last trial treatment administration) 
Other action(s) that may be taken by the investigator include:
•
None
•
Initiation of a concomitant drug therapy for the treatment of the AE
•
Termination of a concomitant drug therapy (please specify; e.g. if this might be the 
cause of the AE)
•
Change of the dose of a concomitant medication
•
Hospitalization or prolongation of hospitalization (please complete SAE-Form)
•
Initiation/termination of a non-drug therapy
•
Other (please specify)
Outcome of events
The investigator has to assess the outcome of an AE (and not the subject’s outcome) at the 
time of documentation based on the following categories:
•
Recovered/Resolved (= complete resolution of the AE)
•
Recovered/Resolved with sequelae (= subject recuperated but retained pathological 
conditions resulting from the AE; the sequelae should be indicated)
•
Recovering/Resolving (= AEs which are improving but not yet resolved completely)
•
Not recovered/Not resolved (= AEs which are ongoing without improving or still 
present when the subject dies due to another AE)


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Outcome of events
•
Fatal (= death due to the AE)*
•
Unknown (e.g., in case the subject is lost to follow-up). 
* In case of a fatal event, the event term should not be “death” but the underlying event which 
led to death (death = outcome). If there is more than one AE in a fatal case, only the AE 
leading to death will be attributed with the outcome “fatal”. A copy of an autopsy report 
should be submitted if available. 
All ongoing AEs will be followed until resolution, considered by the investigator to be stable 
or chronic (resolved with sequelae), the subject is lost to follow-up, the subject withdraws 
consent, or it has been determined that trial treatment or participation is not the cause of the 
AE and a plausible explanation for the cause of the event has been found. If no final status is 
reached at the end of the subject’s trial participation, the investigator must confirm the 
unavailability of a final status. For AEs not related to the trial treatment, the investigator must 
confirm the unavailability of a final status at the end of the safety period for the respective 
subject.
Every effort should be made to follow all SAEs considered to be related to trial treatment or 
trial-related procedures until a final outcome can be reported.
Documentation of particular situations
•
AEs that are secondary to other events:
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. A medically significant secondary AE that is separated in 
time from the initiating event should be documented as an independent AE in the 
source data and eCRF (e.g., if vomiting results in mild dehydration with no additional 
treatment in a healthy adult, only vomiting should be documented as an AE; If 
vomiting results in severe dehydration, both events should be documented as AEs 
separately).
•
Recurrent Adverse Events
A recurrent AE is one that resolves between subject evaluation time points (i.e., visits) 
and subsequently recurs. Each recurrence of an AE should be documented as a separate 
AE in the source data and eCRF.


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Documentation of particular situations
•
Abnormal Laboratory Results and Vital Signs Values
Not every laboratory or vital signs abnormality needs to be documented as an AE. For 
laboratory/vital signs abnormalities, the following definitions and documentation rules 
apply:
A laboratory/vital signs abnormality is clinically significant if it:
•
is a sign of a disease or syndrome. In this case, only the diagnosis of the 
causing disease or syndrome needs to be documented as an AE. 
•
results in specific symptom(s) but no diagnosis of a disease or syndrome can be 
made. In this case, only the symptom(s) need to be documented as AE(s). 
•
is not a sign of a disease or syndrome and does not result in specific symptoms 
but leads to a change in trial treatment or in a medical intervention. In this case, 
the laboratory/vital signs abnormality must be documented as an AE. 
Any laboratory/vital signs abnormality for which none of the above-mentioned criteria 
are applicable are not clinically significant and should therefore not be documented as 
an AE.
•
Increased Body Temperature and Fever
The normal range for the body temperature is defined as >35°C to <38°C. For results 
within this range no source data entry for clinical significance is required, and no AE 
needs to be documented. If an investigator rates a body temperature result within this 
range as clinically significant, the clinical significance needs to be documented in the 
source data and an AE (e.g. with the term “body temperature increased”) needs to be 
documented. For results out of this range, a source data entry for clinical significance is 
required and an AE needs to be documented. The AE should be described (verbatim) 
and rated (intensity) according to NCI CTCAE criteria v5.0:
•
Fever Grade 1: 38°C - 39°C
•
Fever Grade 2: >39°C - 40°C
•
Fever Grade 3: >40°C for ≤24h
•
Fever Grade 4: >40°C for >24h
•
Fever Grade 5: death due to fever
Since fever is an anticipated reaction to BNT411 and the sponsor is very interested in 
details of body temperature changes, an increase of body temperature ≥38 °C should be 
rated as clinically significant and documented as an AE. Conversely, there should be 
very good reasons if an increase of body temperature ≥38 °C is rated as not clinically 
significant and is not documented as an AE.


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Documentation of particular situations
In order to reflect the body temperature results adequately in the verbatim term of the 
AEs, the following should be considered:
•
A clinically significant increase in body temperature <38 °C should be 
documented as an AE with the verbatim “body temperature increased”.
•
A clinically significant increase in body temperature ≥38 °C should be 
documented as an AE with the verbatim “fever” or “pyrexia”.
•
Deaths
All deaths that occur during the period of observation must be recorded on the AE 
eCRF and immediately reported as an SAE to the sponsor, regardless of relationship to 
trial treatment. In addition to reporting as an SAE, the applicable eCRF must be 
completed.
Exemptions to the SAE definition, as defined in Section 10.3.3, also apply for fatal 
cases.
Death should be considered an outcome (“fatal”) and not a distinct event. The event or 
condition that caused or contributed to the fatal outcome should be recorded as the 
single medical event on the AE eCRF. If there is more than one AE in a fatal case, the 
outcome “fatal” should be selected only for the AE leading to death.
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the AE eCRF. If the cause of death 
becomes available later (e.g., after autopsy), “unexplained death” should be replaced 
by the established cause of death. The term “sudden death” should not be used unless 
combined with the presumed cause of death (e.g., “sudden cardiac death”).
Deaths that occur after the AE reporting period should be recorded on the applicable 
eCRF, regardless of cause.
In Germany only: Any death, irrespective if causally related to disease progression or 
not, will be documented as AE and reported as SAE.
•
Adverse Events Associated with an Overdose or Error in Drug Administration
An overdose is the accidental or intentional use of a drug in an amount (per 
administration or cumulatively) higher than the dose being studied (for BNT411) or 
higher than the maximum recommended dose according to the authorized product 
information (for approved concomitant medications). An overdose or incorrect 
administration of a drug is not itself an AE, but it may result in an AE. Intentional 
overdoses taken with possible suicidal/self-harming intent should be reported 
regardless of sequelae. All AEs associated with an overdose or incorrect administration 
should be documented as an AE in the source data and eCRF and reported as SAE if 
applicable.


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Follow-up of AEs and SAEs
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
If a patient dies during participation in the trial or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post-mortem 
findings (including histopathology) if an autopsy or any other testing has been 
performed.
•
New or updated information will be recorded in the originally completed eCRF.
•
The investigator will submit any updated SAE data to the contacts given in 
Section 10.3.4 within 24 hours of receipt of the information.
10.3.4 Reporting of SAEs
SAE Reporting to Sponsor
Safety-related information / Paper-based SAE reports (initial and follow-up reports) have to be 
sent to the following fax number or email address:
Safety Report Fax No.:
Safety Report Email Address:
In the case where an investigator or any other trial team member has questions with regards to 
safety reporting, these can be addressed to: 
 
Email: 
Please note that for medical questions the medical monitor for this trial should be contacted 
(for contact information see Section 8.13).
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE eCRF pages within the designated reporting time frames.
PPD
PPD


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SAE Reporting to Sponsor
•
Information for final description and evaluation of a case report may not be available 
within the required time frames for reporting. Nevertheless, for regulatory purposes, 
initial reports should be submitted if the following minimal information is available: 
• An identifiable subject (number, initials) 
• A suspected medicinal product 
• An identifiable reporting source (investigator/trial site identification) 
• An event or outcome that can be identified as serious 
•
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. If additional information regarding a previously 
submitted SAE is obtained, a follow-up SAE report should be sent to the sponsor 
(indicating that this is a “follow-up” report) without delay and accompanied by 
appropriate anonymous supporting documentation (e.g., hospital reports), until a final 
outcome and date are available.
•
Completed reporting forms need to be signed by an investigator before faxing/mailing 
them to the safety contact provided above. Blank reporting forms are provided to the 
investigator during the site initiation visit and are filed in the Investigator Site File 
(ISF). 
•
If any medical records (for example hospital discharge reports) are considered as 
relevant case information by the investigator, it is recommended that the investigator 
directly provides the medical report to the contact details described above. In the case 
of an SAE including a hospital stay for the subject, the respective discharge letter 
needs to be provided by the site as soon as it is available, at a minimum. To ensure 
clear allocation of the record to a specific subject and SAE, the investigator should 
additionally complete and sign a paper follow-up form (titled: Additional Information 
and Follow-Up Form) and provide the follow up form together with the 
pseudonymized medical record.
•
Original, completed reporting forms have to be filed in the ISF, with copies in the Trial 
Master File. All events initially reported on a paper-based reporting form also have to 
be documented in the eCRF. 
•
If explicitly required according to national legislation, the investigator must submit 
copies of the SAEs to the ethics committee (EC) or authority and retain documentation 
of these submissions in the Site Trial File.


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10.4 Appendix 4: Definition of Reproductive Potential and Contraception
Definition of reproductive potential and measures of contraception for BNT411 are detailed 
below. Further guidance for other trial treatment agents should be according to the authorized 
product information (for approved concomitant medications).
Female Patients
In this trial, patients are considered to have reproductive potential, UNLESS they are 
post-menopausal or permanently sterile: 
•
A postmenopausal state is defined as no menses, in patients >45 years of age, for 
12 months without an alternative medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state in patients not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
•
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. 
All female patients must agree not to donate eggs (ova, oocytes) for the purpose of assisted 
reproduction during the trial and for 6 months after receiving the last dose of BNT411. 
Female patients of reproductive potential must agree to use adequate contraception during and 
for 6 months after the last BNT411 administration. Adequate contraception is defined as highly 
effective methods of contraception (Table 10-2). Birth control methods are considered highly 
effective if they have a failure rate of less than 1% per year, when used consistently and 
correctly. 


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Table 10-2:
Highly Effective Methods of Contraception
•
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation1 (oral, intravaginal, or transdermal) in combination with a barrier method or/and an intrauterine device
•
Progestogen-only hormonal contraception associated with inhibition of ovulation1 (oral, injectable, or 
implantable) in combination with a barrier method or/and an intrauterine device
•
Intrauterine device2
•
Intrauterine hormone-releasing system2
•
Bilateral tubal occlusion2
•
Vasectomized partner2, 3
•
Sexual abstinence4
1
Hormonal contraception may be susceptible to interaction with BNT411, which may reduce the efficacy of 
the contraception method. Therefore, hormonal contraception method alone is not considered as a highly 
effective method of contraception. Hormonal contraception should be combined with a barrier method 
or/and an intrauterine device to be a highly effective method of contraception.
2
Contraception methods that in the context of this guidance are considered to have low user dependency.
3
Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the woman of child-bearing potential (trial patient) and that the vasectomized partner has received 
medical assessment of the surgical success.
4
In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient.
Table adapted from ‘Recommendations related to contraception and pregnancy testing in clinical trials. Advisory 
non-binding guidance represented at the CTFG-meeting in Rome 2014’ (MHRA 2014).
Male Patients
1. Recommendations for male patients with pregnant partner:
Male contraception (condom) is recommended in order to avoid exposure of an existing 
embryo/fetus. Contraception should be continued for 6 months after receiving the last dose of 
BNT411.
2. Recommendations for male patients with non-pregnant WOCBP partner:
The male patient should use condom during treatment and for 6 months after receiving the last 
dose of BNT411. For a non-pregnant WOCBP partner, contraception recommendations should 
also be considered.
All men must also not donate sperm during the trial and for 6 months after receiving the last dose 
of BNT411.
10.4.1 Collection of Pregnancy Information
Details will be collected of all pregnancies in female participants that occurred after the start of 
trial intervention and until 90 days after the last dose of BNT411. These details will be collected 


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after obtaining the necessary signed informed consent from pregnant participants (and if 
applicable their partners).
After obtaining the necessary signed informed consent from pregnant female partners directly, 
details will be collected of all pregnancies in female partners of male participants that occurred 
after the start of trial intervention and until 28 days after the last dose of BNT411. This applies 
only to male participants who receive BNT411.
The initial and follow-up information must be documented on the paper-based Pregnancy 
Reporting Form and submitted to the sponsor within 24 hours of learning of a participant's 
pregnancy/partner’s pregnancy. The completed form needs to be sent to the Safety Report Fax 
number or Email detailed in Section 10.3.4. Completed pregnancy forms need to be signed by an 
investigator before faxing/mailing them to the sponsor. Blank reporting forms are provided to the 
investigator during the site initiation visit and are filed in the ISF.
The investigator will collect follow-up information on the subject/subject’s partner and the 
neonate and the information will be forwarded to the sponsor. Pregnancy follow-up should 
describe the outcome of the pregnancy, including any voluntary or spontaneous termination, 
details of the birth, the presence or absence of any congenital abnormalities, birth defects, 
maternal or newborn complications and their presumed relation to the BNT411. Generally, the 
follow-up will be of a duration determined in consultation with the pediatrician. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. Any post-trial pregnancy related 
SAE considered reasonably related to the trial intervention by the investigator will be reported to 
the sponsor. While the investigator is not obligated to actively seek this information in former 
trial subjects, he or she may learn of an SAE through spontaneous reporting.


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10.5 Appendix 5: Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST 1.1)
Evaluation of Target Lesions
•
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (the sum may 
not be “0” if there are target nodes).
•
Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on trial (this includes the baseline sum if that is the 
smallest on trial). 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 progression.)
•
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease, taking as reference the smallest sum of diameters while 
on trial.
Evaluation of Non-Target Lesions
•
Complete Response - 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).
•
Non-complete response/Non-progressive disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits.
•
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy (see Section 5.1). In the absence of 
measurable disease, change in non-measurable disease comparable in magnitude to the 
increase that would be required to declare progressive disease for measurable disease. 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large,’ an increase in 
lymphangitic disease from localized to widespread.
Appearance of New Lesions
The appearance of new lesions is considered progressive disease according to RECIST v1.1. 
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression. In the absence of rapid clinical deterioration, 


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patients may continue to receive trial treatment if investigators consider that patients continue to 
benefit from treatment.
Evaluation of Overall Response
For the overall response based on RECIST v1.1, confirmation of CR and PR is required by a 
repeat, consecutive assessment no less than 4 weeks from the date of first documentation. A 
confirmatory scan will also be required after an initial assessment of progressive disease for the 
purpose of managing treatment and in order to conduct the exploratory iRECIST analysis. If a 
patient discontinues the trial due to progressive disease and begins another treatment, a 
confirmatory scan is not required. If the next protocol-scheduled scan is due within 2 weeks after 
the confirmatory scan was obtained, the protocol-scheduled scan does not need to be done. 
Treatment of patients may continue between the initial assessment of progressive disease and 
confirmation of progressive disease (which is not required by RECIST v1.1). These patients may 
continue to receive trial therapy beyond confirmed progressive disease if investigators consider 
that patients continue to receive benefit from treatment. In the absence of clinical deterioration, 
such modifications to the RECIST may discourage the early discontinuation of treatment and 
provide a more complete evaluation of trial therapy anti-tumor activity than would be seen with 
conventional response criteria.
Table 10-3 provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions.


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Table 10-3:
Evaluation of Overall Response
Target Lesions
Non-target Lesions
New 
Lesions
Overall Response
Complete response
Complete response (or no non-target 
lesion)
No
Complete response
No target lesiona
Complete response
No
Complete response
Complete response
Not evaluableb
No
Partial response
Complete response
Non-complete response/ 
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable (or no non-target
lesion)b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable (or no non-target
lesion)b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesiona
Not all evaluated
No
Not evaluable
No target lesiona
Non-complete response/ 
non-progressive disease
No
Non-complete response/ 
non-progressive disease
Progressive disease
Any
Yes/No
Progressive disease
Any
Progressive disease
Yes/No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesiona
Unequivocal progressive disease
Yes/No
Progressive disease
No target lesiona
Any
Yes
Progressive disease
a Defined as no target lesion at baseline.
b Not evaluable is defined as when either no or only a subset of lesion measurements are made at an assessment.


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10.6 Appendix 6: iRECIST: guidelines for response criteria for use in trials 
testing immunotherapeutics
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression (Section 8.5.1)
For patients who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a patient on trial intervention until 
repeat imaging is obtained 4 to 8 weeks later (using iRECIST for patient management). This 
decision by the investigator should be based on the patient’s overall clinical condition.
Any patient deemed clinically unstable should be discontinued from trial intervention at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the patient may continue to receive trial 
intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per investigator assessment. Images should continue to be sent into the central 
imaging vendor for potential retrospective Blinded Independent Central Review (BICR).
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 mm 
from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum of 
diameters” will be used in this protocol.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
iRECIST defines new response categories, including immune unconfirmed progressive disease 
(iUPD) and immune confirmed progressive disease (iCPD). For purposes of iRECIST 
assessment, the first visit showing progression according to RECIST 1.1 will be assigned a 
visit (overall) response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 


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The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively as 
New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the patient will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.


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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, and the patient continues to be clinically 
stable, trial treatment may continue and follow the regular imaging schedule. If PD is 
confirmed, patients will be discontinued from trial treatment.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (i.e. achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
•
New lesions


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-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.
Progression must be confirmed before iCPD can occur.


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10.7 Appendix 7: Veterans Administration Lung Study Group (VALG) 
Staging System for SCLC
Stage
Characteristics
Limited SCLC
Disease confined to the ipsilateral hemithorax which 
can be safely encompassed within a radiation field
Extensive SCLC
Disease beyond the ipsilateral hemithorax, including 
malignant pleural or pericardial effusion or 
hematogenous metastases
SCLC   small cell lung cancer.


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10.8 Appendix 8: Risk-benefit assessment of COVID-19 vaccination in 
BNT411-01 trial
BNT411 is a highly potent and selective small molecule TLR7 agonist of the imidazoquinoline 
family which comprises other TLR ligands such as imiquimod (CAS-No. 99011-02-6), 
resiquimod (CAS-No. 144875-48-9) and 852A (CAS-No. 532959-63-0).
Clinically, due to its mechanism of action, chills, fever, malaise and all other flu-like symptoms 
may be the first and most commonly seen adverse reactions in patients treated with BNT411.
At this time, there are three COVID-19 vaccines authorized and recommended in the US: the 
Pfizer-BioNTech COVID-19 vaccine (COMIRNATY), Moderna COVID-19 vaccine (Spikevax), 
and Johnson & Johnson/Janssen COVID-19 vaccine. These vaccines are described on the US 
Centers for Disease Control and Prevention (CDC)’s vaccine page. In the EU and the UK, the 
same vaccines are authorized and recommended with the addition of the Oxford/AstraZeneca 
COVID-19 vaccine. The Pfizer-BioNTech COVID-19 vaccine (COMIRNATY) and the 
Moderna COVID-19 vaccine (Spikevax) are mRNA vaccines, whereas both the Johnson & 
Johnson/Janssen and Oxford/AstraZeneca COVID-19 vaccines are viral vector vaccines. None of 
the vaccines are a live virus vaccine mentioned by the protocol as per exclusion criterion 2 (i.e., 
received any live vaccine within 4 weeks of the start of trial treatment).
The COVID-19 pandemic is an ongoing pandemic with different stages and impacts at any one 
time across the whole world. The governments of the countries involved in this trial have started 
a nationwide vaccination program including vaccination for oncology patients. All prominent 
regulatory, government and professional bodies have recommended COVID-19 vaccination even 
in oncology patients under active treatment. To date, there is no clear or specific guidance for 
patients enrolled in interventional oncology clinical trials and decisions should be taken on a 
case-by-case basis.
Recently results for the short-term safety of the Pfizer-BioNTech mRNA COVID-19 vaccine in 
oncology patients treated with immune checkpoint inhibitors were published (Waissengrin et al. 
2021). Considering the high mortality rates due to COVID-19 in cancer patients undergoing 
treatment, the data supports current guidelines and calls for vaccination of patients being treated 
with immune checkpoint inhibitors, especially during pandemic surges.
The interaction of BNT411 with all the vaccines approved in the US, EU, and UK is not known. 
It is unlikely that there will be any data of TLR7 in combination with any of the COVID-19 
vaccines. However, the sponsor assesses the risk of significant side effects of BNT411 in 
combination with COVID-19 vaccine to be low. The National Comprehensive Cancer Network 
(NCCN) and American Society of Clinical Oncology (ASCO) recommend for the COVID-19 
vaccine to be administered on the same day as oncology therapy, including immunotherapy. 
However, since BNT411 is still under development in a Phase 1 trial and no comprehensive 
clinical data is available yet, the sponsor would recommend at least a 7-day interval between 
COVID-19 vaccination and administration of BNT411 as a precaution. The Pfizer/ BioNTech 
COVID-19 vaccine COMIRNATY results in high antigen expression for around 72 h which then 
decreases to low levels after approximately one week (EMA assessment report 2020). If 
administered within the timeframe of high COVID-19 antigen expression, BNT411 is anticipated 
to strongly boost COVID-19 vaccine induced T-cell responses. On one hand this could result in 
an improved efficacy of the vaccine however, on the other hand it could also lead to an increased 


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reactogenicity as well as to reduced expansion of tumor antigen specific T cells due to T cell 
competition. For this reason, the sponsor would recommend at least a 7-day interval between 
BNT411 treatment and COVID-19 vaccination.
A longer interval may be necessary during the DLT-observation period, before the dose of 
BNT411 has been declared safe as per the trial design. The oncologist should always assess the 
situation on an individual basis and discuss with the sponsor. Considering the high morbidity and 
mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far 
outweigh the risks of vaccine-related AEs in patients enrolled in clinical trials (Desai et al. 
2021).


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10.9 Appendix 9: COVID-19 vaccination in BNT411-01 trial during the 
pandemic
BioNTech as the sponsor of the BNT411-01 trial recommends that patients and their physicians 
discuss on an individual basis the risks and benefits of COVID-19 vaccination in the context of 
the BioNTech oncology trials, considering also guidelines from the FDA, EMA, US Centers for 
Disease Control and Prevention (CDC), American Society of Clinical Oncology (ASCO), 
European Society for Medical Oncology (ESMO) and local agencies. Taking this into account, 
COVID-19 vaccination may be performed with the following recommendations: 
•
Patients with prior COVID-19 vaccination may be allowed to enter the trial with a wash-out 
period of at least 7 days since the last COVID-19 vaccine dose.
•
For patients already enrolled in the clinical trial and still receiving trial treatment, COVID-
19 vaccination may be allowed if an interval of at least 7 days is ensured between the 
COVID-19 vaccination and the trial treatment.
•
COVID-19 vaccination during the DLT evaluation period in the dose escalation parts of the 
trial should be avoided to prevent any confounding effect of the vaccination on the DLT 
evaluation. However, as the data in dose escalation are accumulating, the decision to 
vaccinate should be made by the treating oncologist, and any decision should be discussed 
with the sponsor’s Medical Monitor.
•
Administration of COVID-19 vaccine during participation in the BNT411-01 trial should be 
documented as a concomitant medication.
•
Previous administration of COVID-19 vaccine or past confirmed infection of COVID-19 by 
reverse transcription polymerase chain reaction (RT-PCR) before enrolment in the 
BNT411-01 trial should be documented in the prior/concomitant medication form and 
medical history, respectively.


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10.10 Appendix 10: Abbreviations
ADL
Activities of Daily Living
AEs
adverse events
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APCs
antigen presenting cells
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area-under-the-concentration-time curve
Beta hCG
beta-human chorionic gonadotropin
BSA
body surface area
BW
body weight
CI
confidence interval
CL
clearance
Cmax
maximum concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRS
cytokine release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLs
cytotoxic T-lymphocytes
Ctrough
trough concentration 
CYPs
cytochrome P450 enzymes
DAMPs
danger-associated molecular patterns
DC
dendritic cells
DCR
disease control rate
DEC
dose-expansion cohort
DLTs
dose-limiting toxicities
DOR
duration of response
ECG
electrocardiogram


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ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ES-SCLC
extensive stage small cell lung cancer
FFPE
formalin fixed paraffin embedded
FIH
first-in-human
FSH
follicle stimulating hormone
GFR
glomerular filtration rate
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony stimulating factor
G-CSF
granulocyte-colony stimulating factor
HBV
hepatitis B virus
HCV
hepatitis C virus
Hgb
hemoglobin
HIV
human immunodeficiency virus
HLA
human leucocyte antigen
ICD
immunogenic cell death
ICF
informed consent form
iCPD
immune confirmed progressive disease
iCR
immune complete response
iDCR
immune disease control rate
IEC
Independent Ethics Committees
IFNα 
interferon alpha 
IMP
Investigational Medicinal Product 
INR
International normalized ratio
iORR
immune objective response rate
iPR
immune partial response
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
immune RECIST
IRR
infusion-related reaction
ISF
Investigator Site File


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iSD
immune stable disease
ITT
intent to treat
iUPD
immune unconfirmed progressive disease
LS-SCLC
limited-stage small cell lung cancer
MABEL
minimum anticipated biological effect level
mAbs
monoclonal antibodies
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities 
mITT
modified intent to treat
MoA
mode of action
MRI
magnetic resonance imaging
MTD
maximal tolerated dose
MUGA
multigated acquisition
NCI
National Cancer Institute
NIMPs
Non-Investigational Medicinal Products
NOAEL
no-observed-adverse-effect level
NK
natural killer
NS
non-serious
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PAMP
pathogen associated molecular patterns
PBMCs
peripheral blood mononuclear cells
PCI
prophylactic cranial irradiation
PD
progressive disease 
pDCs
plasmacytoid dendritic cells
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PT
Preferred Term
QTc
corrected QT interval


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RDI
relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
RP2DR
RP2D range
SAE
serious adverse event
SAP
statistical analysis plan
SCCHN
squamous cell carcinoma of the head and neck
SCLC
small cell lung cancer
SCr
serum creatinine
SD
stable disease
SJS
Steven Johnsons Syndrome
SLE
systemic lupus erythematosus
SmPC
summary of product characteristics (EMA)
SoA
Schedule of Activities
SOC
System Organ Class
SRC
Safety Review Committee
SUSAR
suspected unexpected serious adverse reaction
T1/2
terminal half-life
T3
triiodothyronine
T4
thyroxine
TAAs
tumor-associated antigens
TCR
T-cell receptor
TEAEs
treatment-emergent adverse events
TLR7
toll-like receptor 7
Tmax
time to Cmax
TMB
tumor mutational burden
TME
tumor microenvironment
TSH
thyroid stimulating hormone
ULN
upper limit normal
USPI
US prescribing information (FDA)
VALG
Veterans Administration Lung Study
VD
volume of distribution


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WBC
white blood count
WOCBP
women of childbearing potential


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10.11 Appendix 11: Protocol Version/Amendment History
10.11.1
Version 2: 30 October 2019
Overall Rationale for the update to Version 2
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Data Monitoring Safety 
Review Committee
Data Monitoring Committee 
replaced by Safety Review 
Committee to ensure 
consistency throughout the 
protocol
Tables 1-1 and 1-2 Schedule 
of Activities
Safety follow-up 1, visit 
window +5 days aligned with 
section 7.2.2 (replaced +/- 
with +5 days).
Coagulation factors and 
endocrine: X under 
Unscheduled visit.
Footnotes 19 (Medical 
History): Medical history 
includes cancer history and 
20 (Prior/Concomitant 
Medications and Non-Drug 
Therapies): 
Prior/Concomitant 
Medications and Non-Drug 
Therapies include all anti-
cancer pre-treatments added 
to Table 1-1 and footnotes 22 
and 23 added to table 1-2, 
respectively.
Added: Informed Consent for 
genetic testing to both Table 
1-1 and 1-2
Table 1-1: Cycle 1-2, D3, 
vital signs: X added
Typo corrected
Correction of activity in the 
Table
Footnotes added to better 
explain what will be collected 
under Medical history and 
Prior/Concomitant 
Medications and Non-Drug 
Therapies.
Activity of taking informed 
consent for genetic testing 
was missing in Version 1
Correction of vital signs 
activity in the table 1-1, 
aligning with table 1-2


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Table 1-2, footnote 17: After 
4 cycles, prophylactic cranial 
irradiation (PCI) is permitted 
as per local guidelines and 
will be reported on the 
Prophylactic Cranial 
Irradiation Cancer 
Radiotherapy eCRF. 
Table 1-2 Survival Follow-
up: every 12 weeks after last 
dose
Added X under survival 
follow-up with footnote 21 
(Table 1-1) and 24 (Table 1-
2): Prior/Concomitant 
Medication and Non-Drug 
therapies only for BNT 
related AEs
Correction of the eCRF form 
to report PCI
Alignment of Table 1-2 with 
Table 1-1
Added to align with Section 
10.3.3
4.1.1.1 Dose Escalation in 
Part 1A
After completion of the DLT 
period for each cohort, the 
SRC will review the data 
from the DLT period – 
including but not limited to 
all relevant safety and clinical 
data – to propose a dose level 
for the next cohort of 
patients; PK and 
pharmacodynamics data, if 
available, will also be taken 
into consideration. 
Rephrased to make it clearer 
that PK and 
pharmacodynamics data are 
not mandatory for dose 
decision making, but will be 
considered if available.
4.5 End of Trial Definition
However, maximal trial 
duration is 3 years after the 
last patient’s first treatment. 
Thereafter, the Sponsor will 
ensure treatment for ongoing 
patients with a potential 
treatment benefit.
Rephrased to further clarify, 
deleting the words “post-trial 
treatment” that might be 
confusing
6.1.2 Non Investigational 
Medicinal Products
Etoposide: The dose will be 
calculated using the Mosteller 
formula (BSA [m2] = square 
root((height [cm] x weight 
[kg])/3600))
Explained how to calculate 
the etoposide dose, which 
was not mentioned in Version 
1.


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6.5 Concomitant Therapy and 
Procedures
Replaced “enrollment” by 
“signing of the Informed 
Consent Form: Any 
medication or vaccine 
(including over-the-counter 
or prescription medicines, 
vitamins, and/or herbal 
supplements) or procedure 
that the patient is receiving or 
undergoing at the time of 
signing the informed consent 
or receives or undergoes 
during the trial must be 
recorded
Added “treatment”: The 
prohibited medications while 
on trial treatment are as 
follows
Rephrased to clarify the 
starting point of recording 
concomitant therapy
Rephrasing for clarification’s 
sake
7.1 Discontinuation of Trial 
Treatment
Added: Lost to follow-up
Missing in Version 1
8.1 Screening procedures
Added: Evaluation of left 
ventricular function, either by 
echocardiogram (ECHO) or 
multigated acquisition 
(MUGA) scan, will be 
performed at Screening and 
as clinically indicated at other 
time points. See new section 
8.6.8
ECHO or MUGA mentioned 
in the SoAs, were not listed 
under the screening 
procedures
8.6.1 Physical Examination
Replaced “baseline” with 
“screening” and change of 
wording: Abnormalities 
(clinical significant findings) 
observed at screening will be 
recorded on the general 
Medical History/Concomitant 
Diseases page of the eCRF, if 
started before signing the 
ICF. New or worsened 
clinically significant 
abnormalities after signing 
Rephrased for further 
clarification and to better 
align sections 8.6.1 and 
10.3.1 Definition of AE


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the ICF have to be recorded 
on the AE page of the eCRF.
8.6.3 Electrocardiograms
Added: For the assessment 
the subjects will be in the 
supine position, lying still and 
quietly until the assessment 
has been done.
The subject’s position was 
not mentioned in Version 1.
8.7.6 Death Events
If the patient withdraws 
completely from the trial, the 
trial staff may use a public 
information source to obtain 
information about survival 
status only, if not applicable 
by local law.
Removed because not 
applicable for a phase1/safety 
trial.
8.8 Treatment of Overdose
In addition, overdose and/or 
medication errors with 
BNT411 must also be 
recorded in the AE page of 
the eCRF whether when 
associated with an AE or not.
Rephrased to align with 
section 10.3.3
8.11 Genetics
Where required by local or 
country specific regulations, 
each patient must sign a 
separate informed consent 
form if he or she agrees to 
provide samples for genomic 
biomarker analysis genetic 
testing (DNA and RNA) of 
the collected samples. 
Rephrased to avoid confusion 
about genetic testing.
8.12 Biomarkers
Additionally, genomic 
analyses targeted sequencing 
will be performed for TCR 
profiling in order to identify 
potential markers that may 
predict clinical response (see 
Section 8.11).
Rephrased to avoid confusion 
about genetic testing
Table 10-1 Protocol-required 
Safety Laboratory 
Assessments
Albumin assessment added 
under Biochemistry
Albumin assessments were 
not listed under the screening 
procedures, whereas an 
Albumin level is mentioned 
under inclusion criteria: 


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Albumin level at screening 
≥3 mg/dL
10.3.1 Definition of AE
Rephrased: New conditions 
or worsening of pre-existing 
conditions detected or 
diagnosed after signing 
patient informed consent even 
though it may have been 
present before the start of the 
trial.
Rephrased to align sections 
8.6.1 and section 10.3.1
8.5.1 Anti-tumor Activity 
assessment – CT/MRI 
Imaging
Anti-tumor activity will be 
evaluated according to 
RECIST 1.1 (Eisenhauer et 
al., 2009) and iRECIST 
criteria (Seymour et al., 2017) 
and include estimation of 
ORR, DCR and DOR, and 
iORR, iDCR and iDOR (see 
Section 3, Sections 10.5 and 
10.6).
Endpoints deleted, will be 
statistically estimated
Synopsis, Table 1-1 and 1-2 
footnote 11, 4.1 Overall 
Design, 8.5.1 Anti Tumor 
Activity Assessment CT-MRI 
Imaging
Efficacy will be assessed by 
on-treatment imaging at 
Week 6 (+7 days), every 6 
weeks (±7 days) for 50 48 
weeks, and every 12 weeks 
(±7 days) thereafter until 
disease progression is 
assessed by the investigator 
(unless the investigator elects 
to continue treatment), 
withdrawal of consent, trial 
termination by the Sponsor, 
or death, whichever occurs 
first, regardless of whether 
patients start a new anti-
cancer therapy.
Changed 50 weeks to 48 
weeks, to avoid confusion 
about when to take images – 
48 weeks is a multiplier of 6 
weeks


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10.11.2
Version 3.0: 07 May 2020
Rationale for the update to version 3.0:
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
Section # and 
Name
Description of Change
Brief Rationale
IMP changed to BNT411 under Primary Endpoints 
and Exploratory Endpoints.
Rephrased for 
consistency.
Trial design, Part 2 shortened for clarity: 
Deleted: “A “backfilling” approach will be 
implemented where more patients will be enrolled 
in selected dose levels in both Part 1A and Part 1B 
to explore further safety and anti-tumor activity.”
Rephrased for clarity.
Added to Key Exclusion Criteria:
“any live vaccine received within 4 weeks of the 
start of trial treatment”
Added for consistency.
1.1 Synopsis
Added to Key Exclusion Criteria:
“Any contraindications to atezolizumab, carboplatin 
or etoposide as per USPI or SmPC in Part 1B”
Added for consistency.
Serology added to the table as country specific 
testing in Germany for HIV and Hepatitis B/C at 
screening visit. Including new footnote 22.
Requested by EC 
Cologne, Germany.
Footnote 9: ECHO or MUGA scan: Country 
specific information added for Germany, only 
ECHO scan permitted.
Requested by EC 
Cologne Germany.
Schedule of 
Activities Part 1A
(Table 1-1)
Pregnancy Test in Cycle 3-4 and Cycle 5-N:
“As indicated clinically per investigator’s 
assessment and per local guidelines and 
regulations.”
Footnote 18: Serum pregnancy test is performed at 
screening. Thereafter, urine pregnancy test is 
sufficient unless indicated otherwise. The frequency 
of testing during treatment phase may depend on 
clinical indication per investigator's assessment and 
may also depend on local guidelines and 
regulations.
Rephrased for clarity.


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Section # and 
Name
Description of Change
Brief Rationale
Schedule of 
Activities Part 1B
(Table 1-2)
Serology added to the table as country specific 
testing in Germany for HIV and Hepatitis B/C at 
screening visit. Including new footnote 25.
Requested by EC 
Cologne, Germany.
Footnote 1: Added: “A separate treatment 
discontinuation visit should also be done after 
discontinuation of atezolizumab, carboplatin and 
etoposide, if it occurs ≥21 days later than BNT411 
(this visit will be entered as unscheduled visit in the 
eCRF).”
Rephrased for 
consistency.
Footnote 9: ECHO or MUGA scan: Country 
specific information added for Germany, only 
ECHO scan permitted.
Requested by EC 
Cologne, Germany.
Footnote 12: Added “or atezolizumab, or 
carboplatin, or etoposide, whichever occurs later”
Rephrased for 
consistency.
Footnote 13: Country-specific information added:
“Except for Germany and Spain, where AEs related 
to atezolizumab, carboplatin, and etoposide should 
also be reported. Furthermore, in Germany only, all 
SAEs that occur in the patient throughout his or her 
lifetime should be reported – refer to Section 12.2.1 
for further details.”
Rephrased for 
consistency.
Schedule of 
Activities Part 1B
(Table 1-2)
Pregnancy Test in Cycle 3-4 and Cycle 5-N:
“As indicated clinically per investigator’s 
assessment and per local guidelines and 
regulations.”
Footnote 21: Serum pregnancy test is performed at 
screening. Thereafter, urine pregnancy test is 
sufficient unless indicated otherwise. The frequency 
of testing during treatment phase may depend on 
clinical indication per investigator's assessment and 
may also depend on local guidelines and 
regulations. Pregnancy testing should also be done 
after discontinuation of atezolizumab, carboplatin, 
and etoposide if it occurs ≥21 days later than 
BNT411.
Rephrased for clarity.


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Section # and 
Name
Description of Change
Brief Rationale
New footnote 26 added: “A separate safety follow-
up visit should also be done after discontinuation of 
atezolizumab, carboplatin and etoposide, if it occurs 
≥21 days later than BNT411 (this visit will be 
entered as unscheduled visit in the eCRF).”
Rephrased for 
consistency.
Schedule of 
Activities 
(Table 1-3, and 1-
4)
Triplicate ECG assessments added to Day 1 Visit of 
Cycle 3-N, before and at the end of BNT411 
infusion in Phase 1A.
Urine sampling added for any unscheduled visits in 
Part 1A and Part 1B.
Correction of 
inconsistency between 
table and footnote.
Schedule of 
Activities
New Table 1-5
Added: Table 1 5 Overview of Safety Reporting in 
Different Countries
Added due to country 
specific amendments 
introduced with this 
protocol version.
Schedule of 
Activities 
(prev. Table 1-6, 
now 1-7)
Timing of immune phenotyping samples specified 
to “D1 (pre-dose), 24 hours / D2 (±1 hours) and 48 
hours / D3 (±2 hours) after start of infusion in 
Cycles 1 and 2.”
Time point of biomarker 
sampling further 
specified.
Schedule of 
Activities 
(prev. Table 1-7, 
now 1-8)
D2 replaced by D1
Timing of immune phenotyping samples specified 
to: “D1 (pre-dose) and at D3 i.e. 24 hours (±1 hours) 
after start of infusion of BNT411 in Cycles 1 and 
2.”
Time point of biomarker 
sampling further 
specified.
2.3.2 Potential 
Risks Associated 
with BNT411 in 
Combination with 
Atezolizumab, 
Carboplatin, and 
Etoposide
New section added. 
Further information given on the risk mitigation 
strategy of BNT411 given in combination with 
atezolizumab, carboplatin, and etoposide in Part 1b.
Requested by EC 
Cologne, Germany.
2.3.3 Benefit 
Assessment
New text added explaining benefits of BNT411 as a 
monotherapy anticancer agent.
Requested by EC 
Cologne, Germany.
2.3.4 Potential 
Benefits Associated 
with BNT411 in 
New section added.
Requested by EC 
Cologne, Germany.


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Section # and 
Name
Description of Change
Brief Rationale
combination with 
Atezolizumab, 
Carboplatin, and 
Etoposide
The text in this section covers potential benefits 
associated with combination therapy and previously 
belonged to section 2.3.3
Added: “Once a single-patient cohort has been 
expanded, all future cohorts will follow the 3+3 
design.”
Rephrased for clarity.
Added: “Prolongation of the hospitalization beyond 
24 hours may be performed at the investigator’s 
discretion if deemed necessary based on potential 
risks related to the trial treatment and clinical status 
of the patient.”
Additional information 
added for clarification.
4.1.1.1 Dose 
Escalation in 
Part 1A
Added/rephrased: “As long as patients do not 
experience a DLT, patients who have been replaced 
can continue with BNT411 treatment and follow the 
same trial procedures until unacceptable toxicity, 
documented disease progression, and/or the onset of 
a new anti-cancer therapy (palliative radiotherapy 
of, for example, painful bone metastases not defined 
as target lesions will be allowed).”
Rephrased for clarity.
4.1 Overall Design
(and Synopsis)
Trial design, Part 2 shortened for clarity: 
Deleted: “A “backfilling” approach will be 
implemented where more patients will be enrolled 
in selected dose levels in both Part 1A and Part 1B 
to explore further safety and anti-tumor activity.”
Rephrased for clarity.
4.1.3 Adaptive 
Trial Design 
Elements
Added: “The backfilling will be performed once the 
RP2Ds for both Part 1A and Part 1B are defined up 
to a total of 12 patients per cohort. This will be 
implemented through protocol amendment for 
Part 2.”
Rephrased for clarity.
9. Albumin level at screening ≥3 mg/dL ≥30 g/L
Correction
5.1 Inclusion 
Criteria
Added to 15.: “Further guidance on contraceptive 
measures for female patients can be found in 
Section 10.4.”
Added for clarification.


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Section # and 
Name
Description of Change
Brief Rationale
Added to 2.: “any live vaccine within 4 weeks of the 
start of trial treatment”
Added for consistency.
Added:
“23. Any contraindications to atezolizumab, 
carboplatin or etoposide as per USPI or SmPC in 
Part 1B”
Added for consistency.
5.2 Exclusion 
Criteria
(and Synopsis)
Added note to exclusion criteria 16:
“Country specific criteria for Germany: To confirm 
that a patient would be eligible, an active infection 
with HIV/Hepatitis B or C should be ruled out by 
serum blood test (see Section 12.2.1).”
Requested by EC 
Cologne, Germany.
6.1 Trial 
Treatment(s) 
Administered
Text added specifying that BNT411 is considered 
IMP in all countries participating in this trial. 
Additionally, in Germany and Spain only, 
atezolizumab, carboplatin, and etoposide will also 
be considered IMPs.
Added for clarification.
6.1.1 BNT411
(and Synopsis)
Previous headline: “Investigational Medicinal 
Product (IMP)” was replaced by “BNT411”.
Deleted first line: “The IMP in both Part 1A and 
Part 1B is BNT411.”
Changed due to country 
specific amendments 
introduced with this 
protocol version.
6.1.2 
Atezolizumab, 
Carboplatin, and 
Etoposide
(and Synopsis)
Previous headline: Non-Investigational Medicinal 
Products (NIMP) was replaced by “Atezolizumab, 
Carboplatin, and Etoposide”.
Deleted first line: “Atezolizumab, carboplatin, and 
etoposide are background treatments and are 
considered NIMPs.”
Changed due to country 
specific amendments 
introduced with this 
protocol version.
6.5 Concomitant 
Therapy and 
Procedures
Added:
“For further guidance on prohibited and restricted 
medications, please refer to the IB for BNT411, and 
USPI or SmPCs for atezolizumab, carboplatin and 
etoposide.”
Added for clarification.
6.6.6 Safety Alert 
Communication 
Plan
Section added
Added for clarification.


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Section # and 
Name
Description of Change
Brief Rationale
6.7.4.1 Immune-
related Adverse 
Events (irAEs) – 
For Part 1B Only
(Attachment 12.1 
added as new 
section)
Added:
“Furthermore, guidelines for the monitoring and 
management of potential cytokine release syndrome 
(CRS) can be found in Attachment 12.1.”
Added for clarification.
6.7.5 Safety 
Stopping Criteria
Added (in italics)/rephrased:
“The SRC will decide whether and when the trial 
can be restarted after approval of a substantial 
amendment by the regulatory authorities and EC; or 
with the sponsor’s concurrence, whether the trial 
should be stopped.”
Added for clarification.
7.2.2 Safety 
Follow-up 
Evaluations
Added:
“Separate treatment discontinuation visits should 
also be done after discontinuation of atezolizumab, 
carboplatin and etoposide, if it occurs ≥21 days later 
than BNT411.”
Added for clarity.
Added footnote:
“Note: country specific information for Germany: 
left ventricular function should only be assessed by 
an ECHO scan (see Section 12.2.1).”
Requested by EC 
Cologne, Germany.
8.1 Screening 
Procedures
Added footnote:
“Country specific information for Germany: to 
confirm that a patient would be eligible to 
participate in the trial, an active infection with 
HIV/Hepatitis B or C should be ruled out by serum 
blood test (see Section 12.2.1).”
Requested by EC 
Cologne, Germany.
8.6.7 Pregnancy 
Testing
Added:
“A serum pregnancy test is performed at screening. 
Thereafter, urine pregnancy test is sufficient unless 
indicated otherwise. A serum pregnancy test is 
warranted to confirm a positive urine pregnancy 
test.”
Added for clarification.


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Section # and 
Name
Description of Change
Brief Rationale
8.6.8 
Echocardiogram or 
multigated 
acquisition scan
Added footnote:
“Note: country specific information for Germany: 
left ventricular function should only be assessed by 
an ECHO scan (see Section 12.2.1).”
Requested by EC 
Cologne, Germany.
8.8 Treatment of 
Overdose
Added:
“Guidance on overdose for atezolizumab, 
carboplatin and etoposide should be referred to 
SmPC and USPI.”
Additional information 
added for clarification.
8.12 Biomarkers
Added:
“Biomarker analyses may be deferred or not 
performed, if during or at the end of the trial, it 
becomes clear that the analysis will not have 
sufficient scientific value for biomarker evaluation, 
or if there is not enough sample to allow adequate 
evaluation. In the event that the trial is terminated 
early or shows poor clinical efficacy, completion of 
biomarker assessments is based on justification and 
intended utility of the data.”
Added to clarify that 
biomarker analysis is not 
obligatory.
9.3 Analysis Sets
IMP changed to BNT411 for the modified ITT and 
the safety set.
Rephrased due to country 
specific amendments 
introduced with this 
protocol version.
9.4 Statistical 
Analysis
9.4.1: IMP changed to “trial treatment (i.e. BNT411, 
or atezolizumab, carboplatin, and etoposide).”
9.4.2: IMP changed to BNT411 under Primary 
Endpoint(s)
IMP changed to “trial treatment” in the paragraph 
defining AEs.
Rephrased due to country 
specific amendments 
introduced with this 
protocol version.
9.4 Statistical 
Analysis
Moved pharmacodynamics assessment of 
biomarkers from 9.3 Secondary Endpoint(s) to 
9.4. Exploratory endpoint(s).
Correction of 
inconsistency between 
chapter 3 and chapter 9.
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Endocrine tests: “free T3 and free T4” rather than 
“T3 and T4”
Correction of 
inconsistency between 
SoAs and Table 10.1.


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Section # and 
Name
Description of Change
Brief Rationale
Country-specific serology testing added for 
Germany.
10.3 Appendix 3: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
IMP exchanged with “trial treatment” to align with 
the statistical section. Except in the section 
specifying reporting of SAEs after last dose of IMP.
Added to “Period of observation”: “In Germany, all 
SAEs, regardless of relatedness, that occur in a 
patient throughout his or her lifetime should be 
reported (Section 12.2.1)”
Deleted from “SAE exemptions”: “SAEs occurring 
after the period of observation or after initiation of 
another anti-cancer therapy will not be considered 
an SAE.”
Rephrased due to country 
specific amendments 
introduced with this 
protocol version.
10.4 Appendix 4
Added to Table 10-2:
“Therefore, hormonal contraception method alone is 
not considered as a highly effective method of 
contraception. Hormonal contraception should be 
combined with a barrier method or/and an 
intrauterine device to be a highly effective method 
of contraception.”
Added contraception recommendations for male 
patients.
Requested by BfArM, 
Germany.
10.4.1 Collection 
of Pregnancy 
Information
“IMP” exchanged with “BNT411”
Rephrased due to country 
specific amendments 
introduced with this 
protocol version.
10.8 Appendix 8: 
Abbreviations
Two missing abbreviations were added.
Correction
11 References
Three references were added from new Section 
12.1.
Update
12.1 Management 
Recommendations 
in Case of a 
Potential Cytokine 
New section added
Added for better 
guidance and clarification 
to the investigators.


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Section # and 
Name
Description of Change
Brief Rationale
Release Syndrome 
(CRS)
12.2 Country 
Specific 
Information
New section added
Overview of all country 
specific information is 
provided in this new 
section


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10.11.3
Version 4.0: 13 November 2020
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
Section # and 
Name
Description of Change
Brief Rationale
Front page and 
headers throughout
Change of sponsor from BioNTech Small Molecules 
GmbH to BioNTech SE
Change of sponsor
21-day time window prior to Screening added for 
ECHO/MUGA
Correction to match time 
window for CT/MRI-scan
Survival follow-up to start after all other protocol 
required visits have been completed rather than 12 
weeks after last dose.
Correction
Schedule of 
Activities Part 1A 
and 1B
(Table 1-1 and 
Table 1-2)
24-hour time window for laboratory assessments 
corrected to 3 days.
Correction
PK sampling and 
ECG assessment in 
Part 1A and 1B
(Table 1-3 and 1-4 
and Section 8.9)
Added:
“Six-hour urine collection after start of BNT411 
infusion and total volume collected should be 
documented.”
Removed:
Urine sampling later than 6 hours after start of 
BNT411 infusion.
Specification of urine 
sampling
Footnotes X and E3 rewritten for clarification:
Blood sampling/ECG only to be performed in 
potential additional patients enrolled to expand the 
cohorts for RP2D confirmation.
Clarification
Overview of Safety 
Reporting in 
Different Countries
(Table 1-5)
Added for all countries to the survival follow-up 
phase:
“Trial procedure related AEs”
Added for USA, UK, and Spain beyond trial 
closure:
“Trial procedure-related SAEs”
Corrected for consistency 
with the rest of the 
protocol
Section 4.1.3 
Adaptive Trial 
Design Elements
Added:
“Bifurcation is planned to start when Part 1A 
monotherapy dose level 5 (2.4 µg/kg) evaluation is 
completed and considered safe. At this point, 
Bifurcation further 
specified


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Section # and 
Name
Description of Change
Brief Rationale
Part 1B would start with one dose level below (i.e. 
dose level 4 [1.2 µg/kg]). Based on nonclinical data, 
this dose level is considered to be the anticipated 
minimally efficacious dose. If minimal 
pharmacodynamics activity is not reached when 
monotherapy dose level 5 is completed, bifurcation 
to Part 1B may happen at a higher dose level. 
Bifurcation can also start at a lower dose level than 
dose level 5, if pharmacodynamics activity is seen 
earlier. However, the following rule always applies: 
the dose level of BNT411 in Part 1B at any given 
time will always be one dose level below that in 
Part 1A. Decision to bifurcate at any given dose 
level will be discussed and agreed by the SRC.”
6.6 Dose 
Modifications
And 
2.3.2 Potential 
Risks Associated 
with BNT411 in 
Combination with 
Atezolizumab, 
Carboplatin, and 
Etoposide
Neither for other imidazoquinoline compounds nor 
for BNT411 indications for organ-specific 
autoimmunity have been identified.
No indications of organ-specific autoimmunity have 
been identified for BNT411, or for any other 
imidazoquinoline compounds.
Rephrased for clarity
8.7.6 Death Events
Added: “Deaths clearly related to the progression of 
the disease will not be documented and reported as 
AEs and SAEs. These deaths must be collected on 
the death page of the eCRF.”
SAEs due to disease 
progression were 
exempted from the 
standard expedited 
reporting process
8.7.7 Disease-
Related Events 
and/or Disease-
Related Outcomes 
Not Qualifying as 
AEs or SAEs
Added: statement that SAEs due to disease 
progression will be exempted from the standard 
expedited reporting process.
Deleted:
“However, specific symptoms resulting from the 
progression and fatal cases due to the progression 
have to be documented as AEs and reported as 
SAEs if applicable.”
SAEs due to disease 
progression were 
exempted from the 
standard expedited 
reporting process


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Section # and 
Name
Description of Change
Brief Rationale
Removed: “Serum samples”
Adapted urine sampling as in Tables 1-3 and 1-4 
(see above)
Specification of urine 
sampling
8.9 
Pharmacokinetics
Accumulation ratio [RA] added to PK parameters
Specification of PK 
measurements
8.14 24/7 Coverage 
for Urgent 
Protocol-related 
Medical Questions
Updated with new ICON contact details.
Update
10.3 Appendix 3: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
Added to “Events NOT Meeting the AE 
Definition”:
•
The disease/disorder being studied or 
expected progression, signs, or symptoms of 
the disease/disorder being studied, unless 
more severe than expected for the patient’s 
condition. However, specific symptoms at 
time of progression that are considered that 
may be caused by other reason, and fatal 
cases where other reason rather than the PD 
may not be discarded and will have to be 
documented as AEs and reported as SAEs if 
applicable.
Deleted: 
•
The progression of underlying disease (e.g. 
new metastases) during trial participation is not 
considered an AE. However, specific symptoms 
resulting from the progression and fatal cases due to 
the progression have to be documented as AEs and 
reported as SAEs if applicable.
Updated to match criteria 
for SAE reporting
10.3.3 Recording 
and Follow-Up of 
AE and/or SAE
The period of observation starts after informed 
consent has been obtained. After informed consent, 
but prior to initiation of trial treatment, all AEs (but 
only SAEs caused by a protocol-mandated 
Updated to match criteria 
for SAE reporting


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Section # and 
Name
Description of Change
Brief Rationale
intervention) should be reported until 60 days after 
the last dose of trial treatment.
The period of observation starts after informed 
consent has been obtained. After informed consent, 
but prior to initiation of trial treatment, all AEs and 
SAEs should be reported until 60 days after the last 
dose of trial treatment.


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10.11.4
Version 5.0: 01 July 2022
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
Section # and 
Name
Description of Change
Brief Rationale
Sponsor signature 
page
Change of sponsor signatory from:
 MD (Chief Medical Officer) to:
 MD (Senior Director Clinical 
Development)
Update
Section 1.3.1 Dose 
Escalation Phases 
(Parts 1A and 1B) 
And
Section 4.4 Dose 
and Schedule 
Rationale
And
Section 6.1 Trial 
Treatment(s) 
Administered
And
Section 8 Trial 
Assessments and 
Procedures
Added reference to COVID-19 addendum V3.0 
and reference to Sections 10.8 and 10.9 with 
information about COVID-19 vaccinations 
during the trial.
Changes made due to the 
COVID-19 pandemic.
Section 1.3 
Schedule of 
Activities (SoA) 
Table 1-1 Schedule 
of Activities – Part 
1A and Table 1-2 
Schedule of 
Activities – Part 1B
Footnote added (#24 in Table 1-1 and #28 in 
Table 1-2, same text):
“The visit window of +2d on Day 3 should only 
be used if absolutely necessary due to immune 
phenotyping.”
Time windows specified.
Section 1.3 
Schedule of 
Activities (SoA) 
Table 1-1 Schedule 
of Activities – Part 
Added to footnote #4: “Physical examination should be
performed before drug administration.”
New footnote #12: “ECOG status should be assessed
before drug administration.”
Clarification of trial 
procedures.
PPD
PPD


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Section # and 
Name
Description of Change
Brief Rationale
1A and Table 1-2 
Schedule of 
Activities – Part 1B
Section 1.3 
Schedule of 
Activities (SoA) 
Table 1-7 
Biomarker table – 
in Part 1A and 
Table 1-8 
Biomarker table – 
in Part 1B
Footnote #5 moved from the first column “TCR 
profiling 5” to each of the “X”s to clarify that no 
TCR profiling required at C2D1. 
Clarification of trial 
procedures.
Added:
“The safety monitoring period is reduced to at 
least 24 hours when expanding a dose level 
which has already been declared safe.”
Clarification of trial 
procedures.
Section 4.1.1.1 
Dose Escalation in 
Part 1A
Added:
“The sponsor can backfill a certain dose level 
cohort to explore and generate more safety, PK, 
pharmacodynamics, and anti-tumor data up to a 
total of 14 patients in a given cohort. Staggering 
would not be implemented as backfilling would 
occur once the dose level is declared safe by the 
SRC.”
Backfilling of cohorts 
introduced.
Section 4.1.3 
Adaptive Trial 
Design Elements
Added:
“•
The sponsor can backfill a certain dose 
level cohort to explore and generate more safety, 
PK, pharmacodynamics, and anti-tumor data up 
to a total of 14 patients in a given cohort. 
Staggering would not be implemented as 
backfilling would occur once the dose level is 
declared safe by the SRC.”
Backfilling of cohorts 
introduced.
Section 1.1 
Synopsis and 
Section 4.2 
Number of trial sites adjusted from 6 to 12 in 
North America and Europe.
Update.


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Section # and 
Name
Description of Change
Brief Rationale
Planned Number of 
Patients
For possible expansion, location increased from 
North America and Europe to “potentially the rest 
of the World.”
Section 5.1 
Inclusion Criteria
11. d: 
Deleted: “may not transfuse or use erythropoietin 
to obtain this Hgb level”
Many cancer patients will 
only reach ≥9.0 g/dL Hgb 
following transfusion or 
erythropoietin. Removal of 
this wording allows 
inclusion of these patients 
who do not have any other 
treatment options and may 
benefit from participating in 
this clinical trial.
Section 6.6.1 Dose 
Limiting Toxicity 
for Part 1A and 
6.6.2 Dose 
Limiting Toxicity 
for Part 1B
Added to immune-related AEs that are NOT 
considered DLTs:
“o
Grade ≤4 lymphopenia which is not 
considered clinically significant by the 
investigator.”
It has been described for 
TLR7 agonists that upon 
stimulation, lymphocytes 
egress to the periphery and 
return within 24 to 48 hours 
and that this may present as 
transient lymphopenia (see 
Section 2.3.1 for further 
detail). Frequent laboratory 
monitoring is planned to 
observe this expected effect.
Section 8.13 24/7 
Coverage for 
Urgent Protocol-
related Medical 
Questions
ICON Helpdesk contact information updated
Update.
Section 8.5.1 Anti-
tumor Activity 
Assessment – 
CT/MRI Imaging
Added:
“Patients whose treatment schedule has been 
changed (e.g., delay due to toxicity) still should 
follow the original tumor assessment schedule 
(every 6 weeks (±7 days) for 48 weeks, and every 
12 weeks (±7 days) thereafter).”
Clarification of trial 
procedures.
Section 8.6.3 
Electrocardiograms
The full set of triplicates should be completed in 
less than 5 minutes.
Update.


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Section # and 
Name
Description of Change
Brief Rationale
(before: 4 minutes)
Section 8.7.6 Death 
Events
Added:
“In Germany only: Any death, irrespective 
whether causally related to disease progression or 
not, will be documented as AE and reported as 
SAE.”
Update of trial procedures in 
Germany only.
Section 8.7.7 
Disease-Related 
Events and/or 
Disease-Related 
Outcomes Not 
Qualifying as AEs 
or SAEs
Added:
“In Germany only: deaths related to disease 
progression will be reported as AEs or SAEs.”
Update of trial procedures in 
Germany only.
8.10 
Pharmacodynamic 
Biomarkers
Combined text from previous “Section 8.10 
Pharmacodynamics” and “Section 8.11 
Biomarkers” into one section.
Update of document.
Section 10.1.9 
Dissemination of 
clinical trial data
Added new section.
Update.
Section 10.2 
Appendix 2: 
Clinical Laboratory 
Tests
Table 10-1 
Protocol-required 
Safety Laboratory 
Assessments
Added Magnesium under Biochemistry 
assessments
Update of lab assessments to 
be made.
Added to “AE and SAE Recording”:
“In Germany only: Deaths related to disease 
progression will be documented as AE and 
reported as SAE.”
Section 10.3.3 
Recording and 
Follow-Up of AE 
and/or SAE
Added to “Documentation of particular 
situations”:
Update of trial procedures in 
Germany only.


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Section # and 
Name
Description of Change
Brief Rationale
“In Germany only: Any death, irrespective if 
causally related to disease progression or not 
will be documented as AE and reported as SAE.”
Section 10.8 
Appendix 8: Risk-
benefit assessment 
of COVID-19 
vaccination in 
BNT411-01 trial
Added new section.
Changes made due to 
COVID-19 pandemic.
Section 10.9 
Appendix 9: 
COVID-19 
vaccination in 
BNT411-01 trial 
during the 
pandemic
Added new section.
Changes made due to 
COVID-19 pandemic.
10.11.5
Version 5.0_DEU: 09 January 2023
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
Section # and 
Name
Description of Change
Brief Rationale
Section 4.1.3
Rewording of the backfilling approach.
For clarity.
Section 10.11.4
Detailed rationale provided on the change to 
inclusion criterion 11d.
Rationale not previously 
provided.
10.11.6
Version 6.0: 04 July 2023
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.1, 
Section 3, 
Section 9.3, 
Section 9.4.3, 
Section 9.4.4
Specifying that the efficacy secondary endpoint 
(Evaluate anti-tumor activity according to 
RECIST 1.1) and exploratory endpoints (Evaluate 
anti-tumor activity according to iRECIST and 
Evaluate preliminary efficacy) are only 
applicable for Part 2 of the trial
Owing to the heterogeneity 
of cancer types and limited 
number of patients in 
Part 1A and B, it is not 
meaningful to assess 
efficacy


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Section # and 
Name
Description of Change
Brief Rationale
Section 1.1, 
Section 4.2, 
Section 9.2
Population: Number of patients in Part 1A 
increased to 6 to 60 DLT evaluable patients 
(previously 6 to 33 DLT evaluable patients)
Owing to the high levels of 
recruitment for Part 1A of 
the trial
Section 1.3
Table 1:1: Footnote number changed for 
Endocrine assessments
Correction of error
Section 1.3 
Tables 1.3, 1.4, 1.7, and 1.8: Footnote added to 
specify that PBMC collection will no longer be 
required after C3D1
Change due to ethical 
considerations – samples 
taken after C3D1 may not 
be used for analysis
Section 4.5
End of trial definition altered: Patients are no 
longer required to be followed-up for survival for 
at least 1 year. Patients will continue to follow 
the SoA defined by the protocol unless the 
medical monitor gives approval not to do so
For dose escalation cohorts 
(Part 1), OS data is not 
required – this is to align 
with the aforementioned 
change in efficacy endpoints 
(applicable for Part 2 only)
Section 2.3.1
Risk assessment adapted: Cytokine release 
syndrome now listed as an ‘Important identified 
risk’ for BNT411. Addition of a sentence to state 
that there are no important potential risks for 
BNT411
To align with the updated 
version of the investigator’s 
brochure
Section 10.3.4
SAE reporting contact details updated
To reflect updated reporting 
information


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12 Attachments
12.1 Management Recommendations in Case of a Cytokine Release 
Syndrome (CRS)
The following guidelines should serve as recommendations to trial physicians to monitor and 
manage a potential case of CRS. The guidelines should not replace any clinical decisions made 
by the physicians based on their sound clinical judgment depending on individual patient’s 
situation. In any given situation, all measures must be taken by the trial physicians to ensure the 
optimal clinical management is delivered to the patients based on the diagnosis.
For assessment, reporting and analysis of CRS in connection with this trial, all events will be 
graded according to CTCAE version 5.0 as shown in Table 12-1.
Table 12-1:
CRS grading per CTCAE version 5.0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Grading system
CTCAE version 5.0
Fever, with or 
without 
constitutional 
symptoms
Hypotension 
responding to 
fluids. 
Hypoxia 
responding to 
<40% FiO2
Hypotension 
managed with 
one pressor. 
Hypoxia 
requiring ≥40% 
FiO2
Life-threatening 
consequences; 
urgent 
intervention 
needed
Death
CRS Definition: A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or 
hypoxia caused by the release of cytokines.
For treatment recommendations for the management of CRS, the following guidelines are 
adapted based on the American Society for Transplantation and Cellular Therapy (ASTCT) 
Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with 
Immune Effector Cells. The CRS consensus grading of ASTCT (previously known as American 
Society for Bone Marrow Transplant) is given in Table 12-2 (Lee et al, 2019).


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Table 12-2:
American Society for Transplantation and Cellular Therapy CRS consensus grading
CRS parameter
Grade 1
Grade 2
Grade 3
Grade 4
Fever1
Temperature 
≥38°C
Temperature 
≥38°C
Temperature 
≥38°C
Temperature 
≥38°C
with
Hypotension
None
Not requiring 
vasopressors
Requiring vasopressor with 
or without vasopressin
Requiring vasopressors 
(excluding vasopressin)
and/or2
Hypoxia
None
Requiring 
low-flow nasal 
cannula3 or blow-
by
Requiring high-flow nasal 
cannula, facemask, 
nonrebreather mask, or 
Venturi mask
Requiring positive 
pressure (e.g., CPAP, 
BiPAP, intubation and 
mechanical ventilation)
Abbreviations: BiPAP, Bilevel positive airway pressure; CPAP, Continuous positive airway pressure; CRS, Cytokine release syndrome; CTCAE, 
Common terminology criteria for adverse events.
1)
 Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anti-
cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading 
is driven by hypotension and/or hypoxia.
2)
CRS grade is determined by the more severe event: Hypotension or hypoxia not attributable to any other cause. For example, a patient 
with temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring low-flow nasal cannula is classified as 
Grade 3 CRS.
3)
Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low-flow also includes blow-by oxygen delivery, sometimes 
used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute.
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not 
influence CRS grading
For the management of CRS, the following guidelines should apply (Table 12-3): 
Table 12-3:
Guidelines for management of cytokine release syndrome
ASTCT CRS 
Grade
Management
Grade 1
•
Antipyretics and i.v. hydration
•
Diagnostic work-up to rule out infection
•
Consider growth factors and antibiotics if neutropenic
Grade 2
•
Supportive care as in Grade 1
•
i.v. fluid boluses and/or supplemental oxygen
•
Tocilizumab +/- dexamethasone or its equivalent of methylprednisolone
Grade 3
•
Supportive care as in Grade 1
•
Consider monitoring in ICU
•
Vasopressor support and/or supplemental oxygen
•
Tocilizumab + dexamethasone 10-20 mg i.v. q6h or its equivalent of 
methylprednisolone


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ASTCT CRS 
Grade
Management
Grade 4
•
Supportive care as in Grade 1
•
Monitoring in ICU
•
Vasopressor support and/or supplemental oxygen via positive pressure 
ventilation
•
Tocilizumab + methylprednisolone 1000 mg/d
Abbreviations: ASTCT: American Society for Transplantation and Cellular Therapy (previously known as: ASBMT, American Society for Bone 
Marrow Transplant); BiPAP, Bilevel positive airway pressure; CPAP, Continuous positive airway pressure; CRS, Cytokine release syndrome; ICU, 
Intensive care unit; i.v., Intravenous.
Source: Neelapu 2019.


BioNTech SE
BNT411-01 Version 6.0
CONFIDENTIAL
170
12.2 Country Specific Information
12.2.1 Germany
To confirm that a patient would be eligible to participate in the trial, an active infection with 
HIV/Hepatitis B or C should be ruled out by serum blood test of hepatitis B surface antigen 
(HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen 
(anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against HIV-1 and -2 (anti-
HIV 1/2).
For evaluation of left ventricular function, only an ECHO scan will be performed. 
Atezolizumab, carboplatin, and etoposide in Part 1B and Part 2 are considered as IMPs along 
with BNT411.
All SAEs that occur in the patient throughout his or her lifetime should be reported.
12.2.2 Spain
Atezolizumab, carboplatin, and etoposide in Part 1B and Part 2 are considered as IMPs along 
with BNT411.

SAP_001.pdf: 
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BioNTech SE 
Confidential 
Statistical Analysis Plan (SAP) 
BNT411-01 
Page 3 of 55 
Version: Final 2.0 
Date: 21 Feb 2024 
 
 
TABLE OF CONTENTS 
1 
SAP APPROVAL 
5 
2 
VERSION HISTORY 
5 
3 
INTRODUCTION 
8 
3.1 
Objectives and endpoints 
8 
3.2 
Trial design 
10 
3.3 
Schedule of activities 
17 
4 
STATISTICAL HYPOTHESES 
17 
5 
INTERIM ANALYSES AND ANALYSIS SEQUENCE 
17 
6 
SAMPLE SIZE DETERMINATION 
17 
7 
ANALYSIS SETS AND SUBGROUPS 
17 
7.1 
Analysis sets 
17 
7.2 
Protocol deviations 
18 
7.3 
Subgroups 
19 
8 
STATISTICAL ANALYSES 
19 
8.1 
General considerations 
19 
8.2 
Patient disposition 
22 
8.3 
Baseline characteristics 
23 
8.3.1 
Demographics 
23 
8.3.2 
Disease characteristics 
24 
8.3.3 
Prior anti-cancer treatments 
24 
8.3.4 
Prior and Concomitant medication/Procedures/Non-drug Therapy 
25 
8.3.5 
Medical history 
25 
8.4 
Efficacy analyses 
26 
8.4.1 
Primary analysis 
26 
8.4.2 
Supplementary analyses 
26 
8.4.3 
Secondary analyses 
26 
8.4.4 
Exploratory analyses 
26 
8.5 
Safety analyses 
26 
8.5.1 
Extent of exposure 
26 
8.5.2 
Adverse events 
28 
8.5.3 
Laboratory assessments 
32 
8.5.4 
Vital signs 
32 
8.5.5 
ECG  
33 
8.5.6 
Physical examination 
33 
8.5.7 
ECOG performance status 
33 
8.5.8 
Eye examinations 
33 
8.5.9 
ECHO and MUGA 
34 


 
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8.6 
Other analyses 
34 
8.6.1 
Pharmacokinetics 
34 
8.6.2 
Pharmacodynamics and biomarkers 
38 
8.6.3 
New anti-cancer treatment 
38 
9 
REFERENCES 
39 
10 
SUPPORTING DOCUMENTATION 
40 
10.1 
Appendix 1: Changes to protocol-planned analyses 
40 
10.2 
Appendix 2: List of abbreviations 
41 
10.3 
Appendix 3: Reporting conventions 
44 
10.4 
Appendix 4: Schedule of activities 
47 
10.4.1 
Dose Escalation Phases (Parts 1A and 1B) 
47 
10.5 
Appendix 5: Dose escalation table 
54 
10.6 
Appendix 6: BNT411 dose increments 
55 
 
 
 
 
 


 
BioNTech SE 
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BNT411-01 
Page 5 of 55 
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1 
SAP APPROVAL 
This SAP has been prepared, reviewed, and approved in accordance with the 
BioNTech standard operating procedure (SOP). Documentation of this process is 
filed in the trial master file. 
2 
VERSION HISTORY 
Table 1:  
SAP Version History Summary 
SAP 
version 
Approval date 
Change 
Rationale 
Final 
v1.0 
01 DEC 2021 
Not applicable. 
 
Final 
v2.0 
08 FEB 2024 
Updated following an amendment to the BNT411-01 
protocol (Protocol v5.0) 
 
Updated the signature page with the new trial team. 
 
Section 3.2  
• Added clarification for investigational medicinal 
products of and non-investigational medicinal 
products of Part 1B. 
Section 7  
• Updated the wording for the classification of 
important protocol deviation. 
Section 8.1  
• Added clarification about the denominator that 
should be used for percentage calculations.  
• Added details about how to handle partial anti-
cancer therapy dates. 
Section 8.2 
• Added clarification that the screened patient 
summary table is not by cohort.  
Section 8.3.1 
• The weight at screening was replaced by the 
baseline weight for consistency with the other 
parameters. 
Section 8.3.2 
• The tumor stage and TNM stage at diagnosis 
and at baseline was removed from summary 
table as it is collected with free text in the 
electronic Case Report Form (eCRF). 
Section 8.3.3 and Section 8.3.4 
• The anatomical-therapeutic-chemical (ATC) 
level 5 has been replaced by ATC level 4. 
Section 8.4.3: 
• Added clarification that the confirmation of 
complete response (CR) and partial response 
(PR) is required 
Protocol 
amendment 
 
Team update 
 
 
Clarification 
 
 
 
Clarification 
 
 
Clarification 
 
Clarification 
 
 
Clarification 
 
 
Update 
 
 
Update 
 
 
 
Update 
 
 
 
Clarification 
 


 
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BNT411-01 
Page 6 of 55 
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SAP 
version 
Approval date 
Change 
Rationale 
• Added clarification about the minimum duration 
time of stable disease  
• Added clarification that only the responses prior 
to start of new anti-cancer therapy are used for 
the determination of the best overall response.  
Section 8.4.4:  
• Added clarification for iDOR that for the date of 
first occurrence of objective tumor progression. 
Section 8.5.4:  
• Added temperature and weight in the vital signs 
summary table. 
Section 8.6.1:  
• Added urine PK. 
• Added some details for the derivations of the 
PK parameters. 
Section 8.6.2:  
• Updated to clarify that due to the exploratory 
nature of this analysis the PD and Biomarkers 
analyses may be conducted if there is enough 
data. 
Section 10.5 
Appendix 5: Censoring Rules:  
• Amended ‘before’ to ‘not after’. 
• Added clarification for some event or censoring 
rules. 
• Added clarification about the derivations for two 
or more consecutive tumor assessments. 
Section 10.7: 
• Removed this section and the SAS code 
 
 Section 3.1: 
Updated the applicable trial parts to each trial 
objective 
 
Section 3.2: 
• 
Updated the planned number of patients  
• 
Updated the definition of end of trial 
Section 7.1: 
Removed the analysis set for mITT as it is 
applicable only for Part 2 of the trial 
Section 8.1: 
Removed the general considerations related to 
efficacy analysis 
Section 8.4: 
Removed the details pertaining to efficacy 
analysis and added the below statement: 
Clarification 
 
Clarification 
 
 
 
Clarification 
 
 
New analysis 
 
New analysis 
 
Clarification 
 
 
Update 
 
 
 
Update 
Clarification 
 
Clarification 
 
Not required 
in SAP 
 
 
 
 
 
Updated for 
protocol 
amendment 
v6.0 


 
BioNTech SE 
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SAP 
version 
Approval date 
Change 
Rationale 
“Owing to the heterogeneity of cancer types 
and limited number of patients in Part 1A and 
B, no efficacy analysis will be done in Part 1” 
Section 8.4.3: 
Removed the secondary efficacy analysis as 
this is no more applicable for Part 1 of the trial 
Section 8.4.4: 
Remove the exploratory analysis pertaining to 
efficacy as this is no more applicable for Part 1 
of the trial 
 
 
 


 
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3 
INTRODUCTION 
This is an open-label, multicenter phase 1/2a dose escalation, safety, 
pharmacokinetics (PK) and pharmacodynamics (PD) trial of BNT411 with expansion 
cohorts in a mixed population of patients with solid tumors. This statistical analysis 
plan (SAP) describes the detailed procedures for the planned statistical analyses for 
Part 1 of the trial for clinical trial protocol (CTP) v1.0 dated 30 SEP 2019, CTP 
amendment v2.0 dated 30 OCT 2019, CTP amendment v3.0 dated 07 MAY 2020, 
CTP amendment v4.0, dated 13 NOV 2020, CTP addendum related to the 
coronavirus disease (COVID)-19 pandemic v3.0, dated 04 JUN 2021, CTP 
amendment v4.1, dated 14 MAY 2021, CTP amendment v4.2, dated 24 JUN 2021 
and CTP amendment v5.0, dated 11 JUL 2022 and CTP amendment v6.0 dated 04 
JUL 2023 to support the completion of the Clinical Trial Report (CTR). Part 2 of the 
clinical trial is no longer applicable therefore is excluded from this SAP. 
The statistical analyses will be conducted by BioNTech or ICON using SAS® 
software Version 9.4 or higher. 
3.1 
Objectives and endpoints 
Table 2: 
Trial design 
Objectives 
Endpoints 
Primary 
• 
For Parts 1 and 2: Assess 
safety profile 
• Occurrence of Dose-Limiting Toxicities (DLTs) within a 
patient during the DLT evaluation period 
• Occurrence of treatment-emergent adverse events 
(TEAEs) within a patient including grade ≥3, serious, 
fatal TEAE by relationship 
• Occurrence of dose reduction and discontinuation of 
BNT411 within a patient due to TEAEs 
• 
For Part 1: Determine MTD 
and/or RP2D 
• Maximal tolerated dose (MTD) defined as the highest 
tolerated dose 
• Recommended Phase 2 dose (RP2D) based on 
integrated evaluation of safety, tolerability, clinical 
benefit, PK, and PD data, for all dose levels tested 
Secondary 
• 
For Parts 1 and 2: Establish 
PK profile 
• PK parameters Area-under-the-concentration-time 
curve (AUC), clearance (CL) and volume of distribution 
(VD), maximum concentration (Cmax), time to Cmax 
(Tmax), trough concentration (Ctrough), and terminal half-
life (T1/2) 
• 
For Part 2: Evaluate anti-
tumor activity according to 
RECIST 1.1 
• Objective response rate (ORR) defined as the 
proportion of patients in whom a complete response 
(CR) or partial response (PR) is observed as best 
overall response. 
• Disease control rate (DCR) defined as the proportion of 
patients in whom a CR or PR or stable disease 


 
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BNT411-01 
Page 9 of 55 
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Objectives 
Endpoints 
(assessed at least 6 weeks after first dose) is observed 
as best overall response. 
• Duration of response (DOR) defined as the time from 
first objective response (CR or PR) to the date of the 
first occurrence of objective tumor progression or death 
from any cause, whichever occurs first. 
Exploratory 
• 
For Part 2: Evaluate anti-
tumor activity according to 
iRECIST 
• Immune ORR (iORR) defined as the proportion of 
patients in whom a (immune) CR (iCR) or (immune)PR 
iPR is observed as best overall response. 
• Immune DCR (iDCR) defined as the proportion of 
patients in whom a iCR or iPR or (immune) stable 
disease (assessed at least 6 weeks after first dose) is 
observed as best overall response. 
• Immune DOR (iDOR) defined as the time from first 
objective response (iCR or iPR) to the date of the first 
occurrence of objective tumor progression (immune 
confirmed progressive disease (iCPD)) or death from 
any cause, whichever occurs first. 
• 
For Part 2: Evaluate 
preliminary efficacy 
• Progression-free survival (PFS) defined as the time 
from first dose of BNT411 to first occurrence of 
objective tumor progression (per Response Evaluation 
Criteria in Solid Tumors [RECIST 1.1]), or death from 
any cause, whichever occurs first. 
• Overall survival (OS) defined as the time from first dose 
of BNT411 to death from any cause. 
• 
For Parts 1 and 2: Preliminary 
assessment of biomarkers 
that might act as 
pharmacodynamics, anti- 
tumor, and safety indicators of 
activity of BNT411 
monotherapy and in 
combination with 
chemotherapy and 
atezolizumab 
• Changes in selected cytokines and other activation 
markers compared to baseline. 
• Changes in systemic and intra-tumoral immune 
response in blood and tumor tissue compared to 
baseline (e.g. immunophenotyping of immune cells in 
peripheral blood, absolute and relative changes 
compared to baseline in tissues and/or peripheral blood 
mononuclear cells [PBMCs]). 
AUC, area-under-the-concentration-time curve; CL, clearance; Cmax, maximum concentration; (i)CR, (immune) 
complete response; Ctrough, trough concentration; (i)DCR, (immune) disease control rate; DLTs, dose-limiting 
toxicities; DOR, duration of response; iCPD, immune confirmed progressive disease; iRECIST (Protocol 
Appendix 6), immune RECIST; MTD, maximal tolerated dose; (i)ORR, (immune) objective response rate; OS, 
overall survival; PBMCs, peripheral blood mononuclear cells; PD, pharmacodynamic; PFS, progression-free 
survival; PK, pharmacokinetic; (i)PR, (immune) partial response; RECIST (Protocol Appendix 5), Response 
Evaluation Criteria in Solid Tumors; RP2D, recommended Phase 2 dose; (i)stable disease, (immune) stable 
disease; T1/2, terminal half-life; TEAEs, treatment-emergent AEs; Tmax, time to Cmax; VD, volume of distribution. 


 
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3.2 
Trial design 
This is an open-label, multicenter Phase 1/2a dose escalation, safety, PK and PD trial of BNT411 with expansion cohorts in a mixed 
population of patients with solid tumors. The trial consists of three parts: Part 1A, Part 1B and Part 2. An overview of the trial design is 
provided in Table 3. 
 
Table 3: 
Trial design 
 
Part 1A 
Part 1B 
Part 2 
Trial design 
Part 1A will be a monotherapy dose 
escalation in patients with advanced 
solid cancers until the MTD and/or 
RP2D of BNT411 as monotherapy are 
defined. 
Part 1B will be a combination dose 
escalation in patients with 
chemotherapy-naïve ES- SCLC until the 
MTD and/or RP2D of BNT411 in 
combination with atezolizumab, 
carboplatin and etoposide are defined. 
Part 2 will consist of expansion cohorts 
in solid cancers based on data 
generated in Part 1A and Part 1B. 
Trial population 
Patients with advanced solid cancers 
Patients with chemotherapy-naïve ES-
SCLC 
Patients with solid cancers  
Geographic regions 
North America and Europe 
North America and Europe 
North America, Europe and Israel 
Investigational medical 
product(s)  
Name: BNT411 
Dose: according to dose levels outlined 
in Appendix 6  
Schedule: Days 1, 8 and 15 of each 3-
week treatment cycle (21 days) of the 
first 4 cycles. In the following cycles 
thereafter, administration will be every 3 
weeks on Day 1 of each 3-week 
treatment cycle (21 days) 
Name: BNT411 
Dose: according to dose levels outlined 
in Appendix 6  
Schedule: Days 2, 8 and 15 of each 3-
week treatment cycle (21 days) of the 
first 4 cycles. In the following cycles 
thereafter, administration will be every 3 
weeks on Day 2 of each 3-week 
treatment cycle (21 days) 
Name: BNT411 
BNT411 either as monotherapy or in 
combination with other anti-cancer 
agent. 
Dose: This will be initiated by a CTP 
amendment once RP2D is reached at 
the end of Part 1A and Part1B   
Schedule: This will be initiated by a CTP 
amendment 


 
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Part 1A 
Part 1B 
Part 2 
Route of administration: 100 mL 
intravenous infusion. 
Route of administration: 100 mL 
intravenous infusion. 
 
For the purpose of this trial, in the 
USA and UK, atezolizumab, carboplatin 
and etoposide are considered as non-
investigational medicinal products 
(NIMPs). However, the individual drugs 
are considered as IMPs in Spain and 
Germany at the request of the 
competent authorities due to their use in 
combination with BNT411. 
 
Name: Atezolizumab 
Dose: recommended dosage is 1200 
mg 
Schedule: Every 3 weeks 
Route of administration: IV infusion. 
Name: Carboplatin 
Dose: commercially available 
formulation and at the label-
recommended doses 
Schedule: every 3 weeks until cycle 4 
Route of administration: IV infusion. 
Name: Etoposide: 
Dose: commercially available 
formulation and at the label-
recommended doses (100 mg/m2) 
Route of administration: intravenous 
infusion. 


 
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Part 1A 
Part 1B 
Part 2 
Schedule: On Day 1 of each cycle, 
administered over 60 minutes following 
carboplatin administration. On Day 2 
and Day 3 of each cycle, administered 
intravenously over 60 minutes. 
Route of administration: IV infusion. 
 
For combination with atezolizumab and 
chemotherapy, the administration will be 
in the following order: 
Day 1: Atezolizumab > Carboplatin > 
Etoposide 
Day 2: BNT411 > Etoposide 
Day 3: Etoposide 
Planned number of patients 
• 
The number of patients for Part 1A 
is driven by the 3+3 trial design  
• 
Between 6 to 60 DLT-evaluable 
patients are planned to be enrolled 
in Part 1A. 
• 
The number of patients for Parts 
1B is driven by the 3+3 trial design 
• 
Between 6 to 30 DLT-evaluable 
patients are planned to be enrolled 
in Part 1B. 
• 
This will be implemented through a 
CTP amendment. 
Randomization and blinding 
This is a non-randomized, open-label trial 
The expansion cohort may be a single-
arm cohort or a randomized cohort. This 
will be documented in a CTP 
amendment. 
Tumor assessment schedule: 
Efficacy will be assessed by on-treatment imaging at screening (within 21 days 
prior to visit Cycle 1 Day 1)/Baseline and Week 6 (+7 days), every 6 weeks (±7 
days) for 48 weeks, and every 12 weeks (±7 days) thereafter until disease 
progression is assessed by the investigator (unless the investigator elects to 
continue treatment [see Section 8.5.1 of the CTP for conditions of continued 
This will be implemented through a CTP 
amendment. 


 
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Part 1A 
Part 1B 
Part 2 
treatment]), withdrawal of consent, trial termination by the sponsor, or death, 
whichever occurs first, regardless of whether patients start a new anti-cancer 
therapy. 
Other features 
Not applicable 


 
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Part 1B is planned to start before the MTD/RP2D is reached in Part 1A using a bifurcated 
trial design. Bifurcation is planned to start when Part 1A BNT411 monotherapy dose level 
5 (2.4 µg/kg) evaluation is completed and deemed safe. At this point, Part 1B would start 
with one dose level below (i.e., dose level 4 [1.2 µg/kg]). Based on nonclinical data, this 
dose level is the anticipated minimally efficacious dose. Atezolizumab, carboplatin and 
etoposide will be administered at fixed doses approved for the indication of extensive-
stage small cell lung cancer (ES-SCLC). The dose level of BNT411 in Part 1B at any given 
time will always be one dose level below that in Part 1A. 
In case the MTD for BNT411 monotherapy is identified prior to dose level 5, the bifurcation 
will start one dose level below the BNT411 monotherapy MTD dose level. The sponsor 
together with the Safety Review Committee (SRC) may explore intermediate dose levels to 
bifurcate from monotherapy to combination dose escalation based on safety, PK, PD and 
preliminary efficacy data generated. 
In Part 2, once a dose level is deemed safe and endorsed by the SRC, additional patients 
can be included at a given dose level of either BNT411 monotherapy or combination in 
order to explore, e.g., early efficacy in other indications and/or PD signals. Furthermore, 
different doses and schedules might be explored during the dose escalation and/or 
expansion based on the data generated in the dose escalation. 
Additional indication-specific solid cancer cohorts are implemented by CTP amendments. 
The design of the trial is shown in Figure 1. 
Dose escalation in Part 1A 
The dose escalation starts with an accelerated phase consisting of single-patient cohorts 
followed by larger patient cohorts informed by a classical 3+3 design. The single-patient 
cohorts in the first three dose levels will be expanded to 3+3-patient cohorts in case of 
occurrence of grade ≥2 toxicities, or the occurrence of DLTs, or based on the decision of 
the sponsor’s SRC based on safety data generated. In addition, in the single-patient cohort 
phase, the next cohort can only start once the DLT period for the previous dose level has 
been assessed and the next dose level is proposed by the SRC and endorsed by the 
sponsor. Once a single-patient cohort has been expanded, all future cohorts will follow the 
3+3 design. Additional details regarding the SRC can be found in the CTP. The DLT 
period is defined as one cycle (i.e., 21 days). 
Further details can be found in the CTP. 
For the assessments of each cohort, the DLTs will be collected for the first treatment cycle, 
i.e., a DLT evaluation period of 21 days. 
Dose escalation will follow a classical 3+3 design and continue until DLTs are observed in 
2/3 or 2/6 patients as described in the dose escalation table (Section 4.1.1.1 of the CTP). 
Dose escalation in Part 1B 
The dose escalation in Part 1B follows the classical 3+3 design as described above for 
dose escalation in Part 1A. However, in the case that any dose level in Part 1B is declared 


 
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as MTD, dosing in Part 1B should stop (refer to Section 6.6.5 of the CTP for stopping 
criteria). The monotherapy dose escalation in Part 1A can proceed independently of 
Part 1B until MTD and/or RP2D of BNT411 monotherapy are established. 
Expansion phase (Part 2) 
As described in CTP Section 4.1.2, expansion cohorts can be implemented by a CTP 
amendment. The decision to expand is based on the totality of data generated in both 
Part 1A and Part 1B. The expansion cohort can be a single-arm cohort or a randomized 
cohort. Further details can be seen in the CTP. 
Treatment and trial duration 
Patient level: 
Patients will receive treatment until one of the CTP pre-defined discontinuation of 
treatment criteria has been met (refer to Section 7.1 of the CTP). Patients are expected to 
be on-treatment for up to 2 years (maximum). This will be followed by safety follow-up 1 
(30 days after last dose) and a safety follow-up 2 (60 days after last dose). Survival will be 
followed up every 12 weeks after last dose until 1 year. 
Trial level: 
The trial will be considered completed once all patients have completed treatment and 
safety follow-ups. After the sponsor considers the data collection is completed, patients will 
continue to follow the SoA defined by the protocol unless the medical monitor gives 
approval not to do so. 


 
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Figure 1: 
Overall trial design 
DL, dose level; DLT, dose-limiting toxicity; ES-SCLC, extensive-stage small cell lung cancer; MTD, maximal tolerated 
dose; RP2D, recommended phase 2 dose. 
 


 
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3.3 
Schedule of activities 
Refer to Section 10.4 for the schedule of activities. 
4 
STATISTICAL HYPOTHESES 
There are no plans to test statistical hypotheses for this trial. 
5 
INTERIM ANALYSES AND ANALYSIS SEQUENCE 
No formal interim analysis is planned. However, data will be reviewed by the SRC after 
each cohort (details are provided in the CTP). The main statistical analysis will be 
performed once all patients have completed treatment and safety follow-up. Preliminary 
statistical analyses may be performed on selected cohorts once all patients have been 
enrolled and are DLT evaluable. 
6 
SAMPLE SIZE DETERMINATION 
The sample size for Parts 1A and 1B is driven by the 3+3 trial design and will range from 
three to six DLT-evaluable patients per cohort, depending on the number of DLTs which 
may occur. In total, between 6 and 60 DLT-evaluable patients are planned to be enrolled 
in the Part 1A, and between 6 and 30 DLT-evaluable patients are planned to be enrolled in 
the Part 1B. 
7 
ANALYSIS SETS AND SUBGROUPS 
7.1 
Analysis sets 
Enrolled Set 
Enrolled set will have the patients with a valid date of informed consent. 
Safety Set 
The Safety set is defined as all patients who received BNT411 (i.e., at least one dose of 
BNT411). 
DLT Evaluation Set 
The DLT evaluation set includes all patients from the Safety set who either have 
completed the DLT evaluation period (i.e., have been observed for minimum 21 days 
following the first dose) and meet the minimum exposure criterion (i.e., when the relative 
dose intensity [RDI] of BNT411 in Cycle 1 is 100%) or have experienced a DLT during the 
DLT evaluation period (Cycle 1).  


 
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Patients who do not experience any DLT during the DLT evaluation period are considered 
to be evaluable if they have been observed for minimum 21 days following the first dose 
and are considered to have sufficient safety data to conclude that a DLT did not occur.  
Patients who are excluded from the DLT evaluation set will be replaced. 
Pharmacokinetic (PK) Full Set 
The PK Full set will consist of all patients who receive at least one dose of BNT411 and 
have at least one quantifiable post-dose PK sample. 
Pharmacokinetic (PK) Evaluable Set 
The PK Evaluable set will consist of all patients in the PK Full Set with a sufficient number 
of quantifiable PK samples to reliably estimate one or more PK parameters. 
Pharmacodynamic (PD) Set 
The PD set is defined as all patients who received IMP (i.e., at least one dose of BNT411) 
and have at least one valid post-dose PD assessment. 
The DLT evaluation set will be used for the evaluation of DLTs in order to assess the MTD 
and the RP2D. The Safety set will be used for all other safety analyses. The PK Full Set, 
PK Evaluable Set and PD analysis set will be used for the PK and PD summaries, 
respectively. 
Most patient data listings will be based on the Safety set. The Enrolled set will be used to 
summarize the patient disposition summary and some patient data listings. 
For the screened patients, the summary is not by cohort, the number and percentage of 
patients having failed screening (reported as screen failure in the electronic Case Report 
Form [eCRF]) will be presented along with a summary of the primary reason for screening 
failure. 
7.2 
Protocol deviations 
Protocol deviations are failures to adhere to the inclusion/exclusion criteria and protocol 
requirements and will be classified into important protocol deviations (IPDs) and non-
important (NIPDs) protocol deviations.  
The protocol deviation plan describes the classification process of the protocol deviations 
as “Key”/”Non-key”: 
• 
The term “Key” deviation from protocol deviation plan is equivalent to IPDs in the 
SAP.  
• 
The term “Non-key” deviation from protocol deviation plan is equivalent to NIPDs in 
the SAP. 
IPDs will be identified by the trial team on an ongoing basis and will be finalized prior to 
database snapshot for the main analyses. 


 
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All protocol deviations will be presented in a listing. The IPDs will be summarized by cohort 
and total within each trial part for the Safety set. 
7.3 
Subgroups 
There are no planned subgroup analyses. 
8 
STATISTICAL ANALYSES 
8.1 
General considerations 
Unless otherwise specified, the details mentioned are for trial Parts 1A and 1B. The 
summaries will be presented as cohort and total within trial part (Part 1A and Part 1B).  
The presentation of data for Part 2 will be included in a SAP amendment. 
No formal statistical comparisons between cohorts/trial parts will be performed. 
Continuous variables will be summarized by cohort and total (as specified) using the 
following descriptive statistics: number of patients with non-missing data (n), mean, 
standard deviation (SD), median, minimum (min) and maximum (max). 
Categorical variables will be summarized by cohort and total (as specified) presenting 
absolute and relative frequencies (n and %) of patients in each category and the number 
of patients with missing data (missing category will be presented if there is one or more 
missing value). Percentages will be calculated based on the number of patients with non-
missing data (n) in the particular analysis set as the denominator. The text (N=xx) in the 
tables denotes the number of patients in the analysis set within each cohort. For event-
driven occurrence data (e.g., adverse event, concomitant medication, etc.) the 
percentages will be based on the number of patients in the analysis set (N). For reported 
visit data (e.g., gender, [Eastern Cooperative Oncology Group] ECOG performance status, 
etc.) the percentages will be based on the number of patients with non-missing values (n). 
All data collected during the trial will be listed, the trial day will be presented as 
appropriate. The data will be sorted by trial part (Part 1A, Part 1B) cohort, patient number 
cycle (if applicable) and date of assessment (if applicable). 
All analyses will be conducted using SAS® version 9.4 or higher. 
Baseline is defined as last available value prior to first dose of any trial treatment (i.e., for 
Part 1A BNT411 and for Part 1B BNT411 or atezolizumab or carboplatin or etoposide). 
Generally, if there are multiple assessments available for a particular day, the assessment 
that is closest to the day (and time if collected) of the first dose of any trial treatment (i.e., 
BNT411 or atezolizumab or carboplatin or etoposide) will be used as the baseline value in 
the summary/analyses.  
Multiple values at post-baseline visits: if there are multiple post-baseline assessments 
available within a visit/day, the earliest value and corresponding date/time will be 
considered. 


 
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Change from baseline: Unless and otherwise specified, will be calculated as follows: 
Change from baseline = post-baseline assessment value – baseline assessment 
value. 
If either the baseline or post-baseline assessment value is missing, the change from 
baseline is set to missing as well. 
For the derivations of PK and PD data, see Section 8.6.1 and 8.6.2. 
Duration (Other than “Trial Treatment Duration” defined in Section 8.5.1) will be calculated 
as follows:  
• 
Duration = last observation date – first observation date + 1. 
For conversion of days to months or years the following rules will be applied: 
• 
1 month = 30.4375 days 
• 
1 year = 365.25 days 
Trial Day and Treatment Day will be calculated for each trial part (1A and 1B) as follows: 
• 
Trial day: 
− 
If assessment date < treatment start date then trial day = assessment date – 
treatment start date 
− 
If assessment date >= treatment start date then trial day = assessment date – 
treatment start date + 1 
• 
Treatment Day = treatment date – date of first dose of BNT411 +1 
That is, trial day 1 indicates the date of treatment initiation.  
For BNT411, it is Cycle 1 Day 1 of Part 1A and Cycle 1 Day 2 of Part 1B. For 
atezolizumab, carboplatin and etoposide it is Cycle 1 Day 1 of Part 1B. 
All trial data will be presented as collected in the eCRF/visit assigned in external data. No 
windowing of data for the purposes of assigning to a visit will occur.  
Unscheduled assessments will be listed only and not included in summaries/analysis.  
Handling missing data: 
For the purposes of assigning treatment-emergent flag for adverse events (AEs), partial or 
missing AE dates will be handled as follows (trial treatment date is the earliest date of 
BNT411 in Part 1A and earliest date of atezolizumab, BNT411, carboplatin and etoposide 
in Part 1B). 
• 
If the day of the month is missing, the onset day will be set to the first day of the 
month unless it is the same month and year as trial treatment.  In this case, in 
order to conservatively report the event as treatment-emergent, the onset date will 
be assumed to be the first date of trial treatment. 


 
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• 
If the onset day and month are both missing, the day and month will be assumed to 
be January 1, unless the event occurred in the same year as the trial treatment. In 
this case, the event onset will be coded to the day and month of treatment in order 
to conservatively report the event as treatment-emergent.  
• 
A completely missing onset date will be assumed to be the first day of trial 
treatment.   
• 
If an AE has a partial start date that is in the same month/year as the first dose of 
trial treatment, then the AE will be reported as treatment-emergent. 
Partial anti-cancer therapy start dates will be handled as follows: 
• 
If the start of subsequent anti-cancer therapy date is missing, this will be imputed 
to the date of the end of treatment (EOT) visit. 
• 
Missing day, month/year present: If the month/year is the same as the month/year 
of EOT Visit date, then impute missing start dates with EOT Visit date. Otherwise, 
for dates corresponding to a start date, impute with the first day of the month. 
• 
Missing month/day, year present: If the year is the same as the year of EOT Visit 
date, then impute missing start dates with EOT Visit date. Otherwise, for dates 
corresponding to a start date, impute with the first day of the year. 
• 
If the EOT Visit date is missing, the date of last treatment will be used for 
imputation. 
For the purposes of assigning prior or concomitant flag for medications, partial or missing 
medication dates will be handled as follows: 
• 
If end day is missing and month/year are non-missing, then day is the minimum of 
treatment end date and the last day of the month. 
• 
If end day/month are missing and year is non-missing, then day is the minimum of 
treatment end date and the end of the year (31DECYYYY). 
• 
If imputed end date is less than the start date, use the start date as the imputed 
end date. 
Start dates: 
• 
If the start date year is missing, the start date is set to one day prior to treatment 
start date. 
• 
If the start date year is less than the treatment start date year, then: 
− If the month is missing, the start date is assumed to be mid-year point 
(01JULYYYY). 
− Else if the month is not missing, the start date is assumed to be mid-month 
point (15MONYYYY). 
 
• 
If the start date year value is greater than the treatment start date year, then: 
− If the month is missing, the start date is assumed to be the year start point 
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− Else if the month is not missing, the start date is assumed to be the month 
start point (01MONYYYY). 
 
• 
If the start date year value is equal to the treatment start date year value: 
− If the month is missing or the month is equal to the treatment start date 
month, then the start date is assumed to be one day prior to the treatment 
start date. 
− Else if the month is less than the treatment start date month, the start date 
is assumed to the mid-month point (15MONYYYY). 
− Else if the month is greater than the treatment start date month, the start 
date is assumed to be the month start point (01MONYYYY). 
If complete end date is available and the start date assumed from the steps above is 
greater than the end date, then the assumed start date should be set to the end date. 
Missing data, other than that described for AEs/CMs/ above will not be imputed. 
Listings will present all data as reported (i.e., without imputations). 
For analysis of PK and PD data: 
• 
The actual date collected will be used. If the date is not available, the value will be 
considered as missing.  
• 
The actual time of sample collection will be used. If the time is not available, the 
value will, at the discretion of trial pharmacokinetics/pharmacodynamics analysist 
(in consultation with BioNTech), be considered as missing or imputed to be the 
nominal sampling time. 
8.2 
Patient disposition 
Unless otherwise specified, all of the summaries will be presented by cohort and total 
within each trial part (Part 1A and Part 1B). 
For the screened patients, the number and percentage of patients having failed screening 
will be presented along with a summary of the primary reason for screening failure. A 
summary of reason for violation of inclusion/exclusion criteria will also be presented. This 
summary is not by cohort. 
The number and percentage of patients enrolled by site will be presented. The number 
and percentage of enrolled and treated patients will be presented by country and site 
including the number and percentage of IPDs (by cohort and total within each trial part). 
The number and percentage of patients in each analysis set will be summarized by cohort 
and total within each trial part. 
For each analysis set (e.g., Safety set, DLT evaluation set, PK Full set, PK Evaluable set 
and PD set) the number and percentage of patients being excluded from the analysis set 
will be presented by cohort and total along with a summary of the reasons for exclusion 
based on the Enrolled set. 


 
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For the Safety set the number and percentage of patients who are still on-treatment and 
percentage of treated patients who are off treatment will be summarized. Patients who are 
“off treatment” will be the patients who are who are discontinued from treatment. Also, for 
the Safety set the number and percentage of patients discontinued from each trial 
treatment (BNT411, atezolizumab, carboplatin, etoposide) will be presented along with a 
summary of the primary reason for treatment discontinuation as reported in the eCRF. All 
summaries will be by cohort within each trial part. 
The number of patients that entered/not entered safety follow-up 1 and safety follow-up 2 
(defined as had at least one data point collected in safety follow-up 1, safety follow-up 2, 
respectively) and the number of patients that had early discontinuation from the trial 
together with the primary reason for discontinuation will be summarized for the patients in 
the Safety set by cohort and total within each trial part. 
In addition, total number of deaths will be summarized by cohort and total within each trial 
part for the Safety set. 
A listing of patient disposition (including discontinuation from each trial treatment (BNT411, 
atezolizumab, carboplatin, etoposide) and discontinuation from trial) will be presented. 
A listing of Enrolled set patients that are excluded from the Safety, DLT evaluation, PK and 
PD sets will be presented. 
A listing of enrolled patients with protocol deviations will be provided. 
8.3 
Baseline characteristics 
8.3.1 
Demographics 
Demographic data will be summarized by cohort for patients in the Safety set for each part 
of the trial (Part 1A and Part 1B). 
Age (years), will be summarized as continuous data. Age category <65, ≥65 years), 
gender (male vs female), childbearing potential, race (White, Black or African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Not 
reportable, Unknown and other) and ethnicity (Hispanic or Latino, Not Hispanic or Latino 
and Not reportable) will be summarized as categorical data. 
A listing of demography will be provided. 
Baseline characteristics will be summarized by cohort for patients in the Safety set for 
each part of the trial (Part 1A and Part 1B). 
Height (cm), weight (kg), Body Mass Index (BMI (kg/m2)), body surface area (BSA (m2)), 
and Glomerular Filtration Rate (GFR, mL/min/1.73 m2), will be summarized descriptively. 
BMI category (<18 kg/m2, ≥18 kg/m2, <25 kg/m2, ≥25 kg/m2, <30 kg/m2, ≥30 kg/m2) and 
Smoking status (has never smoked, current smoker, ex-smoker) will be summarized with 
frequency counts and percentage by cohort. 
A listing of baseline characteristics will be provided. 


 
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8.3.2 
Disease characteristics 
The following disease characteristics at baseline will be summarized by cohort for patients 
in the Safety set for each part of the trial (Part 1A and Part 1B). 
• 
Time from initial cancer diagnosis to enrollment (months) 
• 
ECOG Performance Status at baseline 
• 
Time from most recent progression (as recorded on the cancer classification and 
staging eCRF page) to start of any trial treatment (BNT411, atezolizumab, 
carboplatin or etoposide) 
• 
Location at initial diagnosis 
Time from initial cancer diagnosis to enrollment (months) will be calculated as:  
Time = date of enrollment – initial diagnosis date + 1. 
In order to calculate the time from initial cancer diagnosis, the following rules will be 
applied for partial dates of first diagnosis: 
• 
The first day of the month will be assumed; 
• 
If the month is missing, January 1st will be assumed.  
Time from most recent progression to start of any trial treatment to start of any trial 
treatment will be calculated as:  
Time = date of first dose of BNT411 - date of most recent progression + 1. 
A listing of disease characteristics will be provided. 
8.3.3 
Prior anti-cancer treatments 
The summary of prior anti-cancer treatments will be based on the Safety set and will be 
presented by cohort and total for each trial part (Part 1A and Part 1B). 
For prior systemic cancer therapy, the following will be summarized: 
• 
The number of prior systemic therapies (0,1, 2, 3+)   
The last prior systemic cancer therapy prior to treatment start date (the prior systemic 
therapy with start date closest to treatment start date) will be summarized as follows: 
• 
Setting (adjuvant, neoadjuvant and metastatic) 
• 
Intent (curative, palliative and unknown) 
• 
Best response during the therapy (CR, PR, progressive disease, stable disease, 
unknown) 
• 
Reason for discontinuation of last prior systemic therapy 
The treatment intent and setting for prior cancer radiotherapy and treatment intent for prior 
cancer surgery will be summarized by cohort and total for each trial part. 


 
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Prior systemic cancer therapies will be coded using the World Health Organization Drug 
Dictionary (WHO DD) version B3 dated March 2023 resulting in anatomical-therapeutic-
chemical (ATC) codes indicating therapeutic classification. 
The number and percentage of patients taking prior systemic cancer therapies will be 
summarized by ATC therapeutic class (ATC level 2), ATC pharmacological class (ATC 
level 3), and chemical subgroup (ATC level 4) for each cohort and total for each part of the 
trial (Part 1A and Part 1B). 
Prior cancer surgeries will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) coding system version 26.0 or higher and will be listed only. 
A listing of prior cancer therapies (systemic cancer therapy, cancer radiotherapy, cancer 
surgery) will be provided. 
8.3.4 
Prior and Concomitant medication/Procedures/Non-drug Therapy 
Prior and concomitant medications will be defined using medication start and stop dates 
recorded, relative to the first and last dose of trial treatment (BNT411, atezolizumab, 
carboplatin, etoposide) for both the trial parts (1A and 1B). 
A prior medication will be defined as any therapy taken 28 days prior up to (but not 
including) the start date of trial treatment.  
A concomitant medication will be defined as any medication either ongoing at the start of 
trial treatment in each trial part (1A and 1B) or with a start date on or after the first dose of 
any trial treatment up to (but not including) the last date of trial treatment (BNT411, 
atezolizumab, carboplatin, etoposide). See Section 8.1 for handing missing dates. 
Medications will be coded using the World Health Organization Drug Dictionary 
(WHODrug) drug codes of version B3 dated March 2023. Resulting in ATC codes 
indicating therapeutic classification. 
The number and percentage of patients who had prior and concomitant medications will be 
summarized by ATC therapeutic class (ATC level 2), ATC pharmacological class (ATC 
level 3), and chemical subgroup (ATC level 4) for each cohort and total within each trial 
part based on the Safety set. The summary will be presented alphabetically. 
A listing of prior and concomitant medications will be provided. 
Procedures and Non-drug therapies will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®) coding system version 26.0 or higher. Procedure and 
non-drug therapies will be listed only. 
8.3.5 
Medical history 
Medical history data will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®) version 26.0 or higher. The number and percentage of patients with each 
medical history will be summarized by System Organ Class (SOC) and Preferred Term 
(PT) for each cohort and total within each trial part based on the Safety set. 
A listing of medical history data will be provided. 


 
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8.4 
Efficacy analyses 
Owing to the heterogeneity of cancer types and limited number of patients in Part 1A and 
B, no efficacy analysis will be done in Part 1. 
8.4.1 
Primary analysis 
Not applicable for this trial as there is no primary efficacy endpoint defined for this trial. The 
primary endpoint is a safety endpoint, this endpoint is described in Section 8.5.2. 
8.4.2 
Supplementary analyses 
Not applicable. 
8.4.3 
Secondary analyses 
Not applicable. 
8.4.4 
Exploratory analyses 
Not applicable. 
8.5 
Safety analyses 
Safety data that will be summarized includes treatment exposure, AEs, clinical safety 
laboratory assessments (including hematology, biochemistry, urinalysis, coagulation 
endocrine tests), vital signs, electrocardiogram (ECGs), ECOG PS, Eye examinations, PD 
and biomarkers. All safety analyses will be based on the Safety set and will be 
summarized by cohort and trial part and if appropriate, by cohort and treatment, for 
example for summary of treatment-related AEs. For all the summaries patients will be 
assigned to the treatments according to the actual treatment they have received (“as 
treated”). The actual treatment will be derived as following: 
• 
If a patient received at least once the planned dose during Cycle 1, then this 
patient will have the actual treatment assigned to the planned treatment. 
• 
Otherwise, the actual treatment will be considered as the dose received in Cycle 1 
day 1. 
All safety data will be listed. 
8.5.1 
Extent of exposure 
The following dose exposure variables will be derived and summarized for each treatment 
(BNT411 in Part 1A also BNT411, atezolizumab, carboplatin, and etoposide in Part 1B). 
The summaries will be based on patients in the Safety set and will be repeated for DLT 
evaluation set. The summary for the DLT evaluation set will be restricted to the exposure 
data from the first cycle (21 days). 
• 
Number of treated cycles. 
• 
Number of BNT411 infusions. 


 
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• 
Number of atezolizumab, carboplatin and etoposide infusions (Part 1B).  
• 
(Actual)Treatment Duration (weeks) defined as follows: (Date of last administration 
- Date of first administration + Planned Duration) / 7, where the Planned Duration 
(days) is defined as the planned time between two consecutive administrations. In 
Part 1A, planned duration for BNT411 is one week for the first four cycles, followed 
by once every 3 weeks. In Part 1B, planned duration for BNT411 for the first four 
cycles is 6 days if the patients’ last dose was the first dose within any cycle, 7 days 
if the patients’ last dose was the second dose within any cycle and 8 days if the 
patients’ last dose was the third dose in within any cycle. After 4 cycles planned 
duration for BNT411 is 3 weeks. Planned duration for atezolizumab is every 3 
weeks, for carboplatin it is 21 days apart till Cycle 4 and for etoposide planned 
duration is one day till day 3 of the Cycle 4. Actual treatment duration is calculated 
for each treatment separately. 
• 
Planned Treatment Duration (weeks) defined as (scheduled date of last 
administration - scheduled date of first administration + Planned Duration) / 7. The 
scheduled date of last administration is the date at which the last administration 
should be given according to the CTP schedule. Planned duration is as above. 
• 
(Actual) Cumulative Dose defined as sum of all administered doses for each trial 
treatment. BNT411 (µg) for Part 1A and Part 1B and atezolizumab (mg), 
carboplatin (mg), and etoposide (mg) for Part 1B. Calculated for each treatment 
separately. 
• 
Planned Cumulative Dose defined as sum of all planned doses, separately, for 
each trial treatment. BNT411 (µg) for Part 1A and Part 1B and atezolizumab (mg), 
carboplatin (mg), and etoposide (mg) for Part 1B.  
• 
Dose Intensity is defined as Cumulative Dose for that trial treatment (unit for that 
trial treatment) / (Actual) Treatment Duration (weeks) for that trial treatment.  
• 
RDI % (using units for BNT411) is defined as follows: 
 
RDI (%) =
Actual Dose Intensity ( µg
week)
Planned Dose Intensity ( µg
week)
 x 100 = DI x TI x 100,  
Where 
 
Actual Dose Intensity ( µg
week) =
(Actual) Cumulative Dose (µg)
(Actual) Treatment Duration (weeks) 
Planned Dose Intensity ( µg
week) =
Planned Cumulative Dose (µg)
Planned Treatment Duration (weeks)  
Dose Index (DI) = Total Administered Dose (µg)
Total Planned Dose (µg)
 


 
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Time Index (TI) = Planned Treatment Duration (weeks)
Actual Treatment Duration (weeks)  
The units in the derivations above are for BNT411. For atezolizumab, carboplatin and 
etoposide the unit is mg.  
The following variables will be presented with summary statistics for each trial treatment by 
cohort for each trial part: 
• 
Number of cycles received (categorical, Cycle 1-2, 3-4, 5-6, 7-8, 9-10, 11-12, 13-
14, 15-16, 17-20 21-24 and so on, aligned to the tumor assessments every 6 
weeks and 12 weeks respectively) 
• 
Number of BNT411 infusions (descriptive statistics) 
• 
Number of BNT411 infusions (categorical, 1, 2, 3 and so on) 
• 
Number of atezolizumab, carboplatin and etoposide infusions (descriptive 
statistics) (Part 1B) 
• 
Number of atezolizumab, carboplatin and etoposide infusions (categorical, 1, 2, 3 
and so on) (Part 1B) 
• 
Treatment duration 
• 
Cumulative dose 
• 
Dose intensity 
• 
RDI 
Additionally, the RDI will be presented categorically (i.e., number and percentage of 
patients with RDI of <60%, 60-<80%, ≥80%).  Moreover, the number and percentage of 
patients with any dose delay, 4-7 days, > 7 days of dose delay and with any dose 
modification, dose reduction, dose increase, at least one dose modification and at least 
two dose modification and any dose interruption will be presented separately for each trial 
treatment for each trial part. Dose reduction and dose increase will be calculated as 
planned dose - given dose or total dose. 
All the above mentioned dose exposure variables will be presented in a by-patient listing. 
A by-patient listing of treatment administration will be presented. 
8.5.2 
Adverse events 
This section includes the description of the analysis planned for the primary endpoints on 
this trial. 
AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA®) coding system version 26.0 or higher to get a SOC and PT for each 
AE and graded for severity using NCI CTCAE v5.0. In case a patient has an AE with 
missing relationship status, the event will be assumed to be related and associated with 
the treatment received in the summaries (will be listed as collected in the listings). No 
imputation for missing NCI-CTC grades will be performed.  


 
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A treatment-emergent AE (TEAE) is defined as any AE with an onset date on or after the 
first administration of trial treatment (BNT411 in part1A and BNT411, atezolizumab, 
carboplatin, and etoposide in Part 1B) (if the AE was absent before the first administration 
of trial treatment) or worsened after the first administration of trial treatment (if the AE was 
present before the first administration of trial treatment). AEs with an onset date more than 
60 days after the last administration of trial treatment will be considered as treatment-
emergent only if assessed as related to trial treatment (BNT411 for Part 1A and BNT411, 
atezolizumab, carboplatin, and etoposide for Part 1B) by the investigator.  
Treatment-emergent AEs will be summarized by cohort and trial part and total within trial 
part. In addition, treatment-related TEAEs will be summarized by cohort and trial treatment 
(BNT411, atezolizumab, carboplatin, and etoposide) within trial part.  
Only TEAE data will be summarized for the Safety set for each trial part (Part 1A and Part 
1B). Non-TEAEs will be listed only. 
Dose-limiting toxicities 
In general, a DLT for a drug or other treatment is defined as one or more AEs that 
prevents an increase of the dose level of that treatment (for details on dose escalation 
decision rules see Appendix 5). 
Serious AEs (SAEs), non-serious grade ≥3 AEs and clinically significant abnormal 
laboratory values grade ≥3 will be collected and assessed for DLTs (for each dose level 
during the first cycle). Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v.5.0 will be used to grade the intensity of AEs. 
More details regarding DLTs can be found in the Section 6.6 of the CTP.  
For the additional rules and considerations of MTD and RP2D other than what was already 
defined in Section 1.1, see Section 4.1.1.2 of the CTP. 
The number and percentage of patients reporting DLTs will be summarized by PT nested 
within SOC for each cohort by trial part using the DLT evaluation set. 
A separate listing of DLTs will be presented, including reported term, SOC, PT, time of 
onset, duration, outcome, relationship to trial treatment, NCI CTCAE grade, and 
seriousness including dose exposure data during the first cycle (i.e., 21 days).  
Overall summary of adverse events (AE) 
The number and percentage of patients reporting at least one AE will be summarized for 
each of the following AE types by cohort and trial part (Parts 1A and 1B). Related applies 
to a separate summary for BNT411 in Part 1A and BNT411, atezolizumab, carboplatin, 
and etoposide and any NIMP/IMP in Part 1B, unless otherwise specified :  
• 
any TEAE 
• 
related TEAE   
• 
grade ≥3 TEAE 
• 
related grade ≥3 TEAE   


 
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• 
any treatment-emergent serious AE (TESAE) 
• 
related TESAE 
• 
TESAE leading to death 
• 
Related TESAE leading to death 
• 
TEAEs leading to dose reduction and dose interruption (BNT411 in Part 1A or 
BNT411, atezolizumab, carboplatin, and etoposide in Part 1B) 
• 
TEAE leading to permanent discontinuation of treatment (BNT411 in Part 1A or 
BNT411, atezolizumab, carboplatin, and etoposide in Part 1B) 
• 
DLTs 
Analyses of adverse events  
The number and percentage of patients reporting at least one TEAE will be summarized 
by PT nested within SOC for each of the above AE categories. If an SOC / PT is reported 
more than once for a patient, the patient will only be counted once for this SOC / PT. 
Strongest relationship or worst grade will be counted if a TEAE is reported more than once 
by the same patient for a SOC / PT. The common TEAE occurring in ≥ 10% of the patients 
will be summarized separately. 
All AE summary tables will be sorted in descending frequency order by SOC and PT within 
SOC. 
Analyses of other adverse events (excluding serious AEs) 
The number and percentage of patients reporting other TEAEs (excluding TESAEs) will be 
summarized by PT nested within SOC. If a SOC / PT is reported more than once for a 
patient, the patient will only be counted once for this SOC / PT.  
All AE summary tables will be sorted in descending frequency order by SOC and PT within 
SOC. 
TEAE by relationship 
The number and percentage of patients with TEAEs will be summarized by ‘ALL’ and 
‘Related’ to trial treatment (BNT411, atezolizumab, carboplatin, and etoposide) by PT 
nested within SOC. If an AE is reported more than once by the same patient for a SOC / 
PT the related AE will be counted once for this SOC / PT. The relationship to trial 
treatment will be counted as related if relationship status is reported as missing for an AE.  
TEAE by NCI-CTC grade 
The number and percentage of patients with TEAEs will be summarized by worst NCI-CTC 
grade by PT nested within SOC. Worst grade will be counted if an AE is reported more 
than once by the same patient for a SOC / PT. The related TEAEs by worst NCI-CTC 
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The number and percentage of patients with grade ≥ 3 AEs and related grade ≥ 3 AEs will 
be summarized by PT nested within SOC. In addition, AEs with a missing grade will be 
presented in the summary table as a grade category of “Missing.” 
Deaths 
• 
All deaths including those that occurred on-treatment (on or after date of first dose 
of BNT411) and post-treatment, will be listed, post-treatment deaths will be 
flagged. In addition to the summary of on-treatment deaths an additional summary 
of all deaths (on-treatment + post-treatment) will be provided along with primary 
reason for death. 
• 
A separate summary of TESAEs leading to death will be provided by PT nested 
within SOC. 
• 
A separate summary of related TESAEs leading to death will be provided by PT 
nested within SOC. 
Serious Adverse Events and Other Significant Adverse Events 
The number and percentage of patients  
• 
with any TESAE, 
• 
with any related TESAE (separately for each trial treatment and total), 
• 
with any TESAE leading to death, 
• 
with any related TESAE leading to death, 
• 
with any TEAE leading to permanent discontinuation of treatment (BNT411, 
atezolizumab, carboplatin, and etoposide), or 
• 
with any TEAE leading to dose reduction or interruption 
will be summarized by PT nested within SOC by cohort within each trial part. 
Deaths 
In addition to a summary of on-treatment (on or after date of first dose of BNT411 until…) 
deaths and primary reason for death an additional summary of all deaths (on-treatment + 
during follow-up) will be provided along with primary reason for death. by cohort for each 
trial part. All deaths including those that occurred on-treatment and during follow-up, will 
be listed, post-treatment deaths will be flagged. 
AE listings 
All deaths, AEs, SAEs and TEAEs leading to permanent discontinuation of treatment, and 
discontinuation from trial will be listed. Also a listing of TEAEs leading to death will be 
provided. DLTs will be flagged in all AE listings. The listings will be sorted by trial part, 
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8.5.3 
Laboratory assessments 
All laboratory assessments except for PK and biomarkers will be processed by local 
laboratories. Summaries of all laboratory data will be based on Safety set for each trial part 
(Parts 1A and 1B) and total within each trial part. 
For the purposes of summarizing and presentation in tables and listings, all laboratory 
values will be summarized by cohort and presented in System International (SI) units. If a 
laboratory value is reported using a nonnumeric qualifier e.g., less than (<) a certain value, 
or greater than (>) a certain value, the given numeric value will be used in the summary 
statistics, ignoring the nonnumeric qualifier. The data as collected will be presented in the 
listings. 
Clinical laboratory data to be summarized includes hematology, biochemistry, urinalysis, 
coagulation factors and endocrine tests. The safety laboratory parameters to be assessed 
are listed in Section 10.2 of the CTP. The scheduled time points for assessment are 
outlined in the SoAs (Section 10.4.1) 
Continuous clinical laboratory variables at each protocol scheduled visit and its change 
from baseline to each post-baseline visit will be summarized using descriptive summary 
statistics for each parameter listed in CTP Table 10-1 by cohort. Categorical variables will 
be summarized using n and %. 
Laboratory values that are below or above the reference ranges will be flagged. 
Abnormal and clinically significant, abnormal and not clinically significant, and normal 
laboratory values will be summarized for each parameter by visit and cohort.   
All laboratory data will be presented in the data listings. Abnormal clinical laboratory values 
will be flagged in the listing.  
Serology and pregnancy results will be listed only. 
8.5.4 
Vital signs 
Vital sign parameters to be summarized include systolic blood pressure (SBP), diastolic 
blood pressure (DBP), body temperature, body weight, respiration rate and pulse rate. 
Vital sign parameters collected at each visit/time-point, and its change from baseline to 
each post-baseline visit (for BNT411 infusion days the value collected pre-infusion will be 
used for this summary) will be summarized using descriptive summary statistics for each 
parameter by cohort and visit for each trial part.  
Vital sign parameters collected on BNT411 infusion days and its change from baseline 
(pre-infusion value at that visit) to each post-baseline time-point will be summarized for 
each time-point using descriptive summary statistics for each parameter by cycle, cohort, 
and trial part. 
Body weight, which is collected at screening and at the beginning of each cycle of 
treatment, will be summarized using descriptive summary statistics by cycle, cohort, and 
trial part. 


 
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All vital sign data will also be presented in a data listing. 
8.5.5 
ECG              
Triplicate (during trial treatment) or single (at other time points) 12-lead ECG will be 
collected as shown in CTP Table1-4 and Table 1-5.  
The triplicate ECG values will be listed only. For the summary at each time-point, the first 
assessment will be considered. 
ECG variables to be summarized include heart rate, QRS, QTc. QTcF Absolute values 
collected at each time-point, and its change from baseline to each post-baseline time-point 
(for BNT411 infusion days the value collected pre-infusion will be used for this summary) 
will be summarized using descriptive summary statistics for each parameter by cohort, visit 
and trial part. 
ECG variables collected on BNT411 infusion days and its change from baseline (pre-
infusion value at that visit) to each post-baseline time-point will be summarized for each 
time-point using descriptive summary statistics for each parameter by cycle, cohort, and 
trial part. 
In addition, the number of patients with abnormal QT, and QTcF (number of patients in the 
following categories <=450 ms, >450-480 ms, >480-500 ms, >500 ms, and increase <=30 
ms, >30-60 ms and >60 ms over baseline) will be summarized by cohort and visit for each 
trial part. 
Additionally, the results of ECG interpretation (normal, abnormal not clinically significant or 
abnormal clinically significant) will be summarized with number and percentage of patients 
by cohort and visit. For the triplicate assessments, only the first assessment will be 
considered for the summary. 
A listing of ECG data will also be provided. 
8.5.6 
Physical examination 
A listing of physical examination findings will also be presented. 
8.5.7 
ECOG performance status 
The frequencies and percentages of patient’s ECOG performance status will be provided 
by cohort and visit for each trial part.  
Additionally, a shift table from baseline to each post-baseline visit by cohort will be 
provided.  
A listing of ECOG performance status will also be provided. 
8.5.8 
Eye examinations 
The eye examination data will be summarized for the patients by cohort and visit for each 
trial part.  
• 
Ophthalmologic entry criteria: Presence/absence for each at baseline  


 
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• 
Slit-lamp examination results will be summarized with frequencies and percentages 
of patients 
A listing of eye examination will also be provided. 
8.5.9 
ECHO and MUGA 
ECHO and MUGA data will be listed only. 
8.6 
Other analyses 
8.6.1 
Pharmacokinetics 
Plasma and urine samples will be collected for measuring concentrations of BNT411 and 
its metabolites as per the schedule of timing for collection of samples for PK assessments 
mentioned in Table 1.3 and Table 1.4 of the CTP. For urine sampling, the exact time of 
sampling and the volume (mL) excreted over each collection interval must be documented. 
Full pharmacokinetic profiles will be documented in additional patients enrolled to confirm 
the RP2D. The actual date and time (24-hour clock time) of each sample will be recorded. 
Plasma concentrations of BNT411 and its metabolites (if available) will be listed and 
summarized by cycle, day, nominal time, and cohort for each part of the trial (Part 1A and 
Part 1B) using descriptive statistics (n, arithmetic mean, SD, coefficient of variation [CV%], 
geometric mean, geometric CV%, median, minimum, and maximum) for the Full PK 
analysis set. The geometric CV% will be calculated as the square root of the 
exponentiated SD of the natural log-transformed data SQRT (exp(sln2)-1), where 
appropriate. Mean and individual plots of plasma concentrations will be presented in both 
the original and semi-logarithmic scales. 
All PK parameters will be summarized by cohort for each part of the trial (Part 1A and Part 
1B). For T1/2, the following descriptive statistics will be calculated, if possible, n, arithmetic 
mean, median, CV%, SD, minimum and maximum and, for Tmax, n, median, minimum and 
max will be calculated. All other PK parameters will be summarized using n, arithmetic 
mean, SD, CV%, geometric mean, geometric CV%, median, minimum, and maximum. 
The following PK parameters will be determined from plasma concentrations of BNT411 
after the first dose on Cycle 1 Day 1 (or Cycle 1 Day 2 for Part B):  
• 
AUC0-24: partial AUC from time 0 to 24 hours calculated using the linear-log 
trapezoidal method. 
• 
AUC0-48: partial AUC from time 0 to 48 hours calculated using the linear-log 
trapezoidal method. 
• 
AUC0-last: AUC from time 0 to the last measurable time-point calculated using the 
linear-log trapezoidal method. 
• 
AUC0-: AUC from time 0 to the end of the 168-hour dosing interval () calculated 
using the linear-log trapezoidal method. 


 
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• 
AUC0-inf: AUC from time 0 extrapolated to infinity, calculated as 
AUC0-inf = AUC0-last + Clast/z, where Clast is the last quantifiable (measurable) 
concentration.  
• 
Cmax: Maximum (peak) concentration. 
• 
Tmax: Time of maximum (peak) concentration. 
• 
z: terminal elimination rate constant. 
• 
T1/2: terminal elimination half-life computed as (ln 2)/z. 
• 
CL: Clearance, calculated as Dose/AUC0-inf. Dose will be converted, as necessary, 
to reflect the amount of anhydrous BNT411 administered (molecular weight 
439.5579 g/mole). 
• 
VD: Volume of distribution, calculated as [CL/z]. 
The following PK parameters will be determined from plasma concentrations of BNT411 
after the fourth dose on Cycle 2 Day 1 (or Cycle 2 Day 2 for Part B): 
• 
AUC0-24: partial AUC from time 0 to 24 hours calculated using the linear-log 
trapezoidal method. 
• 
AUC0-last: AUC from time 0 to the last measurable time-point calculated using the 
linear-log trapezoidal method. 
• 
AUC0-: AUC from time 0 to the end of the 168-hour dosing interval () calculated 
using the linear-log trapezoidal method. 
• 
Cmax: Maximum (peak) concentration. 
• 
Tmax: Time of maximum (peak) concentration. 
• 
z:  Terminal elimination rate constant estimated by linear regression of log 
concentration vs. time; at least three data points are required to compute this 
parameter. 
• 
T1/2: Terminal elimination half-life computed as (ln 2)/z. 
• 
CL: Clearance, calculated as Dose/AUC0-. Dose will be converted, as necessary, 
to reflect the amount of anhydrous BNT411 administered (molecular weight 
439.5579 g/mole). 
• 
VD: Volume of distribution, calculated as [CL/z]. 
• 
RA,Cmax: Accumulation ratio for Cmax computed as Cmax after Cycle 2 Day 1 (or 
Cycle 2 Day 2 for Part B) divided by Cmax after Cycle 1 Day 1 (or Cycle 1 Day 2 for 
Part B). 
• 
RA,AUC: Accumulation ratio for AUC computed as AUC after Cycle 2 Day 1 (or 
Cycle 2 Day 2 for Part B) divided by AUC after Cycle 1 Day 1 (or Cycle 1 Day 2 for 
Part B). 
• 
T1/2,eff: Effective half-life for accumulation computed as ln(2)/ln(RA,AUC/[RA,AUC-1]). 
AUC will be computed using the linear-log trapezoidal rule. When necessary, interpolation 
or z extrapolation may be used to estimate partial AUCs and AUC0-. The value of the 
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to be considered well estimated. If this proportion is > 20%, then the values of AUC will be 
treated with caution. When AUC is calculated and listed, the AUC%extrap will also be listed. 
Where AUC%extrap >20%, AUC and all related parameters (i.e., CL, VD) will be presented 
but excluded from the calculation of summary statistics. All values excluded from the 
summaries should be flagged in the individual listings with an explanation for the 
exclusion. 
The z will be estimated by log-linear regression of the concentration-time data associated 
with this phase. The decision as to which data points describe the terminal phase will be 
reached by inspecting the semi-logarithmic plot of the data, only considering 
concentrations at time points beyond Tmax. A minimum of three data points will be used for 
the estimation of z preferably covering a time span of at least two half-lives. Ideally, the 
adjusted r2 value of the estimated z will be > 0.80. If z is poorly estimated (i.e., if a time 
span of at least two half-lives is not used or adjusted r2  0.80), the corresponding T1/2 and 
other parameters derived using z (i.e., AUC0-inf, CL, and VD) will be flagged in the report 
and excluded from summaries for PK parameters dependent on z. 
In addition to the two plasma PK profiles collected for doses administered on Cycle 1 
Day 1 (or Cycle 1 Day 2 for Part B) and Cycle 2 Day 1 (or Cycle 2 Day 2 for Part B), 
sparse PK samples will be collected at additional times throughout the trial (see CTP 
Table 1-3 and Table 1-4). Concentrations of BNT411 in pre-dose samples will be 
considered Ctrough values provided they are collected between 156 and 180 hours after the 
start of the prior dose (i.e., 168 ± 12 hours). Concentrations of BNT411 collected within 
5 minutes after the end-of-infusion will be considered end-of-infusion concentrations (Ceoi). 
Values of Ctrough and Ceoi will be summarized longitudinally in tabular and graphical format 
by nominal elapsed time since the start of first infusion of BNT411. 
After a pre-dose void, all urine will be collected over the interval 0 to 6 hours after the start 
of dosing on Cycle 1 Day 1 in Part 1A and Cycle 1 Day 2 in Part 1B. Actual start and end 
times and total volumes of urine collections will be recorded. 
The following PK parameters will be determined from urine volumes (Vu) and BNT411 
concentrations (Cu) on Cycle 1 Day 1 and Cycle 2 Day 1 of Part 1A and Cycle 1 Day 2 
and Cycle 2 Day 2 of Part 1B:  
• 
Ae0-6: amount of BNT411 excreted in urine over the collection interval between 
start and end times calculated as Cu  Vu for the interval. 
• 
fe0-6: fraction of the administered BNT411 dose excreted in urine over the collection 
interval between 0 and 6 hours calculated as Aet1-t2/Dose. Dose will be converted, 
as necessary, to reflect the amount of anhydrous BNT411 administered (molecular 
weight 439.5579 g/mole). 
• 
CLR,0-6: renal clearance of BNT411 over the collection interval between 0 and 6 
hours calculated as Ae0-6/AUC0-6. Partial AUCs will be computed for plasma as 
described above. 


 
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Since BNT411 cannot be present in urine until after dosing, the start of the 0- to 6-hour 
urine collection interval will be the start of BNT411 infusion at Cycle 1 Day 1 in Part 1A or 
Cycle 1 Day 2 in Part 1B.  
BNT411 dosing and concentration data will be combined with relevant extrinsic and 
intrinsic covariates and used to develop a population-based pharmacokinetic (PopPK) 
model suitable for subsequent simulation and exploration of exposure-response trends. 
The methods to be used in the development of the PopPK model, and its subsequent 
application, will be described in a separate Modeling and Simulation Analysis Plan (MSAP) 
and results reported in a separate PopPK report. 
Treatment of outliers: 
Individual concentration-time points, if considered anomalous, may be excluded from the 
analysis at the discretion of the pharmacokineticist following a review of the available 
documentation. Any such exclusion will be discussed with BioNTech and clearly outlined in 
the trial report. 
Entire individual treatment profiles for a patient may be excluded following review of the 
available documentation and discussion with the sponsor. However, results of analysis 
with and without the excluded profiles may be presented in the trial report. Any such 
exclusion will be clearly listed in the trial report along with justification for exclusion. 
Non-quantifiable concentrations: 
All concentration values reported as no results (not collected or not determined) values will 
be treated as missing. For the calculation of concentration summaries, all concentrations 
below the quantifiable limit (BLQ) will be treated as 0. For the purpose of calculating PK 
parameters and plotting mean and individual concentration-time profiles, BLQ values will 
be treated as 0 prior to the first measurable concentration. After the first measurable 
concentration, subsequent BLQ values within the PK profile will be treated as missing. 
Descriptive statistics at any point will only be calculated if at least 2/3 of the individual data 
were measured and were quantifiable. 
Dose-proportionality analysis: 
The dose-proportionality of the PK parameters AUC0-last, AUC0-inf, and Cmax for the 
single-dose PK profile and AUC0- and Cmax for the multiple-dose PK profile will be 
investigated over the administered dose range using the following power model,  
ln(parameter) = a + b * ln(dose), where a is the intercept and b is the slope. 
Dose proportionality will be assessed for Cycle 1 Day 1 (or Cycle 1 Day 2 for Part B) and 
Cycle 2 Day 1 (or Cycle 2 Day 2 for Part B) of the trial separately.  
Each log-transformed PK parameter will be fit with a power model with a fixed effect term 
for log-transformed dose. For each PK parameter, the slope and associated 90% CI will be 
presented. Dose proportionality will be assessed based on whether the 90% CI includes 
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8.6.2 
Pharmacodynamics and biomarkers 
Due to the exploratory nature of this analysis the PD and Biomarkers analyses may be 
conducted if there is enough data.  
8.6.3 
New anti-cancer treatment 
New anti-cancer treatment as collected at trial withdrawal, safety follow-up and survival 
follow-up will be listed. 
 
 


 
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9 
REFERENCES 
1. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Guideline E3: Note for 
Guidance on Structure and Content of Clinical Study Reports (CPMP/ICH/137/95), 
July 1996. Retrieved on 30 January 2018 from 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/
E3_Guideline.pdf 
2. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Guideline E9: Statistical 
Principles for Clinical Trials (CPMP/ICH/363/96), March 1998. Retrieved on 21 April 
2019 from 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/
Step4/E9_Guideline.pdf 
3. 
Brookmeyer R. and Crowley J. A confidence interval for the median survival time. 
Biometrics 38:29-41, 1982 
4. 
Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrika 26: 404-413, 1934 
5. 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics. FDA December 2018. 
 
 


 
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10 
SUPPORTING DOCUMENTATION 
10.1 
Appendix 1: Changes to protocol-planned analyses 
• 
An ‘enrolled set’ was defined to summarize the patient disposition summary and 
patient data listings of screen failures and exclusion from analysis sets. 
• 
The protocol mentions summarizing adverse events, it was clarified during SAP 
development that only TEAEs should be summarized. All AEs will be listed. 
 
 


 
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10.2 
Appendix 2: List of abbreviations 
AE 
Adverse event 
Aet1-t2 
Amount of BNT411 excreted in urine over the time interval from time=t1 to 
time=t2 
AJCC 
American Joint Committee on Cancer Staging 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
Area Under the Curve of concentration versus time 
AUC%extrap 
Extrapolated portion of any AUC 
AUC0-24 
Area Under the Curve of concentration versus time calculated from the 
time of dosing to 24 hours post-dose 
AUC0-48 
Area Under the Curve of concentration versus time calculated from the 
time of dosing to 48 hours post-dose 
AUC0-inf 
Area Under the Curve of concentration versus time calculated from the 
time of dosing to infinity 
AUC0-last  
Area Under the Curve of concentration versus time calculated from the 
time of dosing to the last measurable concentration 
AUC0- 
AUC from time 0 to the end of the 168-hour dosing interval () 
BCVA 
Best Corrected Visual Acuity 
BMI 
Body Mass Index 
bpm 
Beats per minute 
BSA 
Body surface area 
Ceoi 
End-of-infusion concentrations 
CI 
Confidence interval 
CL 
Clearance, calculated as Dose/AUC0-inf 
CLR,t1-t2 
Renal clearance of BNT411 over the collection interval between t1 and t2 
Cmax 
Maximum concentration 
CR 
Complete response 
Ctrough 
Trough concentration 
CRO 
Contract Research Organization 
CTR 
Clinical Trial Report 
Cu 
BNT411 concentrations 
CV 
Coefficient of Variation 
DBP 
Diastolic blood pressure 
DCR 
Disease control rate 
DEC 
Dose-expansion cohort 
DI 
Dose intensity 
DLT 
Dose-limiting toxicities 
DMC 
Data monitoring committee 


 
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DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
ES-SCLC 
Extensive-stage small cell lung cancer 
FDA 
Food and Drug Administration 
fet1-t2 
Fraction of BNT411 dose excreted in urine over the time interval from 
time=t1 to time=t2 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl-Transpeptidase 
IPD 
Important Protocol Deviations 
iRECIST 
immune Response Evaluation Criteria in Solid Tumors 
IRR 
Infusion-related Adverse Events 
ITT 
Intent-To-Treat 
irAE 
Immune-related Adverse Events 
kg 
kilogram 
KM 
Kaplan-Meier 
LLN 
Lower Limit of Normal 
LLOQ 
Lower limit of quantification 
LNH 
Low, Normal, High 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mL 
millilitre 
mmHg 
millimeter of mercury 
MSAP 
Modeling and Simulation Analysis Plan 
MTD 
Maximal tolerated dose 
MUGA 
Multigated acquisition 
N 
Number of Patients 
n 
Number of Observations 
NCI CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events 
NIPD 
Non-Important Protocol Deviations 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamics 
PFS 
Progression-Free Survival 


 
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PopPK 
population-based pharmacokinetic 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
RA,AUC 
Accumulation ratio for AUC computed as AUC after Cycle 2 Day 1 
divided by AUC after Cycle 1 Day 1 
RA,Cmax 
Accumulation ratio for Cmax computed as Cmax after Cycle 2 Day 1 divided 
by Cmax after Cycle 1 Day 1 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SI 
International System of Units 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SQRT 
Square Root 
T1/2 
Terminal phase half-life 
T1/2,eff 
Effective half-life for accumulation computed as ln(2)/ln(RA,AUC/[RA,AUC-1]) 
TCR 
T-cell receptor 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
Tmax 
Time from dosing to the maximum observed plasma concentration 
ULN 
Upper Limit of Normal 
VD 
Volume of distribution 
Vu 
Urine volume 
WHO DD 
World Health Organization Drug Dictionary 
z 
Terminal elimination rate constant 
μg 
Microgram 


 
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10.3 
Appendix 3: Reporting conventions 
SAS version 9.4, or higher, will be used to produce all tables, listings, and figures. 
For summary statistics, the mean and median will be displayed to one decimal place 
greater than the original value and the measure of variability (e.g., SD) will be displayed to 
two decimal places greater than the original value. Minimum and maximum will be 
reported to the same decimal places as the original value. Percentages (%) will be 
displayed with one decimal place and 95% CIs will be displayed with one decimal place 
greater than the original value. 
Cohort in the Table 4 will be used for the Tables/Figures/Listings display as appropriate:  
 
 


 
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Table 4: 
Treatment Descriptors 
Trial part 
Cohort 
Cohort label 
Treatment code 
Part 1 A – Monotherapy dose 
escalation 
BNT411 0.05 
(µg/kg) 
Dose escalation BNT411 
0.05 (µg/kg) cohort 
1 
BNT411 0.15 
(µg/kg) 
Dose escalation BNT411 
0.15 (µg/kg) cohort 
2 
BNT411 0.45 
(µg/kg) 
Dose escalation BNT411 
0.45 (µg/kg) cohort 
3 
BNT411 1.2 
(µg/kg) 
Dose escalation BNT411 1.2 
(µg/kg) cohort 
4 
BNT411 2.4 
(µg/kg) 
Dose escalation BNT411 2.4 
(µg/kg) cohort 
5 
BNT411 4.8 
(µg/kg) 
Dose escalation BNT411 4.8 
(µg/kg) cohort 
6 
BNT411 6.0 
(µg/kg) 
Intermediary dose escalation 
BNT411 7.2 (µg/kg) cohort 
7 
BNT411 7.2 
(µg/kg) 
Intermediary dose escalation 
BNT411 6.0 (µg/kg) cohort 
8 
BNT411 9.6 
(µg/kg) 
Dose escalation BNT411 9.6 
(µg/kg) cohort 
9 
Part 1B – combination 
(Atezolizumab + carboplatin + 
etoposide + BNT411) dose 
escalation  
BNT411 
(1.2 µg/kg) 
combination 
therapy 
atezolizumab + carboplatin + 
etoposide + BNT411 
(1.2 µg/kg) Dose escalation 
cohort 
101 
BNT411 
(2.4 µg/kg) 
combination 
therapy 
atezolizumab + carboplatin + 
etoposide + BNT411 
(2.4 µg/kg) Dose escalation 
cohort 
102 
Note: The treatment code will be used in the statistical procedures.  
 
Trial part 
Cohort 
Cohort label 
Treatment code 
Part 1A 
Same as above table 
Same as above table 
Same as above table 
Part 1B 
Atezolizumab 
atezolizumab 1200 mg 
201 
carboplatin 
carboplatin (mg) 
301 
etoposide 
etoposide 100 mg/m2 
401 


 
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BNT411 
BNT411 DL x.x 
50x 
 
For Part 1B, x.x in BNT411 ranges from 1.2 µg/kg to 2.4 µg/kg. 


 
 
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10.4 
Appendix 4: Schedule of activities 
10.4.1 
Dose Escalation Phases (Parts 1A and 1B) 
Table 5 and Table 6, respectively, list all of the assessments to be performed in Parts 1A 
and 1B (dose escalation phases) of the trial. 
 
 
 
 


 
 
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Table 5: 
Schedule of Activities – Part 1A 
Treatment 
Cycle 
Screen
ing 
Cycle 1 to 2 
Cycle 3 to 4 
Cycle 5 to 
N 
Treatment 
discontinu
ation1 
Safety 
follow-
up 1 
Safety 
follow-
up 2 
Surviva
l 
follow-
up2 
Unsched
uled 
Day (D) 
≤21 da
ys 
prior to 
Visit C
1 (D1) 
D1 D
2 
D3
24 
D8 D1
5 
D1 D8 D1
5 
D
1 
D8 D1
5 
- 
30 days 
after 
last 
dose 
60 
days 
after 
last 
dose 
Every 
12 wee
ks  
 
Visit window 
 
±D
3 
- 
+D
2 
±D
1 
±D
1 
±D
3 
±D
1 
±D
1 
±
D
3 
±D
1 
±D
1 
- 
+D5 
±D7 
±D14 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent for 
genetic testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X3 
Physical 
examination4 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X3 
Eye 
examination5 
X 
X6 
 
 
 
 
 
 
 
X6 
 
 
X 
X 
 
 
X7 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X3 
ECHO or 
MUGA scan9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
ECG 
X 
Refer to CTP Section 8.6.3 and Table 1-3 for details on ECG assessments  
CT/MRI scan 
X10 
Refer to CTP Section 8.5.1 for details on Imaging assessments11 
ECOG 
performance 
status12 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X3 
Adverse 
events13 
X 
CONTINUOUS  
X14 
X3 
Prior/concomita
nt medications 
and non-drug 
therapies21 
X 
CONTINUOUS 
X22 
X3 
BNT411 
administration15 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
End of 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
New anti-
cancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Survival follow-
up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
LABORATORY ASSESSMENTS (to be performed up to 3 days before administration days, unless indicated otherwise) 
Hematology 
X16 
X17 X 
X 
X17 X17 X17 X17 X17 X1
7 
X17 X3 
X 
X 
X 
 
X3 


 
 
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Treatment 
Cycle 
Screen
ing 
Cycle 1 to 2 
Cycle 3 to 4 
Cycle 5 to 
N 
Treatment 
discontinu
ation1 
Safety 
follow-
up 1 
Safety 
follow-
up 2 
Surviva
l 
follow-
up2 
Unsched
uled 
Day (D) 
≤21 da
ys 
prior to 
Visit C
1 (D1) 
D1 D
2 
D3
24 
D8 D1
5 
D1 D8 D1
5 
D
1 
D8 D1
5 
- 
30 days 
after 
last 
dose 
60 
days 
after 
last 
dose 
Every 
12 wee
ks  
 
Visit window 
 
±D
3 
- 
+D
2 
±D
1 
±D
1 
±D
3 
±D
1 
±D
1 
±
D
3 
±D
1 
±D
1 
- 
+D5 
±D7 
±D14 
 
Biochemistry 
X16 
X17 X 
X 
X17 X17 X17 X17 X17 X1
7 
X17 X3 
X 
X 
X 
 
X3 
Coagulation 
factors 
X16 
X17 
 
 
X17 X17 X17 X17 X17 X1
7 
X17 X3 
X 
X 
X 
 
X3 
Endocrine18 
X16 
X17 
 
 
 
 
X17 
 
 
X1
7 
 
X3 
X 
 
 
 
X3 
Urinalysis 
X16 
 
 
 
X17 
 
X17 
 
X17 X1
7 
 
X3 
X 
X 
X 
 
X3 
Pregnancy 
test19 
X16 
X17 
 
 
 
 
As indicated clinically per 
investigator’s assessment 
and per local guidelines 
and regulations.  
X 
X 
X 
 
X3 
Serology 16 
X23 
 
 
 
 
 
 
 
 
 
 
 
PK sampling 
(includes blood 
and urine) 
Refer to CTP Table 1-3 for details of PK samplings 
Tumor biopsy, 
biomarkers 
Refer to CTP Table 1-7 for detailed biomarker assessment schedule 
1 
If the patient has to go off treatment per treatment withdrawal criteria (refer to CTP Section 7.1), the treatment discontinuation visit 
should be performed as soon as possible after permanent discontinuation of BNT411. 
2 
Survival follow-up starts after all other protocol required visits have been completed and may be performed as telephone, email, or 
clinic visit. 
3 
Only if relevant or clinically indicated. 
4 
Full physical examination should be performed at screening, thereafter a limited physical examination is performed as indicated by 
the patient’s symptoms, AEs, or other findings as determined by the investigator. Physical examination should be performed before 
drug administration. 
5 
To be performed by an ophthalmologist. Must at least include visual acuity testing, slit-lamp examination and direct or indirect 
ophthalmoscopy to help diagnose cataracts, glaucoma, detached retina, macular degeneration, and cornea injuries. Patients who 
wear glasses must have their baseline visual acuity properly documented. Further examinations such as visual field testing, non-
contact tonometry and retinal tomography can be done if required. 
6 
Eye examination will be done at baseline (during screening), up to 3 days before Cycle 2 and thereafter up to 3 days before every 
third cycle (i.e., C2, C5, C8, C11, etc.). 
7 
The investigator should schedule eye examination with an ophthalmologist if there is suspicion of worsening of the eyesight, or if the 
patient complains about decrease in visual acuity or ocular discomfort. Patients should be referred to an ophthalmologist at the 
investigator’s discretion at any time-point of the trial. 
8 
Temperature, blood pressure, pulse rate and respiratory rate as according to Section 8.6.2 and Table 1-6 of the CTP on BNT411 
administration days. On days when BNT411 is not administered, vital signs only need to be obtained once any time during the visit. 
9 
Evaluation of left ventricular function, either by echocardiogram (ECHO) or multigated acquisition (MUGA) scan, will be performed 
within 21 days prior to Screening and as clinically indicated at other time points. Note: country specific information for Germany, left 
ventricular function should only be assessed by an ECHO scan (see CTP Section 12.2.1). 
10 All patients will have a CT scan with contrast agent or MRI of thorax, abdomen, and pelvis during screening. Head and neck 
imaging is also required for patients with squamous cell carcinoma of the head and neck (SCCHN). Imaging of the pelvis is not 
required for patients with SCCHN but is strongly recommended. If a CT scan or MRI has been performed within 21 days before the 
Cycle 1 Day 1 visit as part of standard procedures, then this scan will be acceptable as a screening scan for the trial. If brain 
metastases/tumors are indicated, a CT scan or MRI of the brain will be performed within 21 days before the Cycle 1 Day 1 visit. 
Scans that exceed the 21-day window may be used for trial enrollment with sponsor approval. 


 
 
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11 On-treatment imaging will be performed at Week 6 (+7 days), every 6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) 
thereafter until disease progression is assessed by the investigator (unless the investigator elects to continue treatment [see CTP 
Section 8.5.1 for conditions of continued treatment]), withdrawal of consent, trial termination by the sponsor, or death, whichever 
occurs first, regardless of whether patients start a new anti-cancer therapy. Refer to CTP Sections 10.5 and 10.6 for RECIST 1.1. 
and iRECIST imaging and treatment guidelines. 
12 ECOG status should be assessed before drug administration. 
13 Adverse events (AEs) and serious adverse events (SAEs) should be reported from the time of signing the informed consent to 
60 days (±7 days) after the patient receives the last dose of BNT411. 
14 Suspected BNT411-related AEs only. Furthermore, in Germany only, all SAEs that occur in the patient throughout his or her lifetime 
should be reported – refer to CTP for further details. 
15 Patients who experience a delay in the administration of BNT411 should return to the clinic at least every 2 weeks (±3 days) and 
assessments listed under ‘unscheduled visit’ should be performed and reported in the eCRF. Unscheduled visit assessments should 
be performed at the investigator’s discretion. 
16 All labs at the screening visit must be obtained within 7 days of Cycle 1 Day 1. All lab assessments except for PK and biomarkers 
are done locally. 
17 Laboratory samples should be obtained up to 3 days before treatment administration. 
18 TSH, free-T3 and free-T4 will only be measured at screening, Cycle 1 Day 1, Cycle 2 Day 1, and on Day 1 of every evenly 
numbered cycle thereafter. 
19 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The 
frequency of testing during treatment phase may depend on clinical indication per investigator's assessment and may also depend 
on local guidelines and regulations. 
20 Medical history includes cancer history. 
21 Prior/Concomitant Medications and Non-Drug Therapies include all anti-cancer pre-treatments. 
22 Prior/Concomitant Medication and Non-Drug therapies only for BNT411 related AEs. 
23 Country specific procedure for Germany: To confirm that a patient would be eligible to participate in the trial, an active infection with 
HIV/Hepatitis B or C should be ruled out by serum blood test of hepatitis B surface antigen (HBsAg), antibody to hepatitis B core 
antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against 
HIV-1 and -2 (anti-HIV 1/2). 
24 The visit window of +2d on Day 3 should only be used if absolutely necessary due to immune phenotyping. 
 
 


 
 
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Table 6 
Schedule of Activities – Part 1B 
Treatment 
Cycle 
Screeni
ng 
Cycle 1-2 
Cycle 3- 4 
 
Cycle 5–N 
Treatme
nt 
disconti
nuation1 
Safety 
follow-up 
1 27 
Safety 
follow-up 
2 27 
Surviva
l follow-
up2 
Unsched
uled 
Day (D) 
≤21 day
s prior 
to 
Visit C1 
(D1) 
D1 D2 D3 D8 D1
5 D1 D2 D3 D8 D1
5 D1 D2 D8 D1
5 
30 days 
after last 
dose 
60 days 
after last 
dose 
Every 
12 week
s  
Visit window 
 
±D
3 
- +D2 ±D
1 
±D
1 
±D
3 
- +D
2 ±D1 ±D
1 
±D
3 
- ±D
1 
±D
1 
+D5 
±D7 
±D14 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
genetic testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X3 
Physical 
Examination4 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X2.,3 
Eye 
Examination5 
X 
X6 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
X 
X 
 
 
X7 
Vital Signs8 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X3 
ECHO or 
MUGA scan9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
ECG 
X 
Refer to CTP Section 8.6.3 and Table 1-3 for details on ECG assessments 
CT/MRI Scan 
X10 
Refer to CTP Section 8.5.1 for details on Imaging assessments11 
ECOG 
Performance 
Status12 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X3 
Adverse 
Events13 
X 
CONTINUOUS 
X14 
X3 
Prior/Concomit
ant 
Medications 
and Non-Drug 
Therapies24 
X 
CONTINUOUS 
X25 
X3 
BNT411 
Administration1
5 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Atezolizumab 
Administration1
6 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Carboplatin 
Administration1
7 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etoposide 
Administration1
7 
 
X X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 
If the patient has to go off treatment per treatment withdrawal criteria (refer CTP Section 7.1), the treatment discontinuation visit 
should be performed as soon as possible after permanent discontinuation of BNT411. A separate treatment discontinuation visit 
should also be done after discontinuation of atezolizumab, carboplatin and etoposide, if it occurs ≥21 days later than BNT411 (this 
visit will be entered as unscheduled visit in the eCRF). 
2 
Survival follow-up starts after all other protocol required visits have been completed and may be performed as telephone, email, or 
clinic visit. 
3 
Only if relevant or clinically indicated. 
4 
Full physical examination should be performed at screening, thereafter a limited physical examination is performed as indicated by 
the patient’s symptoms, AEs, or other findings as determined by the investigator. 
5 
To be performed by an ophthalmologist. Must at least include visual acuity testing, slit-lamp examination exam and direct or indirect 
ophthalmoscopy to help diagnose cataracts, glaucoma, detached retina, macular degeneration, and cornea injuries. Patients who 
wear glasses must have their baseline visual acuity properly documented. Further examinations such as visual field testing, non-
contact tonometry and retinal tomography can be done if required. 
6 
Eye examination will be done at baseline (during screening), up to 3 days before Cycle 2 and thereafter up to 3 days before every 
third cycle (i.e., C2, C5, C8, C11, etc.) 
7 
The investigator should schedule an eye examination with an ophthalmologist if there is suspicion for worsening of the eyesight, or if 
the patient complains about decrease in visual acuity or ocular discomfort. Patients should be referred to an ophthalmologist at the 
investigator’s discretion at any time-point of the trial. 
8 
Temperature, blood pressure, pulse rate and respiratory rate as according to CTP Section 8.6.2 and Table 1-6 on BNT411 
administration days. On days when BNT411 is not administered, vital signs only need to be obtained once any time during the visit. 
Treatment 
Cycle 
Screeni
ng 
Cycle 1-2 
Cycle 3- 4 
 
Cycle 5–N 
Treatme
nt 
disconti
nuation1 
Safety 
follow-up 
1 27 
Safety 
follow-up 
2 27 
Surviva
l follow-
up2 
Unsched
uled 
Day (D) 
≤21 day
s prior 
to 
Visit C1 
(D1) 
D1 D2 D3 D8 D1
5 D1 D2 D3 D8 D1
5 D1 D2 D8 D1
5 
30 days 
after last 
dose 
60 days 
after last 
dose 
Every 
12 week
s  
Visit window 
 
±D
3 
- +D2 ±D
1 
±D
1 
±D
3 
- +D
2 ±D1 ±D
1 
±D
3 
- ±D
1 
±D
1 
+D5 
±D7 
±D14 
Prophylactic 
cranial 
irradiation 
 
 
 
 
 
 
 
 
 
 
 
X18 
 
 
 
 
 
 
 
 
End of 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
New anti-
cancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Survival follow-
up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
LABORATORY ASSESSMENTS (to be performed up to 3 days before administration days, unless indicated otherwise) 
Hematology 
X19 
X20 X 
X X20 X20 X20 
 
 
X20 X20 X20 
 
X20 X20 
X 
X 
X 
 
X3 
Biochemistry 
X19 
X20 X 
X X20 X20 X20 
 
 
X20 X20 X20 
 
X20 X20 
X 
X 
X 
 
X3 
Coagulation 
factors 
X19 
X20  
 
X20 X20 X20 
 
 
X20 X20 X20 
 
X20 X20 
X 
X 
X 
 
X3 
Endocrine21 
X19 
X20  
 
 
 
X20 
 
 
 
 
X20 
 
 
 
X 
 
 
 
X3 
Urinalysis 
X19 
 
 
 
X20 
 
X20 
 
 
 
X20 X20 
 
 
 
X 
X 
X 
 
X3 
Pregnancy 
Test22 
X19 
X20  
 
 
 
As indicated clinically per 
investigator’s assessment and per 
local guidelines and regulations. 
X 
X 
X 
 
X3 
Serology 19 
X26 
 
 
 
 
 
 
 
 
 
 
 
PK Sampling 
(includes blood 
and urine) 
Refer to CTP Table 1-3 for details of PK samplings 
Tumor biopsy, 
biomarkers 
Refer to CTP Table 1-7 for detailed biomarker assessment schedule 


 
 
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9 
Evaluation of left ventricular function, either by echocardiogram (ECHO) or multigated acquisition (MUGA) scan, will be performed 
within 21 days prior to Screening and as clinically indicated at other time points. Note: country specific information for Germany: left 
ventricular function should be assessed by an ECHO scan (see CTP Section 12.2.1) 
10 All patients will have a CT scan with contrast or MRI of thorax, abdomen, and pelvis during screening. Head and neck imaging is 
also required for patients with squamous cell carcinoma of the head and neck (SCCHN). Imaging of the pelvis is not required for 
patients with SCCHN but is strongly recommended. If a CT scan or MRI has been performed within 21 days prior to visit Cycle 1 
Day 1 as part of standard procedure, it is acceptable as a screening scan for the trial. If there is suggestion of brain 
metastases/tumors, a CT scan or MRI of the head and neck will be performed within 21 days prior to the Cycle 1 Day 1 visit. Scans 
that exceed the 21-day window may be used for trial enrollment with sponsor approval. 
11 On-treatment imaging will be performed at Week 6 (+7 days), every 6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) 
thereafter until disease progression is assessed by the investigator (unless the investigator elects to continue treatment [see CTP 
for conditions of continued treatment]), withdrawal of consent, trial termination by the sponsor, or death, whichever occurs first, 
regardless of whether patients start a new anti-cancer therapy. Refer to CTP Sections 10.5 and 10.6 for RECIST 1.1. and iRECIST 
imaging and treatment guidelines. 
12 ECOG status should be assessed before drug administration. 
13 Adverse events (AEs) and serious adverse events (SAEs) should be reported from the time of signing the informed consent to 
60 days (±7 days) after the patient receives the last dose of BNT411, or atezolizumab, or carboplatin or etoposide, whichever 
occurs later. 
14 Suspected BNT411 related AEs only. Except for Germany and Spain, where AEs related to atezolizumab, carboplatin, and 
etoposide should also be reported. Furthermore, in Germany only, all SAEs that occur in the patient throughout his or her lifetime 
should be reported – refer to CTP Table 1-5 and Section 10.3.4 for further details. 
15 Patients who experience a delay in the administration of BNT411 should return to the clinic at least every 2 weeks (±3 days) and an 
unscheduled visit should be performed and reported in the eCRF. Unscheduled visit assessments should be performed at the 
investigator’s discretion. 
16 After discontinuation of chemotherapy, atezolizumab will be administered in combination with BNT411. 
17 The recommended number of chemotherapy cycles is 4. If the investigator decides to administer more than four cycles, this should 
be discussed with the Medical Monitor. 
18 After 4 cycles, prophylactic cranial irradiation (PCI) is permitted as per local guidelines and will be reported on the cancer 
radiotherapy eCRF. No systemic anti-cancer therapies should be administered concurrently with PCI. A delay of ≤21 days in 
administering systemic anti-cancer therapies due to PCI is not considered a protocol deviation. 
19 All labs at the screening visit must be obtained within 7 days of Cycle 1 Day 1. All lab assessments except for PK and biomarkers 
are done locally. 
20 Laboratory samples should be obtained up to 3 days before treatment administration. 
21 TSH, free-T3 and free-T4 will only be measured at screening, Cycle 1 Day 1, Cycle 2 Day 1, and on Day 1 of every evenly 
numbered cycle thereafter. 
22 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The 
frequency of testing during treatment phase may depend on clinical indication per investigator's assessment and may also depend 
on local guidelines and regulations. Pregnancy testing should also be done after discontinuation of atezolizumab, carboplatin, and 
etoposide if it occurs ≥21 days later than BNT411. 
23 Medical history includes cancer history. 
24 Prior/Concomitant Medications and Non-Drug Therapies include all anti-cancer pre-treatments. 
25 Prior/Concomitant Medications and Non-Drug Therapies only for BNT411 related AEs. 
26 Country specific procedure for Germany: an active infection with HIV/Hepatitis B or C should be ruled out by serum blood test of 
hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-
HBs), antibody against hepatitis C virus (anti-HCV), antibody against HIV-1 and -2 (anti-HIV 1/2). 
27 A separate safety follow-up visit should also be done after discontinuation of atezolizumab, carboplatin and etoposide, if it occurs 
≥21 days later than BNT411 (this visit will be entered as unscheduled visit in the eCRF). 
28 The visit window of +2d on Day 3 should only be used if absolutely necessary due to immune phenotyping. 
 


 
 
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10.5 
Appendix 5: 
Dose escalation table 
Number of evaluable patients with 
DLT at a given dose level after the 
first treatment cycle 
Escalation decision rule 
0 out of 3 
OR 
1 out of 6  
Enter patients at the next higher dose level  
1 out of 3  
Enter more patients at this dose level to a total of at least six 
evaluable patients or two patients with DLT  
2 out of 3  
OR  
at least 2 out of 6 
Dose escalation will be stopped, the MTD will be considered to be 
reached at the one before the last dose level explored. The sponsor 
will decide, based on a discussion between the investigators and 
the sponsor at a dose escalation meeting, if additional patients 
need to be enrolled and at which dose to finalize the trial 
Any condition which would require 
further clarification of safety 
A cohort of 6 patients can eventually be extended and more 
patients can be enrolled in a cohort if decided by the sponsor based 
on a discussion between the investigators and the sponsor at a 
dose escalation meeting 
DLT = dose-limiting toxicity; MTD = maximal tolerated dose. 
 
The dose escalation will potentially (dependent on data collected during the trial) evaluate 
BNT411 at eight main dose levels as shown in Appendix 6. 
 
 


 
 
BioNTech SE 
Confidential 
Statistical Analysis Plan (SAP) 
BNT411-01 
Page 55 of 55 
Version: Final 2.0 
Date: 21 Feb 2024 
 
 
10.6 
Appendix 6: 
BNT411 dose increments 
 
Dose level 
Dose of BNT411* 
(μg/kg/administration) 
Dose increment* 
1** 
0.05 
Starting dose 
2** 
0.15 
200% 
3** 
0.45 
200% 
4 
1.2 
166% 
5 
2.4 
100% 
6 
4.8 
100% 
7 
9.6 
100% 
8 
16.0 
66% 
* Can be reduced or increased as a function of the observed biologic activity and based on other data generated during 
the trial for dose optimization. 
** Accelerated titration (single-patient cohorts). Will be expanded to 3+3-patient cohorts in case of occurrence of 
grade ≥2 toxicities, or the occurrence of DLTs, or based on the decision of the sponsor’s SRC based on safety data 
generated. 
 
In addition to the above mentioned dose level, BioNTech proposes seven optional, 
intermediate dose levels at 0.075, 0.225, 0.9, 1.8, 3.6, 7.2 and 12.8 µg/kg.