Open-label, Randomized Phase II Trial With BNT111 and Cemiplimab in Combination or as Single Agents in Patients With Anti-PD-1-refractory/Relapsed, Unresectable Stage III or IV Melanoma
Phase: PHASE2
Conditions: Melanoma Stage III, Melanoma Stage IV, Unresectable Melanoma
Sponsor: BioNTech SE

 
Page 1 of 133 
 
Statement of Compliance: This trial will be conducted in according to this protocol, the ethical principles that have their 
origin in the Declaration of Helsinki, good clinical practice (GCP), and applicable regulatory requirements. 
Confidentiality Statement: The information contained in this document is the property and copyright of BioNTech SE. 
Therefore, this document is provided in confidence to the recipient. No information contained herein shall be published, 
disclosed or reproduced without prior written approval of the proprietor(s). 
 
 
CLINICAL TRIAL PROTOCOL 
BNT111-01 
 
Version: 
7.0 
Date: 09 FEB 2023 
Sponsor: 
BioNTech SE 
 
 
Trial title: 
Open-label, randomized Phase II trial with BNT111 and 
cemiplimab in combination or as single agents in patients with 
anti-PD-1/PD-L1-refractory/relapsed, unresectable Stage III or IV 
melanoma 
Trial phase: 
Phase II 
Indication: 
Melanoma (Stage III and IV) 
Product: 
BNT111, cemiplimab 
Coordinating investigator:  Paolo Ascierto 
Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131, 
Naples, Italy 
Trial sites: 
This will be a multi-site trial with approximately 60 sites in up to 
15 countries 
Sponsor’s responsible 
person: 
Özlem Türeci, MD, Chief Medical Officer, BioNTech SE 
Sponsor address: 
BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany 
Phone: +49 (0)6131 9084 – 0 
Clinical research 
organization (CRO): 
ICON plc, South County Business Park, Leopardstown, Dublin 18, 
D18 X5R3, Ireland 
Regulatory identifiers: 
IND: 25176; EudraCT: 2020-002195-12; NCT: 04526899 
Medical monitor: 
Medical monitor name and contact information will be provided 
separately 
 

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Population 
180 patients with anti-PD-1/PD-L1-refractory/relapsed, unresectable Stage III or IV 
melanoma. 
Key inclusion criteria 
Patients are only eligible to be enrolled in the trial if they meet the following criteria: 
• 
Patients must have histologically confirmed, unresectable Stage III or IV 
(metastatic) cutaneous melanoma and measurable disease by RECIST 1.1. 
• 
Patients must have confirmed disease progression on/after approved anti-
PD-1/PD-L1 regimen for melanoma as defined by RECIST 1.1. 
− 
Previous exposure to approved anti-PD-1/PD-L1 containing regimen for at least 
12 consecutive weeks and 
− 
Current radiological progression to be confirmed by two scans 4 to 12 wks 
apart. If progression is accompanied by new symptoms, or deterioration of 
performance status (PS) not attributed to toxicity, one scan is sufficient and 
− 
Inclusion into this trial must be within 6 months of confirmation of disease 
progression on anti-PD-1/PD-L1 treatment, regardless of any intervening 
therapy. 
• 
Eastern Cooperative Oncology Group (ECOG) PS ≤ 1. 
• 
Patients must have serum lactate dehydrogenase (LDH) ≤ upper limit of normal 
(ULN). 
Key exclusion criteria 
Patients are excluded from the trial if they present any of the following criteria: 
• 
History of uveal, acral, or mucosal melanoma. 
• 
Ongoing or recent evidence (within the last 5 years) of significant autoimmune 
disease that required treatment with systemic immunosuppressive treatments 
which may pose a risk for irAEs. 
Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related 
hypothyroidism who are in remission, or on a stable dose of thyroid-replacement 
hormone, vitiligo, or psoriasis may be included. 
• 
Current use or use within 3 months prior to trial enrollment of systemic immune 
suppression including: 
− 
Use of chronic systemic steroid medication (up to 5 mg/day prednisolone 
equivalent is allowed); patients using physiological replacement doses of 
prednisone for adrenal or pituitary insufficiency are eligible, 
− 
Other clinically relevant systemic immune suppression. 

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Trial treatments 
BNT111 will be given as intravenous (IV) injection at a dose of
µg total ribonucleic acid 
(RNA) for the first dose and subsequently at a dose of 
 µg total RNA. BNT111 will be 
given once-weekly for the first 6 wks, followed by treatments once every 3 wks (±3 d). 
Cemiplimab will be given once every 3 wks (±3 d) as IV infusion at a dose of
mg. 
Cemiplimab will be administered after administration of BNT111 with at least 30 min 
interval. 
For further details of trial treatment schedules, see Section 6.2. 
 
CCI
CCI
CCI

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1.2 
Schema (graphical representation of the trial) 
 
 
Figure 1: 
Trial schema 
Abbreviations: DCR = disease control rate; DOR = duration of response; mon = months; N,n = number of patients; ORR 
= objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; 
RECIST = Response Evaluation Criteria in Solid Tumors; TTR = time to response. 
 

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e 
After the last trial visit, information on survival status and new anti-cancer therapy will be collected via phone calls, patient medical records, and/or clinic visits approximately every 3 mon until death 
(unless the patient withdraws consent for survival follow-up or the sponsor terminates the trial). If a patient asks to be withdrawn from survival follow-up, this request must be documented in the 
source documents and signed by the investigator. 
f 
"n" represents the number of the respective cycle (e.g., C4 means fourth cycle of treatment). 
g 
Visit CnD1 should occur 21 (± 3) d after the first day (i.e., treatment visit) of the previous cycle. 
h 
Informed consent must be documented before any trial-specific screening procedure is performed. 
i 
Eligibility should be confirmed and documented in the eCRF. This should be performed when all screening results are available and within 21 d after initiation of screening. 
j 
Underlying disease history should include histology, TNM stage at diagnosis (including which AJCC edition), prior anti-cancer therapies/procedures, date of last progression. 
k 
BRAF V600 mutation status may be obtained from medical history data. 
l 
TNM staging at the time of trial entry to be performed according to AJCC 8th edition. 
m 
Concomitant medication and therapy includes any therapies (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
in addition to protocol-mandated trial treatment from 28 d prior to initiation of trial treatment until the SFU2 visit. 
n 
Vital signs (body temperature, pulse rate, respiratory rate, and blood pressure) should be measured within 60 min prior to the administration of the trial treatment(s) and at 30 (±10) min, 
60 (±10) min, 4 h (±10 min), and 6 h (±10 min) after administration, or if clinically indicated (see Section 8.2.3 for guidelines on reduction or expansion of these time points). 
o 
At screening and at EoT assessments must include a full physical examination. Record abnormalities observed on the respective eCRF pages as appropriate. For all subsequent physical 
examinations perform a limited, symptom-directed examination at specified time points and as clinically indicated at other time points. Record new or worsened clinically significant abnormalities on 
the AE eCRF. 
p 
Single 12-lead ECG recordings will be obtained during screening, at EoT, and as clinically indicated at other time points. Patients should be resting in a supine position for ≥ 10 min prior to ECG 
recording. The interpretation of the ECG recording will be done locally by the investigator. 
q 
Tumor response will be measured by RECIST 1.1 / iRECIST. Patients will undergo tumor assessments at screening, every 6±1 wks for the 3 mon after trial treatment start, every 9±1 wks for the 
next 9 mon, and every 12±2 wks thereafter, regardless of dose delays, until (confirmed) disease progression (even if the patients discontinue trial treatment for other reasons) or until the start of 
next-line anti-cancer therapy (whichever occurs first). An extra scan should be scheduled if clinically indicated. Patients in Arms 2 and 3 who experience (confirmed) disease progression under 
single-agent treatment may be offered addition of the respective other compound to the ongoing treatment. In such cases, tumor assessments are to continue, and additional images should be 
collected in accordance with the imaging schedule and modalities outlined in Section 1.3.2. 
r 
All measurable and evaluable lesions should be assessed at screening and target as well as non-target lesions identified and documented following RECIST 1.1 criteria. Tumor assessments, 
including brain imaging, performed as standard of care prior to obtaining informed consent and within 28 d prior to randomization do not have to be repeated at screening. Radiological progression 
to be confirmed by two scans, 4 to 12 wks apart. If progression is accompanied by new symptoms or deterioration of PS not attributed to toxicity, one scan is sufficient. 
s 
Any brain lesions present at screening must be stable as per eligibility criteria and should be followed and assessed at all subsequent tumor assessment visits. Brain imaging performed as standard 
of care prior to obtaining informed consent and within 28 d prior to randomization do not have to be repeated at screening. If no brain lesions are present at screening, brain imaging does not need 
to be repeated, only if clinically indicated as per investigator judgment. Brain imaging should be done by MRI, only in the case of a contra-indication for MRI, a contrast-enhanced CT brain scan will 
be acceptable. 
t 
After informed consent has been obtained, all AEs will be documented on the eCRF, and all SAEs should be reported to the sponsor within the appropriate time frame. All AEs will be reported until 
90 d after the last dose of trial treatment (i.e., SFU2 visit). In addition, the sponsor should be notified (even after SFU2 visit), if the investigator becomes aware of any SAE that is believed to be 
related to prior exposure to trial treatment or a trial procedure. 
u 
Patient-reported outcomes/quality of life assessment questionnaires must be completed before any assessments are done or any treatment is given on the dosing day. Patients will provide 
PRO/QoL assessment during trial visits at baseline (C1D1 prior Treatment), C2D1, C3D1, C4D1, every 9±1 wks for the next 9 mon, and every 12±2 wks thereafter until SFU1. 

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v 
Randomization must be done before administration of trial treatment. 
w 
Treatment with BNT111 must be initiated no later than 7 d after confirmed eligibility. After administration of BNT111, an initial observation time of at least 6 h is required (see Section 6.8.4.1). 
Treatment is to be continued up to 24 mon or until confirmed disease progression, patient withdrawal of consent or unacceptable toxicity. 
x 
Treatment with cemiplimab must be initiated no later than 7 d after confirmed eligibility. Cemiplimab will be given according to the valid Prescribing Information in the country. The first administration 
of cemiplimab will be on Cycle 1 Day 1, followed by every 3 wks (±3 d) thereafter. Cemiplimab will be administered after administration of BNT111 with at least a 30 min interval (if feasible, both trial 
drugs should be given on the same day, a maximal window of 1 wk between administrations would be allowed). There should be an initial observation time of first administration of cemiplimab. 
From second administration of cemiplimab, no observation time is stipulated with reference to cemiplimab (local protocol should be followed). Treatment to be continued up to 24 mon or until 
confirmed disease progression, unacceptable toxicity, or patient withdrawal of consent. 
y 
Hematology assessment should be performed at screening, ≤ 24 h prior to each drug administration, on treatment discontinuation, and at 30 d SFU1 or if clinically indicated (see Section 10.2 for 
assessments to be done). Samples should be assessed by both the central and local laboratory. Results of local laboratory assessments need to be reviewed prior to drug administration. 
Unscheduled assessments can be performed locally, or sent to the central laboratory. 
z 
Serology assessments for patients will include HBsAG, anti-HBc, anti-HBs and anti-HCV. HIV (1/2) testing required if the patient has never been tested for HIV or if testing was prior to primary 
cancer diagnosis or performed ≥ 12 mon prior to trial start. Samples should be shipped to a central laboratory. 
aa 
Chemistry panel should be performed at screening, ≤ 24 h prior to each drug administration, on treatment discontinuation, and at 30 d SFU1 or if clinically indicated (see Section 10.2 for 
assessments to be done). Samples should be assessed by both the central and local laboratory. Results of local laboratory assessments need to be reviewed prior to drug administration. 
Unscheduled assessments can be performed locally, or sent to the central laboratory. 
bb 
Coagulation assessments to be performed at screening, at EoT and if clinically indicated (see Section 10.2 for assessments to be done). Samples should be shipped to a central laboratory; 
unscheduled assessments can be performed locally. 
cc 
TSH and free T4 will be assessed at screening, once every two cycles, on treatment discontinuation, at SFU1, and as clinically indicated. Samples should be shipped to a central laboratory and, if 
required, to the local laboratory. Unscheduled assessments can be performed locally, or sent to the central laboratory. 
dd 
All WOCBP will have a serum pregnancy test at screening, within 10 d prior to initiation of trial treatment. Urine or serum pregnancy test will be performed at the start of every cycle (starting from 
Cycle 2) or according to local requirements (in cases where more frequent testing is required) and at EoT and SFU1. If a urine pregnancy test is positive, hold dosing and confirm the result with a 
serum pregnancy test.  
ee 
For urinalysis assessments dipsticks are to be used, microscopic evaluation should be performed per investigator’s discretion. Tests will be done locally with material provided by the central 
laboratory. 
ff 
Peripheral blood for assessment of cytokines will be drawn from all patients of Arms 1 and 2 prior to administration of BNT111 and 4 to 6 h post application. The tests will be performed centrally. 
gg 
Only applicable for Cycle 3. 
hh 
At selected trial sites, as part of the biomarker sub-study, blood for isolation of PBMCs for analysis of cellular immune responses should only be taken in patients randomized to Arm 1 or 2 at the 
following timepoints: prior to the first dosing with BNT111, on C3D1, C5D1, C8D1 and every six cycles afterwards, and at EoT. At C5D1, blood draws may be replaced by a leukapheresis.  
ii 
At selected trial sites, as a part of the biomarker sub-study, three paired biopsies are to be taken in patients randomized to Arm 1 or 2 at the following timepoints: prior to the first dosing with 
BNT111, under treatment at approximately 6 to 8 wks after treatment start, and optionally at progression, if considered clinically feasible by the investigator. The tumor sample can be from a core 
biopsy or from resected tumor tissue. Fine needle aspirates and cytological specimens are not acceptable. For patients who are part of the biomarker sub-study, if a biopsy is not taken at baseline 
prior to the first dose of BNT111, no subsequent biopsies are to be taken during the trial as part of the biomarker sub-study procedures. It is recommended to perform the biopsy on progression only 
if 4 wks or more have elapsed since the last biopsy (on-treatment biopsy). If the time is shorter, no biopsy on progression should be taken. 
For other trial sites, if any biopsies or resections are to be performed as part of standard clinical care, tissue samples from such procedures should be provided (if feasible) for the sponsor for 
biomarker testing. 

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jj 
All patients must provide a tumor tissue sample (formalin fixed paraffin-embedded [FFPE] blocks/slides) from a fresh biopsy collected before Visit C1D1, or archival tissue, which should be shipped 
to the central laboratory only following confirmation of eligibility. The archival tissue can be an FFPE block (not older than 3 years) or freshly cut slides (special storage conditions and immediate 
shipment to a specialty lab are required), with tissue preferably derived from advanced disease stage. The fresh or archival tissue must have been taken using core needle biopsy (18-gauge needle 
or larger) or surgical excision. Note: fine needle aspirate biopsies will not be acceptable.  
kk 
Optional whole blood sampling at screening if patient has signed ICF for pharmacogenomic analyses. 
ll 
At selected trial sites, as part of the biomarker sub-study, a blood sample for HLA typing should be taken which should be stored at -80°C. 
 
Abbreviations: AJCC = American Joint Committee on Cancer; d = day; CT = computer tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; 
d = day(s); eCRF = electronic case report form; EoT = end of treatment; FU = follow-up; h = hour(s); HBc = hepatitis B core antigen; HBs = hepatitis B surface antigen; HBsAG = hepatitis surface 
antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; ICF = informed consent form; LTFU = Lost to follow-up; mon = month; MRI = magnetic 
resonance imaging; PGIC= Patient Global Impression of Change; PGIS= Patient Global Impression of Severity; PRO/QoL = patient-reported outcomes/quality of life; SOA = schedule of activity; 
T4 = Thyroxine; TNM = tumor, node, metastasis; TSH = thyroid-stimulating hormone; wks = week(s); WOCBP = women of childbearing potential. 
 
 

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f 
"n" represents the number of the respective cycle (e.g., AOC3 means the third cycle of add-on therapy). 
g 
Visit X should occur 21 (± 3) d after the first day (i.e., treatment visit) of the previous cycle. 
h 
Continued record of concomitant medication and therapy after add-on, includes any therapies (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated trial treatment until the SFU2 visit. 
i 
If baseline and AOC1D1 are on the same day, assessment only needs to be taken once. 
j 
Vital signs (body temperature, pulse rate, respiratory rate, and blood pressure) should be measured prior to the administration of the trial treatments, and at 30 (±10) min, 60 (±10) min, 4 h 
(±10 min), and 6 h (±10 min) after administration, or if clinically indicated (see Section 8.2.3 for guidelines on reduction or expansion of these time points). 
k 
At baseline and at EoT assessments must include a full physical examination. Record abnormalities observed on the respective eCRF pages as appropriate. For all subsequent physical 
examinations perform a limited, symptom-directed examination at specified time points and as clinically indicated at other time points. Record new or worsened clinically significant abnormalities on 
the AE eCRF. 
l 
Single 12-lead ECG recordings will be obtained during baseline, at EoT, and as clinically indicated at other time points. Patients should be resting in a supine position for at least 10 min prior to 
ECG recording. The interpretation of the ECG recording will be done locally by the investigator. 
m 
Baseline image may not be older than 21 d prior to AOC1D1. Target lesions and non-target lesions can be redefined at baseline assessment for add-on therapy. 
n 
Tumor response will be measured by RECIST 1.1 / iRECIST. Patients will undergo tumor assessments every 6±1 wks for the 3 mon after start of add-on treatment, every 9±1 wks for the next 
9 mon, and every 12 ± 2 wks thereafter, regardless of dose delays, until (confirmed) disease progression (even if the patients discontinue trial treatment for other reasons) or until the start of next-
line anti-cancer therapy (whichever occurs first). An extra scan should be scheduled if clinically indicated. 
o 
Patients with new brain lesions identified at baseline for add-on therapy cannot continue with add-on therapy, patients with known brain lesions during monotherapy (Arm 2 or 3) should have stable 
brain lesions at baseline for add-on therapy, the lesions should be followed and assessed at all subsequent tumor assessments. If no brain lesions are present at baseline assessment for add-on 
therapy, brain imaging does not need to be repeated, only if clinically indicated as per investigator judgment. 
p 
All AEs will be documented in the eCRF, and all SAEs should be reported to the sponsor within the appropriate time frame. All AEs will be reported until 90 d after the last dose of trial treatment 
(i.e., SFU2 visit). In addition, the sponsor should be notified (even after SFU2 visit), if the investigator becomes aware of any serious AE that is believed to be related to prior exposure to trial 
treatment or a trial procedure. 
q 
Patient-reported outcomes/quality of life assessment questionnaire must be completed before any assessments are done or any treatment is given on the dosing day. Patients will provide PRO/QoL 
assessments during trial visits at baseline for add-on therapy, AOC2D1, AOC3D1, AOC4D1, every 9±1 wks for the next 9 mon, and every 12±2 wks thereafter until SFU1. 
r 
After administration of BNT111, initially an observation time of at least 6 h is required (see Section 6.8.4.1). Treatment to be continued up to 24 mon or until confirmed disease progression, 
unacceptable toxicity or patient withdrawal of consent. 
s 
Weekly dosing applicable to patients who have received cemiplimab monotherapy (Arm 3). Also applicable to patients who have received BNT111 monotherapy (Arm 2) if the patient has previously 
received ≤ 4 doses of BNT111. 
t 
Cemiplimab will be given according to valid Prescribing Information in the country every 3 wks (±3 d). The first administration of cemiplimab will be on Cycle 1 Day 1, followed by every 3 wks (±3 d) 
thereafter. Cemiplimab will be administered subsequently after administration of BNT111 with at least 30 min interval. There should be an initial observation time of 6 h after administration of 
cemiplimab. From the second administration of cemiplimab, no observation time is stipulated with reference to cemiplimab (local protocol should be followed). Treatment to be continued up to 
24 mon or until confirmed disease progression, unacceptable toxicity or patient withdrawal of consent. 
u 
Hematology assessment should be performed at baseline for add-on therapy, ≤ 24 h prior to each drug administration, on treatment discontinuation, and at 30 d SFU1 or if clinically indicated (see 
Section 10.2 for assessments to be done). Samples should be assessed by both the central and local laboratory. Results of local laboratory assessments need to be reviewed prior to drug 
administration. Unscheduled assessments can be performed locally or sent to the central laboratory. 

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v 
Chemistry panel should be performed at baseline for add-on therapy, ≤ 24 h prior to each drug administration, on treatment discontinuation, and at 30 d SFU1 or if clinically indicated (see 
Section 10.2 for assessments to be done). Samples should be assessed by both the central and local laboratory. Results of local laboratory assessments need to be reviewed prior to drug 
administration. Unscheduled assessments can be performed locally or sent to the central laboratory. 
w 
Coagulation assessments are to be performed at baseline for add-on therapy, at EoT, and if clinically indicated (see Section 10.2 for assessments to be done). Samples should be shipped to a 
central lab; unscheduled assessments can be performed locally. 
x 
TSH and free T4 will be assessed at baseline for add-on therapy, once every two cycles, on treatment discontinuation, and at SFU1. Samples should be shipped to a central laboratory and, if 
required, to the local laboratory. Unscheduled assessments can be performed locally or sent to the central laboratory. 
y 
All WOCBP will have a serum pregnancy test at baseline, within 10 d prior to initiation of trial treatment. Urine or serum pregnancy test will be performed at the start of every cycle (starting from 
Cycle 2) or according to local requirements (in cases where more frequent testing is required) and at EoT and SFU1. If a urine pregnancy test is positive, hold dosing and confirm the result with a 
serum pregnancy test. 
z 
For urinalysis assessments dipsticks are to be used, microscopic evaluation should be performed per investigator’s discretion. 
aa 
Peripheral blood for assessment of cytokines will be drawn from all patients prior to administration of BNT111 and 4 to 6 h post application. The tests will be performed centrally. This is only 
applicable for the first three cycles with BNT111, if cytokines were collected in Arm 2 for three cycles, no further cytokines need to be collected. 
bb 
Only applicable for Cycle 3. 
cc 
At selected trial sites, as part of the biomarker sub-study, blood for isolation of PBMCs for analysis of cellular immune responses should be taken during baseline (unless previous blood draw was 
< 7 wks, then the baseline sample can be omitted) and on AOC3D1, AOC5D1, AOC8D1, every six cycles afterwards, and at EoT. This applies only to patients in Arm 2 and Arm 3 add-on therapy 
who have consented to the biomarker sub-study. 
dd 
Should be done within 3 wks after BNT111 administration. 
ee 
Only for patients entering Arm 3 add-on therapy who have not yet provided a sample for HLA typing: a blood sample for HLA typing should be taken which should be stored at -80°C. 
ff 
At selected trial sites, as part of the biomarker sub-study, optional biopsies at baseline, under treatment and at progression will be performed. The tumor biopsy will be performed, if considered 
clinically feasible by the investigator. This applies only to patients in Arm 2 and Arm 3 add-on therapy who have consented to the biomarker sub-study. The tumor sample can be from a core biopsy 
or from resected tumor tissue. Fine needle aspirates and cytological specimens are not acceptable. In patients who have had biopsies taken during BNT111 monotherapy, the number of biopsies 
during add-on is to be adjusted as appropriate (up to three in total during the duration of the trial). It is recommended to perform the biopsy on progression only if 4 wks or more have elapsed since 
the last biopsy (on-treatment biopsy). If the time is shorter, no biopsy on progression should be taken.  
For other trial sites, if any biopsies or resections are to be performed as part of standard clinical care, tissue samples from such procedures should be provided (if feasible) for the sponsor for 
biomarker testing. 
Abbreviations: AOCnDn = add-on, cycle “n”, day “n”; d = day; CT = computer tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; d = day(s); 
eCRF = electronic case report form; EoT = end of treatment; FU = follow-up; h = hour(s); LTFU = Lost to follow-up; mon = month; MRI = magnetic resonance imaging; PGIC= Patient Global Impression 
of Change; PGIS= Patient Global Impression of Severity; PRO/QoL = patient-reported outcomes/quality of life; SOA = schedule of activity; T4 = Thyroxine; TSH = thyroid-stimulating hormone; wks = 
week(s); WOCBP = women of childbearing potential. 
 

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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY 
3 
1.1 
Trial synopsis 
3 
1.2 
Schema (graphical representation of the trial) 
10 
1.3 
Schedules of activities 
11 
1.3.1 
Schedule of activities for Arm 1, Arm 2, and Arm 3 patients (SOA1) 
11 
1.3.2 
Schedule of activities for patients receiving add-on therapy (SOA2) 
21 
TABLE OF CONTENTS 
26 
LIST OF TABLES 
30 
LIST OF FIGURES 
31 
TRIAL-SPECIFIC ABBREVIATIONS 
31 
2 
INTRODUCTION 
33 
2.1 
Background 
33 
2.1.1 
Treatment option overview for unresectable Stage III and Stage IV and 
recurrent melanoma 
33 
2.1.2 
Introduction to the investigational treatments 
35 
2.2 
Trial rationale 
37 
2.3 
Benefit/risk assessment 
38 
2.3.1 
Risk assessment 
38 
2.3.2 
Benefit assessment 
39 
2.3.3 
Risk/benefit assessment of COVID-19 vaccination 
40 
2.3.4 
Overall benefit/risk conclusion 
41 
3 
OBJECTIVES AND ENDPOINTS 
42 
4 
TRIAL DESIGN 
44 
4.1 
Overall design 
44 
4.1.1 
Screening period 
44 
4.1.2 
Treatment period 
44 
4.1.3 
Add-on therapy for patients in Arm 2 or 3 
44 
4.1.4 
Safety follow-up 
45 
4.1.5 
Efficacy follow-up 
45 
4.1.6 
Survival follow-up 
45 
4.1.7 
Planned number of patients 
45 
4.2 
Scientific rationale for the trial design 
45 
4.3 
Justification for dose 
47 
4.3.1 
BNT111 
47 
4.3.2 
Cemiplimab 
47 

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4.4 
End of trial definition 
48 
5 
TRIAL POPULATION 
48 
5.1 
Inclusion and exclusion criteria 
48 
5.1.1 
Inclusion criteria initial treatment 
48 
5.1.2 
Exclusion criteria initial treatment 
50 
5.1.3 
Inclusion criteria for entering add-on therapy 
53 
5.1.4 
Exclusion criteria for entering add-on therapy 
53 
5.2 
Screen failures 
54 
6 
TRIAL TREATMENTS 
54 
6.1 
Trial treatments administered 
54 
6.2 
Schedule of trial treatments 
55 
6.3 
Duration of treatments 
56 
6.4 
Preparation/handling/storage/accountability 
56 
6.5 
Measures to minimize bias: randomization and blinding 
56 
6.6 
Trial treatment compliance 
57 
6.7 
Concomitant therapy 
57 
6.7.1 
Permitted concomitant therapy 
57 
6.7.2 
Prohibited concomitant therapy 
58 
6.8 
Dose modifications and interruptions 
58 
6.8.1 
Interruption of the intravenous infusion of cemiplimab 
58 
6.8.2 
Dose modification for BNT111 
59 
6.8.3 
Dose modification for cemiplimab 
60 
6.8.4 
Mitigation plans for specific AEs 
64 
6.9 
Treatment after the end of the trial 
72 
7 
DISCONTINUATION OF TRIAL TREATMENT AND PATIENT 
DISCONTINUATION / WITHDRAWAL 
72 
7.1 
Discontinuation of trial treatment 
72 
7.1.1 
Temporary discontinuation 
73 
7.1.2 
Rechallenge 
73 
7.2 
Patient discontinuation/withdrawal from the trial 
73 
7.3 
Lost to follow-up 
74 
7.4 
Discontinuation of trial by the sponsor 
74 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
75 
8.1 
Efficacy assessments 
76 
8.1.1 
Confirmation of anti-PD-1/PD-L1-refractory/relapsed patients 
76 
8.1.2 
Tumor evaluations 
76 
8.1.3 
Blinded independent central review 
78 
8.1.4 
Survival follow-up 
78 

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8.1.5 
Patient-reported outcomes/quality of life 
79 
8.1.6 
ECOG performance status 
79 
8.2 
Safety assessments 
79 
8.2.1 
Physical examinations 
79 
8.2.2 
Height and body weight 
80 
8.2.3 
Vital signs 
80 
8.2.4 
Electrocardiograms 
81 
8.2.5 
Safety laboratory assessments 
81 
8.2.6 
Viral serology 
81 
8.2.7 
Safety follow-up (SFU1 and SFU2) 
82 
8.3 
Adverse events and serious adverse events 
82 
8.3.1 
Time period and frequency for collecting adverse event and serious adverse 
event information 
82 
8.3.2 
Method of detecting adverse events and serious adverse events 
82 
8.3.3 
Follow-up of AEs and SAEs 
83 
8.3.4 
Regulatory reporting requirements for SAEs 
83 
8.3.5 
Pregnancy 
84 
8.3.6 
Death events 
84 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs 
or SAEs 
84 
8.3.8 
Immune-related adverse events 
85 
8.4 
Adverse events of special interest 
85 
8.5 
Treatment of overdose 
86 
8.6 
Pharmacokinetics 
86 
8.7 
Pharmacodynamic 
86 
8.8 
Genetics 
86 
8.9 
Biomarkers 
86 
8.10 
Immunogenicity assessments 
87 
8.11 
Blood collection 
87 
9 
STATISTICAL CONSIDERATIONS 
89 
9.1 
Statistical hypotheses 
89 
9.2 
Sample size determination 
89 
9.3 
Analysis sets 
90 
9.4 
Statistical analyses 
91 
9.4.1 
General considerations 
91 
9.4.2 
Primary endpoints 
92 
9.4.3 
Secondary endpoints 
93 
9.4.4 
Exploratory endpoints 
94 

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9.4.5 
Safety analyses 
94 
9.4.6 
Other analyses 
96 
9.5 
Interim analyses and analysis sequence 
96 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
 
 
96 
10.1 
Regulatory, ethical, and trial oversight considerations 
96 
10.1.1 
Regulatory and ethical considerations 
96 
10.1.2 
Financial disclosure 
97 
10.1.3 
Informed consent process 
97 
10.1.4 
Data protection 
98 
10.1.5 
Committee’s structure (IDMC) 
98 
10.1.6 
Dissemination of clinical trial data 
99 
10.1.7 
Data quality assurance 
99 
10.1.8 
Source documents 
99 
10.1.9 
Trial and site start and closure 
100 
10.1.10 
Publication policy 
100 
10.1.11 
Protocol preparation and approval 
101 
10.2 
Safety laboratory tests 
101 
10.3 
Adverse events: Definitions and procedures for recording, evaluating, follow-up, 
and reporting 
102 
10.3.1 
Definition of AE 
102 
10.4 
Contraceptive guidance and collection of pregnancy information 
113 
10.4.1 
Definitions 
113 
10.4.2 
Collection of pregnancy information 
114 
10.5 
Genetics 
115 
10.6 
Liver safety: suggested actions and follow-up assessments 
115 
10.7 
Investigators and trial administrative structure 
115 
10.7.1 
Investigators and trial site personnel 
115 
10.7.2 
Trial site personnel assigned trial-related duties 
115 
10.7.3 
Contract research organizations 
116 
10.7.4 
The sponsor and sponsor’s personnel 
116 
10.8 
Country-specific requirements 
116 
10.9 
Other standard abbreviations and definitions 
117 
10.10 
Protocol amendments 
118 
10.10.1 
Protocol amendment no. 01 
118 
10.10.2 
Protocol amendment no. 02 
118 
10.10.3 
Protocol amendment no. 03 
118 
10.10.4 
Protocol amendment no. 04 
119 

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10.10.5 
Protocol amendment no. 05 
119 
10.10.6 
Protocol amendment no. 06 
119 
10.10.7 
Protocol amendment no. 07 
120 
10.11 
Data collection and management 
120 
10.11.1 
Case report forms 
120 
10.11.2 
Patient-reported outcomes 
120 
10.11.3 
Data management 
120 
10.11.4 
Investigator’s Site File and the Trial Master File 
121 
10.12 
Other data 
121 
10.12.1 
Demographic data 
121 
10.12.2 
Medical history and underlying disease history 
121 
11 
REFERENCES 
122 
12 
APPENDICES 
127 
12.1 
Appendix 1 Definition of irAEs 
127 
 
LIST OF TABLES 
Table 1: 
Summary of important, potential risks and mitigation actions taken 
39 
Table 2: 
Trial treatments administered 
55 
Table 3: 
Dose modification for cemiplimab 
61 
Table 4: 
Recommendations for dose modifications in case of fever 
65 
Table 5: 
Recommendations for management of flu-like symptoms/influenza-like illness 
related to BNT111 
66 
Table 6: 
Recommendations for dose modifications in case of hypotension 
67 
Table 7: 
Recommendations for management of infusion-related reactions related to trial 
drug  
68 
Table 8: 
Description of ECOG PS assessments 
79 
Table 9: 
Overview of blood collection for safety assessments (Central Safety Laboratory)
 
 
88 
Table 10: Overview of blood collection for cellular immune response analysis in Arm 1 and 
Arm 2 (including patients entering Arm 2 add on therapy, selected trial sites only)
 
 
88 
Table 11: Overview of blood collection for cellular immune response analysis in Arm 3 add-
on therapy (selected trial sites only) 
88 
Table 12: Analysis sets 
90 
Table 13: Operational characteristics of interim and final analysis of ORR 
93 
Table 14: Safety laboratory tests 
101 
Table 15: Highly effective methods of contraception 
113 
Table 16: List of irAEs definitions by MedDRA and composite terms 
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2 INTRODUCTION 
2.1 
Background 
Overview of the disease 
Melanoma is a malignant tumor of melanocytes. Most melanomas arise in the skin, but 
they may also arise from mucosal surfaces or at other sites to which neural crest cells 
migrate, including the uveal tract. Mucosal and uveal melanomas differ significantly from 
cutaneous melanoma in incidence, prognostic factors, molecular characteristics and 
treatment. The word melanoma, unless specified otherwise, will only refer to cutaneous 
melanoma in this protocol. 
Melanoma is the 19th most common malignancy worldwide, with an estimated age-
standardized incidence rate of 3.0 per 100,000. Approximately 287,700 new cases of 
melanoma and 60,700 deaths were estimated worldwide in 2018 (Ferlay et al. 2019). In 
North America, melanoma is the fifth most common cancer in males and sixth most 
common cancer in females (Siegel et al. 2018). In the United States (US), approximately 
106,110 patients will be diagnosed and there will be about 7,180 estimated deaths in 
2021. The incidence has been increasing over the past 30 years. Invasive melanoma 
represents about 1% of skin cancers but results in the most deaths (ACS 2021). In 
Europe, melanoma is less common, being the seventh most common cancer 
(GLOBOCAN 2020). Five-year survival for patients with early stage disease (i.e., localized) 
is achieved in approximately 99% of patients. However, 5-year survival for patients with 
distant disease is approximately 27% (NCI 2019). There is an increasing appreciation of 
the variations in specific genetic alterations among distinct clinical subtypes of melanoma, 
some of which have different therapeutic implications (NCCN 2021). 
2.1.1 
Treatment option overview for unresectable Stage III and Stage IV and 
recurrent melanoma 
Advanced or metastatic melanoma (unresectable Stage III and Stage IV) remains a lethal 
disease with a high proportion of patients being resistant to approved therapies. 
Furthermore, there are limited treatment options for patients who progress on targeted 
therapy or immunotherapy. Therefore, there is a high unmet medical need justifying the 
development of novel therapies for advanced melanoma patients who have failed existing 
therapies. 
Systemic treatment 
There are two approaches for systemic treatment of unresectable Stage III/IV and 
recurrent melanoma. Either immune checkpoint inhibition (CPI) or targeting the mitogen-
activated protein kinase (MAPK) pathway, they have both demonstrated improvement in 
PFS and OS in randomized trials. 
Immune checkpoint inhibitors 
CPIs targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; e.g., ipilimumab) 
and PD-1, e.g., nivolumab and pembrolizumab, have been approved for the treatment of 

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advanced or metastatic melanoma as single agents or in combination. In first-line therapy, 
nivolumab and ipilimumab combination therapy is associated with an improved ORR (57% 
vs 19% vs 44%) and median PFS (11.5 months vs 2.9 months vs 6.9 months) compared 
with single-agent ipilimumab or nivolumab, respectively. However, the combination is 
associated with substantial toxicity and the impact of combination therapy on OS is not yet 
fully established (Wolchok et al. 2017). In addition, Opdualag® was approved by the US 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2022 for 
the treatment of melanoma (Opdualag US Prescribing Information; Opdualag Summary of 
Product Characteristics). Opdualag is a fixed dose combination of nivolumab and 
relatlimab, a LAG-3 inhibitor. Monotherapy treatment with PD-1 inhibitors (e.g., 
pembrolizumab or nivolumab) or cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) 
inhibitors (e.g., ipilimumab) is also an option for patients who are not candidates for 
combination therapy. 
Signal transduction inhibitors 
Approximately 50% patients with metastatic cutaneous melanoma harbor an activating 
mutation of proto-oncogene B-Raf (BRAF), an intracellular signaling kinase in the MAPK 
pathway. BRAF inhibitors (e.g., vemurafenib and dabrafenib) have shown clinical activity in 
BRAF V600-mutated melanoma. BRAF inhibitors have monotherapy efficacy in patients 
with BRAF-mutated melanoma, but half of patients relapse within approximately 6 months 
due to development of drug resistance. Combination therapy with BRAF and MEK 
inhibitors circumvents resistance and has superior efficacy (i.e., improved ORR, DOR, 
PFS, and OS) when compared to BRAF inhibitor monotherapy in patients with previously 
untreated unresectable or metastatic disease. Nevertheless, 50% of patients who respond 
to combination therapy still progress within the first 12 months (Mackiewicz et al. 2018; 
Gellrich et al. 2020). Pembrolizumab and nivolumab are also approved as first-line 
treatments for patients with BRAF-mutated melanoma. For patients with BRAF V600-
mutated tumors that do not progress quickly, the currently recommended therapeutic 
sequence is immunotherapy (e.g., with an anti-PD-1 inhibitor) followed by targeted therapy 
with BRAF/MEK inhibitors (Michielin et al. 2019). 
Intralesional therapy 
Talimogene laherparepvec (T-vec, tradename Imlygic) is a genetically modified oncolytic 
viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, 
and nodal lesions in patients with melanoma recurrent after initial surgery. T-vec is a 
modified type 1 herpes simplex virus (HSV-1) that has undergone genetic modifications, 
e.g., insertion of two copies of the human cytokine granulocyte-macrophage colony-
stimulating factor (GM-CSF) gene to promote selective viral replication in tumor cells, while 
reducing viral pathogenicity and promoting immunogenicity. In a randomized Phase III trial, 
intratumoral T-vec compared to subcutaneous GM-CSF showed an ORR of 26% vs 5.7%. 
However, the difference seen in OS did not reach statistical significance and the response 
rate in visceral lesions was poor (Rehman et al. 2016). Therefore, this treatment will only 
be an option for selected patients. 

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Other therapies 
Treatment options for patients with advanced or metastatic melanoma who have 
progressed on targeted therapy or immunotherapy may include high-dose interleukin (IL)-2 
or other cytotoxic therapies (e.g., dacarbazine, carboplatin/paclitaxel, albumin-bound 
paclitaxel). These agents have modest response rates of less than 20% in the first- and 
second-line settings, but no data exist in post-PD-1 settings. Furthermore, little consensus 
exists regarding optimal standard chemotherapy (NCCN 2021). The first promising results 
were shown for a c-kit-inhibitor with an ORR of 23.3% (Guo et al. 2011) whereas the multi-
kinase-inhibitor sorafenib targeting both the MAPK-cascade as well as the vascular 
endothelial growth factor and platelet-derived growth factor cascades did not improve 
median PFS when compared to placebo in a Phase III, randomized, double-blind, placebo-
controlled trial in combination with carboplatin and paclitaxel (Hauschild et al. 2009). 
2.1.2 
Introduction to the investigational treatments 
BNT111 
BNT111 is a fixed set of four liposome-formulated protein-encoding ribonucleic acids 
(RNAs; henceforward referred to as RNA-lipoplexes [RNA-LPX]). The four RNAs are 
individually complexed with liposomes and administered separately via IV injections. The 
RNA-LPX formulation is designed for specific targeting of antigen-presenting cells (APCs) 
in lymphoid organs. 
The RNA components of BNT111 code for four tumor-associated antigens (TAAs), namely 
New York esophageal squamous cell carcinoma-1 (NY-ESO-1), tyrosinase, melanoma 
antigen A3 (MAGE-A3), and transmembrane phosphatase with tensin homology (TPTE). 
All target antigens are known to be immunogenic and, with the exception of TPTE, have 
already been extensively studied as TAAs in numerous diverse clinical settings (Chen et 
al. 2005; Shackleton et al. 2004; Slingluff et al. 2003; Sanderson et al. 2005; Marchand et 
al. 2003; Carrasco et al. 2008; Brichard et al. 2007; Tyagi et al. 2009; Banchereau et al. 
2005; Toungouz et al. 2001; Oshita et al. 2012; Weide et al. 2009; Wilgenhof et al. 2011). 
BNT111 is currently being tested in Germany in an ongoing first-in-human dose-
escalation, multi-site, open-label interventional and sequential Phase I trial in patients with 
advanced melanoma (NCT02410733; further referred to as the Lipo-MERIT trial). 
The RNA design is optimized for the induction of strong antigen-specific immune 
responses. The RNA sequence contains naturally occurring sequence elements at 3’ and 
5’ untranslated regions that significantly increase the intracellular half-life and the 
translational efficiency of the molecule (Holtkamp et al. 2006). The encoded proteins are 
flanked by natural peptide tags which improve the processing of the antigens resulting in 
efficient presentation of antigen-derived peptide epitopes on major histocompatibility 
complex (MHC) class I and II molecules (Kreiter et al. 2008). These tags include a 
secretory signal peptide for translocation of the nascent polypeptide chain into the 
endoplasmic reticulum and the transmembrane and cytoplasmic domain of the MHC 
class I molecule. The synthetic cap structure (beta-S-ARCA) increases the resistance of 
the RNA molecules to degradation by extracellular and intracellular ribonucleases (Kuhn et 

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al. 2010). The TAAs are fused to the tetanus toxoid epitopes (P2P16), which are well-
known universal T helper epitopes to break immune tolerance. 
The liposome formulation of BNT111 is designed to deliver mRNA that encode the 
antigens into dendritic cells in lymphoid organs and exploits anti-viral innate and adaptive 
immune mechanisms for induction of highly potent antigen-specific T cell responses. IV 
injected RNA-LPX home to secondary lymphatic tissues, e.g., spleen, lymph nodes, and 
bone marrow, are rapidly taken up by resident professional APCs. The proteins translated 
from the RNA components of the BNT111 vaccine are processed and presented on the 
patient’s individual set of both human leukocyte antigen (HLA)-class I and HLA-class II 
molecules (Kranz et al. 2016). The close proximity of APCs to T cells in lymphoid tissues is 
the ideal microenvironment for efficient priming and amplification of CD8+ and CD4+ T cell 
responses (Zinkernagel et al. 1997). RNA-LPX activate APCs via toll-like receptor 
signaling, which results in a pulsatile release of pro-inflammatory cytokines, such as 
interferon (IFN)-α, IL-6, IFN-γ, and interferon gamma-induced protein 10 (IP-10). The 
secretion of type I IFN concomitant to efficient antigen presentation stimulates immune 
cells and directly inhibits regulatory T cells (Srivastava et al. 2014) which, in combination 
with cognate CD4+ T cell help, is necessary for overcoming tolerance to self-antigens. 
Based on this mechanism of action, the repeated application of RNA-LPX cancer vaccines 
allows potent priming and fast amplification of antigen-specific CD8+ T cell responses. 
The RNA-LPX-based cancer vaccines have demonstrated a favorable safety and 
tolerability profile in different indications, different treatment settings (metastatic, post neo-
adjuvant, adjuvant) and with different types of cancer vaccine antigens. In the Lipo-MERIT 
trial, 108 patients were treated and the TEAEs considered related to trial treatment were 
transient, mostly Grade 1 and 2, and associated with the specific format of encoding and 
delivering the vaccine antigens, namely single-stranded RNA formulated as a 
DOTMA/DOPE lipoplex. The identified risks consisted of mild-to-moderate, transient and 
manageable flu-like aEs and transient lymphopenia (by sequestration). In 8% of patients, 
Grade 2 or 3 hypotension (as per National Cancer Common Terminology Criteria for 
Adverse Events [NCI-CTCAE]) was seen within the first hours after vaccination, 
sometimes with a sudden onset, and in general patients responded well to fluids. 
The Lipo-MERIT trial has provided promising signals for single-agent and anti-PD-1 
combination activity of BNT111 in pre-treated CPI-experienced patients with high medical 
need and limited treatment options. It was further demonstrated that in the majority of 
patients, the vaccine displays its expected mechanism of action and induces T cells 
against at least one of the TAAs. A considerable fraction of these immune responses was 
strong (measurable ex vivo) and both new T cells were primed and pre-existing T cells 
were expanded. Responses were both CD8+, but also CD4+, indicating that effector T cells 
received cognate T cell help in the priming process (Sahin et al. 2020). 
It is expected that in particular for patients that are refractory to or relapsing after anti-PD-1 
therapy (meaning that activation of pre-existing memory T cells only is not sufficient to 
mediate clinical activity) combining the vaccine with a PD-1 inhibitor (which would rescue 
newly primed T cells specificities from exhaustion) is synergistic as supported by 

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preclinical treatment studies in syngeneic and xenograft mouse tumor models (see the 
BNT111 investigator’s brochure [IB]). 
Cemiplimab 
Cemiplimab is a high-affinity IgG4P human antibody to the PD-1 receptor (PDCD1, 
CD279) that blocks PD-1/PD-L1-mediated T cell inhibition. Cemiplimab (LIBTAYO®) is 
approved in several countries worldwide for the treatment of advanced cutaneous 
squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), cervical cancer, and non-
small cell lung cancer (NSCLC). 
The clinical activity of cemiplimab has been shown in multiple cancer indications and, 
given the activity of other immune checkpoint inhibitors in melanoma, it is thus reasonable 
to expect activity of cemiplimab in this indication. Additional background information on the 
trial drug and development program can be found in the cemiplimab IB. 
2.2 
Trial rationale 
This trial is designed to address the high unmet medical need of patients with unresectable 
Stage III or IV melanoma (8th Edition of AJCC melanoma classification [Amin et al. 2017]) 
who failed anti-PD-1/PD-L1 therapy. Due to the mechanisms of action of BNT111 and 
cemiplimab, it is expected that the combination of the two agents will have a synergistic 
anti-tumor effect in patients that have failed previous anti-PD-1/PD-L1 therapy. 
Both compounds have single-agent activity in melanoma or other tumors. Cemiplimab has 
been approved based on its single-agent activity in advanced CSCC. For BNT111, 
preliminary indications of single-agent activity have been observed in the ongoing 
Lipo-MERIT Phase I trial testing pre-treated CPI-experienced patients with 
unresectable/metastatic melanoma Stages IIIB, IIIC and IV. 
Activation, expansion and differentiation of naïve T cells, particularly in the context of 
persistent antigen encounter, is physiologically associated with induction of PD-1 
expression, which contributes to regulation of the immune responses. PD-1 blockade acts 
by re-activation and expansion of pre-existent antigen-specific T cells of the patient 
directed particularly against mutation-derived neo-antigens. More than half of the patients 
with metastatic melanoma have a moderate to low mutational burden. These patients are 
less likely to have pre-formed neo-antigen-specific T cells and thus at higher risk of anti-
PD-1 treatment failure and progression (Hugo et al. 2016). BNT111 has been shown to 
prime, activate and expand CD4+ and CD8+ T cell specificities and thus generate a 
complementary pool of T cell specificities directed against non-mutant TAAs that are 
frequently expressed in human melanoma irrespective of the mutational burden of the 
tumor. In patients with melanoma treated with BNT111, induction of antigen-specific 
T cells has been shown to correlate with upregulation of PD-1 expression. Thus, 
mechanistically, anti-PD-1 blockade is expected to augment vaccine-induced T cell 
responses. This is supported by preclinical data in mice inoculated with syngeneic 
melanoma cells and by an early efficacy signal observed in the BNT111/anti-PD-1 
(nivolumab, pembrolizumab) combination cohort of the Lipo-MERIT trial. Thus, we 
consider the combination of cemiplimab and BNT111 to be synergistic and anticipate that 

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patients who failed prior anti-PD-1 treatment will be sensitized by the BNT111 vaccine to 
respond to the anti-PD-1 component in the combination. 
2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks, and 
reasonably expected adverse events (AEs) for this trial are given in Section 6.2 of the 
BNT111 IB and Section 6.4 of the cemiplimab IB.  
2.3.1 
Risk assessment 
Expected adverse drug reactions (ADR) for BNT111 are fever, chills, lymphopenia, 
increase of cytokines and dizziness, not considered to have a significant impact on the 
risk-benefit profile of the product. NCI-CTCAE Grade 2 or 3 hypotension was seen in 8% 
of patients within 4 to 6 h after BNT111 administration, typically after the first or second 
vaccination, and patients with hypotension responded well to fluids. In rare cases, more 
severe events of cytokine release syndrome associated with pyrexia, hypotension, and 
hypoxia of higher NCI-CTCAE grades occurred. The onset was sometimes sudden; vital 
signs should therefore be carefully monitored for 6 h after at least the first three 
vaccinations.  
Immune-related adverse reactions can occur with cemiplimab. Most of these, including 
severe reactions, resolved following initiation of appropriate medical therapy or withdrawal 
of cemiplimab. The most common immune-related adverse reactions seen in clinical trials 
(591 patients) were hypothyroidism (7.1%), pneumonitis (3.7%), immune-related skin 
adverse reactions (2.0%), hyperthyroidism (1.9%) and hepatitis (1.9%). Adverse reactions 
were serious in 8.6% patients and led to permanent discontinuation of cemiplimab in 5.8% 
of patients. See Section 6.8.4.2 for special warnings and precautions. 
BNT111 has been given in combination with anti-PD-1 therapy in the Lipo-MERIT trial, no 
increase of AEs for any of the components was seen for the combination therapy 
compared to monotherapy. Safety data from the BNT111-01 trial interim analysis was in 
line with that observed in the Lipo-MERIT trial (Section 5.2 of the BNT111 IB). Based on 
the available safety data on TESAEs and treatment-emergent deaths, no safety signal was 
detected which would change the safety profile or benefit/risk assessment of BNT111 
established in Lipo-MERIT trial. This was supported by the outcome of all IDMC meetings 
that recommended to continue the trial without modification. 
 

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2.3.3 
Risk/benefit assessment of COVID-19 vaccination 
2.3.3.1 
Risk assessment 
BNT111 
BNT111-induced adaptive immune responses are expected to be highly specific and 
limited to the TAAs (see Section 2.1.2). Similarly, available European and US approved 
COVID-19 vaccines elicit a specific response towards the selected severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens. It is thought that adaptive 
immune responses driven by these entirely distinctive antigens (melanoma and SARS-
CoV-2) should not cross-react with each other. Consequently, BNT111 administration is 
not expected to impact COVID-19 vaccine efficacy and vice versa. 
In parallel to the activation of the adaptive immune response mechanisms, BNT111, as 
observed with other RNA-LPX-based cancer vaccines, also induces an innate immune 
response and its administration is expected to be followed by a pulsatile release of 
cytokines with peaks observed at approximately 6 h after dosing and values returning to 
baseline by 24 h or earlier. Similarly, COVID-19 vaccination is expected to trigger a 
transient elevation of cytokine concentration in the peripheral blood. A 7 d interval between 
COVID-19 and BNT111 vaccination is therefore recommended to mitigate the risk of 
increased, cumulative toxicity related to cytokines release. 
Cemiplimab 
As outlined in Section 2.1.2, cemiplimab is a high-affinity human monoclonal antibody that 
belongs to the class of PD-1/PD-L1 inhibitors. By targeting and binding to PD-1, 
cemiplimab blocks PD-1/PD-L1-mediated inhibitory signaling in helper and cytotoxic 
T cells, thus releasing cytotoxic T cells to target cancer cells (for more information, refer to 
the cemiplimab IB). This mechanism may potentially lead to breaking of peripheral 
tolerance towards self-antigens and induction of unwanted immune responses towards a 
patients’ own tissues. COVID-19 vaccination induces adaptive immune responses to the 
selected SARS-CoV-2 antigens and has no identified cross-reactivity with human antigens. 
Therefore, increased autoimmune toxicity is unlikely, although clinical data is needed to 
support this hypothesis. The efficacy of COVID-19 vaccination is not expected to be 
adversely impacted by concomitant administration of PD-1 inhibitors as PD-1/PD-L1 
blockade would circumvent T cell deactivation. 
BNT111 and cemiplimab combination 
Based on the single-agent mechanism of action of BNT111 and cemiplimab, it is expected 
that the efficacy of COVID-19 vaccination will not be decreased when administered in this 
treatment setting. In the Lipo-MERIT trial, BNT111 was given in combination with PD-1 
inhibitor therapy (nivolumab or pembrolizumab) and no increase of toxicities or AEs for any 
of the components was observed for the combination therapy when compared to 
monotherapy, and no overlapping toxicities or safety concerns were reported with the 
combination therapy. However, confirmation with clinical observation that the safety profile 
remains unchanged in patients with concomitant COVID-19 vaccination is required. 

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Melanoma (disease-specific section) 
There are no specific data from clinical trials on COVID-19 vaccine safety and efficacy in 
cancer patients, and in particular those with advanced malignant melanoma. Based on 
clinical experience with other vaccines, and depending on the type of vaccine, efficacy 
and/or safety might be affected in immunocompromised cancer patients (Rieger et al. 
2018). 
2.3.3.2 
Benefit assessment 
It is generally assumed that cancer patients may be at an increased risk of severe 
COVID-19 due to immunosuppression that may result from both anti-cancer treatment and 
the malignancy itself (Cook et al. 2020; Dai et al. 2020; Liang et al. 2020). As for the entire 
population, immunization with COVID-19 vaccine reduces the likelihood of SARS-CoV-2 
infection as well as severity of disease in patients with cancer. Additionally, decreasing the 
likelihood of SARS-CoV-2 infection by COVID-19 vaccination may allow better adherence 
to anti-cancer therapeutic regimens and in doing so potentially increase treatment efficacy. 
2.3.3.3 
Risk/benefit summary of COVID-19 vaccination 
Based on the available non‐clinical and clinical data, the sponsor considers that the 
potential benefits of COVID-19 vaccination in patients with melanoma treated with BNT111 
either as monotherapy or in combination with cemiplimab outweigh the anticipated risks. 
The following recommendations are proposed to mitigate potential risks: 
• 
Patients with prior COVID-19 vaccination may be allowed to enter the trial with a 
wash-out period of at least 7 d since the last COVID-19 vaccine dose. 
• 
Patients who are already enrolled in the clinical trial and still receiving trial 
treatment may be allowed COVID-19 vaccination if it is ensured that there are at 
least 7 d between individual doses of COVID-19 vaccine and trial treatment. 
• 
In terms of the risk/benefit of COVID-19 vaccination, the final decision for individual 
patients should be taken by the investigator in accordance with individual country 
guidance on vaccination in patients with active cancer. 
• 
Patients treated with BNT111 should not be immunized directly prior to and during 
the trial with live-attenuated vaccines, as per prohibited concomitant therapy (see 
Section 6.7.2). 
2.3.4 
Overall benefit/risk conclusion 
Based on the available clinical and non‐clinical data, the poor prognosis and the unmet 
medical need for melanoma patients, the potential anticipated benefits of the RNA-based 
immunotherapy BNT111 in combination with cemiplimab outweigh the anticipated limited 
risks of this approach. This benefit/risk evaluation remains unchanged after having 
enrolled about 50% of originally planned patients based on the input of the IDMC. 
Overall, the sponsor considers the benefit/risk ratio to be acceptable for a trial of this type. 

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4 TRIAL DESIGN 
4.1 
Overall design 
Patients with anti-PD-1/PD-L1-refractory/relapsed, unresectable Stage III or IV melanoma 
will be screened for the trial and 180 patients will be randomized in a 2:1:1 ratio to Arm 1 
(BNT111 + cemiplimab) and calibrator Arm 2 (BNT111 monotherapy), and Arm 3 
(cemiplimab monotherapy). Randomization will be stratified by metastatic status (M0, M1a, 
M1b vs M1c, M1d) and by number of prior lines of systemic treatment (1 vs 2 to 5).  
Patients in Arms 2 and 3 who experience centrally verified disease progression under 
single-agent treatment may be offered addition of the respective other compound to the 
ongoing treatment after re-consent. 
4.1.1 
Screening period 
Screening procedures will be performed within 21 d before the start of treatment on Day 1 
of Cycle 1. 
A signed informed consent form (ICF) must be obtained before any screening procedure 
may begin. 
4.1.2 
Treatment period 
Patients will be randomized to receive either BNT111 + cemiplimab combination therapy 
(Arm 1), BNT111 monotherapy (Arm 2) or cemiplimab monotherapy (Arm 3). 
Treatments with BNT111 will be given once-weekly for the first 6 wks, followed by 
treatments once every 3 wks (±3 d). Cemiplimab will be given once every 3 wks (±3 d) 
throughout the trial. 
The treatment period starts on Day 1 of Cycle 1 and continues for up to 24 months or until 
confirmed progression of disease, withdrawal of consent or unacceptable toxicity. 
4.1.3 
Add-on therapy for patients in Arm 2 or 3 
Patients who experience disease progression under monotherapy may continue with add-
on therapy. Disease progression must be verified centrally. The eligibility of patients for the 
add-on therapy needs to be checked based on the inclusion criteria (Section 5.1.3) and 
exclusion criteria (Section 5.1.4). Patients need to re-consent for participation in the add-
on therapy. 
Patients in Arm 2 (add-on of cemiplimab to BNT111): Cemiplimab will be given once every 
3 wks (±3 d). BNT111 will be continued according to the planned schedule; a patient must 
have received a total of 6 weekly injections during the initial trial treatment and the add-on 
therapy before moving to a once every 3 wk schedule of injections. 
Patients in Arm 3 (add-on of BNT111 to cemiplimab): BNT111 will be given once-weekly 
for the first 6 wks of add-on therapy, followed by treatments once every 3 wks (±3 d). 
Cemiplimab will continue to be given once every 3 wks (±3 d). 

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Treatments will continue up to a total treatment duration (monotherapy and add-on 
therapy) of 24 months. 
4.1.4 
Safety follow-up 
The treatment period is followed by a safety follow-up period with visits after 30 and 
90 days after last treatment to assess AEs. If the patient is not able to visit the 
clinic/hospital, the AE assessment will be done by phone call. 
In cases where a new anti-cancer therapy is started within 90 days after last treatment, the 
safety follow-up visit should be performed just prior to starting the new anti-cancer therapy. 
Adverse events after start of new anti-cancer therapy do not need to be reported unless a 
causal relationship to BNT111-01 or cemiplimab is suspected. 
4.1.5 
Efficacy follow-up 
Patients whose last disease assessment on trial treatment was CR, PR or SD will continue 
to have efficacy assessments. 
Efficacy is assessed with regular efficacy assessments every 6 wks for the first 3 months 
after treatment start, then every 9 wks for the next 9 months and every 12 wks thereafter 
until PD, start of a new anti-cancer therapy, withdrawal of consent, death or lost to 
follow-up. 
4.1.6 
Survival follow-up 
Patients will be followed for survival every 3 months for approximately up to 48 months of 
OS follow-up from the randomization of the last patient. 
4.1.7 
Planned number of patients 
180 patients with anti-PD-1/PD-L1-refractory/relapsed, unresectable Stage III or IV 
melanoma. 
4.2 
Scientific rationale for the trial design 
Proposed patient population: 
Currently, the treatment paradigm in unresectable Stage III and Stage IV melanoma is 
either to treat first-line with a combination of nivolumab and ipilimumab, which is 
associated with significant toxicities for the patient, or to treat with either nivolumab or 
pembrolizumab monotherapy. However, approximately 40 to 45% of patients experience 
no response to initial therapy, showing primary resistance, and another 30 to 40% 
experience an initial response but eventually progress, having secondary resistance 
(Mooradian and Sullivan 2019). This subset of CPI-failed patients represents a population 
with a very high unmet medical need. It is expected that a vaccine and anti-PD-1 
combination which addresses several of the potential reasons for primary or acquired non-
responsiveness to a CPI may provide clinical benefit. Based on available non-clinical data 
of the melanoma cancer vaccine in combination with anti-PD-1, as well as the preliminary 
efficacy data, BNT111 can work synergistically with anti-PD-1 by overcoming resistance 

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and refractoriness to CPI therapy, which is expected to result in higher ORR compared to 
current standard of care. 
Patients with ECOG PS 0 and 1 and LDH ≤ ULN are eligible. The reason for this criterion 
is the higher potential for a cancer vaccine to show efficacy in patients with a good PS and 
with lower tumor burden. This is further supported by data from the Lipo-MERIT trial 
(NCT02410733), where all patients with clinical benefit (PR or SD) presented with 
LDH ≤ ULN. 
The clinical setting is further justified by several factors recognized as relevant and 
important for development of cancer vaccines, also listed in the FDA Guidance for Industry 
‘Clinical Considerations for Therapeutic Cancer Vaccines’. These include the time to 
develop an anti-tumor response, which is generally longer for immunotherapies; there is a 
higher chance for a cancer vaccine to show efficacy in patients with a lower tumor burden 
and with limited prior therapy exposure. 
Proposed trial design and trial endpoints: 
The primary endpoint of ORR by RECIST 1.1 and BICR as well as secondary endpoints 
for testing the BNT111 + cemiplimab combination were selected based on the FDA 
Guidance for Industry ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics’. The guideline specifically states that tumor response is widely accepted by 
oncologists in guiding cancer treatments. As ORR is directly attributable to drug effect, 
single-arm trials conducted in patients with refractory tumors where no available therapy 
exists provide a justifiable assessment of efficacy. The proposed target population fulfils 
both criteria of refractory tumors without available therapy. To delineate the contribution of 
components in the same well-defined patient population, the ORR of each single agent is 
assessed in two calibrator arms and the trial is randomized. Randomization will be 
stratified by metastatic status (M0, M1a, M1b vs M1c, M1d) and by number of prior lines of 
systemic treatment (1 vs 2 to 5). 
Add-on therapy for patients in Arm 2 or 3: 
Addition of the respective single-agent treatment in Arms 2 and 3 to the 
BNT111 + cemiplimab combination upon disease progression is justified and strengthens 
equipoise and the requirement for patients to have LDH ≤ ULN mitigates risk by ensuring 
low tumor burden. Specifically, this is the case for the cemiplimab monotherapy arm, 
because the patient population per definition has failed on prior anti-PD-1 therapy and for 
the BNT111 monotherapy arm as BNT111-induced T cells are expected to be blunted by 
natural PD-1-upregulation. 
BNT111 dose and schedule: 
BNT111 will follow a prime and boost schedule: 6 once-weekly doses (Q1W) followed by 
once every 3 wks (± 3 d) (Q3W) up to 24 months and until confirmed disease progression, 
patient withdrawal of consent or unacceptable toxicity. BNT111 is administered repeatedly 
to reflect the prime/boost paradigm as referred to in the FDA Guidance for Industry 
‘Clinical Considerations for Therapeutic Cancer Vaccines’. The first 6-wkly doses are for 
priming and subsequent efficient expansion of naïve CD4+ and CD8+ T cells. This is 

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followed by 3-wkly administrations from Cycle 3 onwards to maintain the expanded T cell 
specificities at a high level and obtain durable immune responses. 
4.3 
Justification for dose 
4.3.1 
BNT111 
The dose range of BNT111 chosen for this Phase II trial is based on the established 
recommended Phase II dose range from Phase I dose finding and dose expansion in the 
Lipo-MERIT trial. The starting dose is
µg followed by 
µg target dose for each 
patient, and
µg dose for dose reduction. 
The following preliminary observations were made in the Lipo-MERIT trial: 
1. PRs with BNT111 alone or in combination with anti-PD-1 occurred in patients treated 
with BNT111 at target doses of 
µg 
2. BNT111 + anti-PD-1 combination induced clinical and radiological responses clustered 
in the 
µg cohort 
3. Target doses of BNT111 at
µg induced robust CD4+ and CD8+ T cell 
immune responses, the magnitude of which was not dose-dependent 
4. BNT111 in the range of
µg gives rise to secondary immune response-
supporting cytokines (e.g., IL12). 
Thus, the proposed dose range of 
 µg is expected to be within the efficacious 
dose range. The intra-patient dose titration reflects the individual needs of a patient in light 
of high inter-patient variability of the innate immune sensor-signaling-associated immune-
related effects. 
4.3.2 
Cemiplimab 
The cemiplimab dose and schedule of
mg Q3W is the FDA-approved dose for 
advanced CSCC, basal cell carcinoma, and non-small cell lung cancer (LIBTAYO®) and 
for all ongoing registrational trials in the cemiplimab program including CSCC, basal cell 
carcinoma, and cervical cancer indications. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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4.4 
End of trial definition 
A patient is considered to have completed the trial if he/she has completed all phases of 
the trial including survival follow-up. 
The end of the trial will be declared at the time at which: 
• 
all patients have discontinued trial treatment; and 
• 
all patients have completed safety follow-up assessment at day 90 subsequent 
to last dose; and 
• 
all patients have been followed-up for at least 24 months subsequent to first 
dose; 
or 
• 
the sponsor discontinues the trial. 
5 TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion and exclusion criteria 
5.1.1 
Inclusion criteria initial treatment 
Patients are eligible to be included in the trial only if all the following general criteria apply: 
1. Patients must sign the written ICF before any screening procedure. 
2. Patients must be aged ≥ 18 years on the date of signing the ICF. 
3. Patients must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, and other requirements of the trial. 
4. Patients must have histologically confirmed unresectable Stage III or IV (metastatic) 
cutaneous melanoma and measurable disease by RECIST 1.1. 
5. Patients must have confirmed disease progression on/after an approved anti-
PD-1/PD-L1 regimen for melanoma as defined by RECIST 1.1 
a. Previous exposure to approved anti-PD-1/PD-L1 containing regimen for at least 
12 consecutive weeks and 
b. Current radiological progression to be confirmed by two scans 4 to 12 wks apart. If 
progression is accompanied by new symptoms, or deterioration of PS not 
attributed to toxicity, one scan is sufficient and 
c. Inclusion into this trial must be within 6 months of confirmation of disease 
progression on anti-PD-1/PD-L1 treatment, regardless of any intervening therapy 
6. Inclusion criterion 6 was deleted. 

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7. Patients should have received at least one but no more than five lines of prior therapy 
for advanced disease (see Section 8.1.1 for definition of line of therapy). 
8. Patients must be able to tolerate additional anti-PD-1/PD-L1 therapy (i.e., did not 
permanently discontinue anti-PD-1/PD-L1 therapy due to toxicity). 
9. Patients must have known BRAF mutation status. 
10. Patients with BRAF V600-positive tumor(s) should have received prior treatment with a 
BRAF inhibitor (alone or in combination with a MEK inhibitor). 
Note: Considering the possible negative impact of a prior BRAF/MEK therapy on 
immune system targeting therapies, patients with BRAF V600-positive tumors with no 
clinically significant tumor-related symptoms or evidence of rapid PD may be eligible for 
participation. This should be based on investigator assessment AND provided they are 
ineligible for, intolerant to, or have refused BRAF V600 mutation targeted therapy after 
receiving the information on possible other therapies including BRAF/MEK inhibitor-
based therapy during the informed consent process. 
11. Patients must have an ECOG PS ≤ 1. 
12. Adequate bone marrow function as defined by hematological parameters: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L achieved without the use of 
granulocyte colony-stimulating factor (G-CSF). 
b. Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L). No transfusion is allowed within 1 wk prior 
to treatment initiation. 
c. Platelet count ≥ 100 × 109/L. 
13. Patients must have serum LDH ≤ ULN. 
14. Patient should have adequate hepatic function, as determined by: 
a. aspartate aminotransferase (AST) ≤ 3 × ULN; alanine aminotransferase (ALT) 
≤ 3 × ULN (regardless of liver involvement);  
b. serum bilirubin ≤ 1.5 × ULN, except in patients with Gilbert's Syndrome who must 
have a total bilirubin < 3 mg/dL. 
15. Patient should have adequate kidney function, assessed by the estimated glomerular 
filtration rate (eGFR) ≥ 30 mL/min using the chronic kidney disease epidemiology 
collaboration (CKD-EPI) equation. 
16. Patient should be stable with adequate coagulation, as determined by: 
a. international normalized ratio (INR) or prothrombin time ≤ 1.5 × ULN (unless on 
therapeutic anticoagulants with values within therapeutic window), and 
b. activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless on therapeutic 
anticoagulants with values within therapeutic window). 
17. Patients must provide the following biopsy samples: 
a. All patients: must provide a tumor tissue sample (formalin fixed paraffin-embedded 
[FFPE] blocks/slides) from a fresh biopsy collected before Visit C1D1, or archival 
tissue. The archival tissue can be an FFPE block (not older than 3 years) or freshly 
cut slides (special storage conditions and immediate shipment to specialty lab are 
required), preferably derived from advanced disease stage. 

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b. Patients at selected trial sites: After additional consent, patients should be 
amenable to pre-treatment and on-treatment PBMC sampling and optional biopsy. 
If amenable, patients should provide a PBMC sample and optionally a biopsy 
which contains tumor tissue after failure/stop of last prior trial treatment. 
18. Women of childbearing potential (WOCBP) must have a negative serum (beta-human 
chorionic gonadotropin [beta-hCG]) at screening. Patients that are post-menopausal or 
permanently sterilized can be considered as not having reproductive potential. For a 
definition of WOCBP, see Section 10.4. 
a. Female patients of reproductive potential must agree to use highly effective 
contraception during and for 6 months after the last trial drug administration 
(Section 10.4). 
19. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during trial starting at screening, during the trial and for 6 months after 
receiving the last trial treatment. 
20. A man who is sexually active with a WOCBP 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 trial 
treatment. For a definition of adequate contraception, see Section 10.4. 
 
5.1.2 
Exclusion criteria initial treatment 
Patients are not eligible to be included in the trial only if any of the following criteria apply: 
Medical conditions: 
1. Patients must not be pregnant or breastfeeding. 
2. Patients must not have history of uveal, acral, or mucosal melanoma. 
3. Patients must have no ongoing or recent evidence (within the last 5 years) of 
significant autoimmune disease that required treatment with systemic 
immunosuppressive treatments which may pose a risk for irAEs. 
Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related 
hypothyroidism who are in remission, or on a stable dose of thyroid-replacement 
hormone, vitiligo, or psoriasis may be included. 
4. Patients must have no known primary immunodeficiencies, either cellular 
(e.g., DiGeorge syndrome, T cell-negative severe combined immunodeficiency [SCID]) 
or combined T and B cell immunodeficiencies (e.g., T and –B negative SCID, Wiskott 
Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency). 
5. Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal 
insufficiency are not eligible. 

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6. Patients must have no uncontrolled infection with human immunodeficiency virus, 
hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency that is related to, 
or results in chronic infection. Mild cancer-related immunodeficiency (such as 
immunodeficiency treated with gamma globulin and without chronic or recurrent 
infection) is allowed. 
a. Patients with known HIV who have controlled infection (undetectable viral load and 
CD4 count above 350 either spontaneously or on a stable anti-viral regimen) are 
permitted. For patients with controlled HIV infection, monitoring will be performed 
per local standards. 
b. Patients with known hepatitis B virus (HBV) who have controlled infection (serum 
hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-
viral therapy for hepatitis B) are permitted. Patients with controlled infections must 
undergo periodic monitoring of HBV DNA per local standards. Patients must 
remain on anti-viral therapy for at least 6 months beyond the last dose of trial 
treatment. 
c. Patients who are known hepatitis C virus (HCV) antibody positive who have 
controlled infection (undetectable HCV RNA by PCR either spontaneously or in 
response to a successful prior course of anti-HCV therapy) are permitted. 
d. Patients with HIV or hepatitis must have their disease reviewed by the specialist 
(e.g., infectious disease specialist or hepatologist) managing this disease prior to 
commencing and throughout the duration of their participation in the trial. 
Note: should be discussed with the medical monitor in case of uncertainties. 
7. Patients with another primary malignancy that has not been in complete remission for 
at least 2 years, with the exception of those with a negligible risk of metastasis, 
progression or death (such as adequately treated carcinoma in situ of the cervix, basal 
or squamous cell skin cancer, localized prostate cancer, non-invasive, superficial 
bladder cancer or breast ductal carcinoma in situ). 
Note: should be discussed with medical monitor in case of uncertainties. 
Prior/concomitant therapy: 
8. Current use or use within 3 months prior to trial enrollment of systemic immune 
suppression including: 
a. use of chronic systemic steroid medication (up to 5 mg/day prednisolone 
equivalent is allowed); patients using physiological replacement doses of 
prednisone for adrenal or pituitary insufficiency are eligible, 
b. other clinically relevant systemic immune suppression. 
9. Treatment with other anti-cancer therapy including chemotherapy, radiotherapy, or 
investigational or biological cancer therapy within 3 wks prior to the first dose of trial 
treatment (6 wks for nitrosureas). Adjuvant hormonotherapy used for breast cancer in 
long-term remission is allowed (refer to exclusion criterion 7). 

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Other comorbidities: 
10. Current evidence of ongoing NCI-CTCAE (v5.0) Grade > 1 toxicity of prior therapies 
before the start of treatment, with the exception of hair loss, hearing loss, Grade 2 
peripheral neuropathy, or laboratory abnormalities not considered clinical significant 
per investigator’s discretion, and those Grade 2 toxicities listed as permitted in other 
eligibility criteria. 
11. Patients who have a local infection (e.g., cellulitis, abscess) or systemic infection (e.g., 
pneumonia, septicemia) which requires systemic antibiotic treatment within 2 wks prior 
to the first dose of trial treatment. 
12. Patients who have had a splenectomy. 
13. Patients who have had major surgery (e.g., requiring general anesthesia) within 4 wks 
before screening, have not fully recovered from surgery, or have a surgery planned 
during the time of trial participation. 
14. Current evidence of new or growing brain or spinal metastases during screening. 
Patients with leptomeningeal disease are excluded. Patients with known brain or spinal 
metastases may be eligible if they: 
a. had radiotherapy or another appropriate therapy for the brain or spinal bone 
metastases, 
b. have no neurological symptoms that can be attributed to the current brain lesions, 
c. have stable brain or spinal disease on the CT or MRI scan within 4 wks before 
randomization (confirmed by stable lesions on two scans at least 4 wks apart, the 
second scan can be carried out during screening), 
d. do not require steroid therapy within 14 days before the first dose of trial treatment, 
e. spinal bone metastases are allowed, unless imminent fracture or cord 
compression is anticipated. 
15. History or current evidence of significant cardiovascular disease including, but not 
limited to: 
a. angina pectoris requiring anti-anginal medication, uncontrolled cardiac 
arrhythmia(s), severe conduction abnormality, or clinically significant valvular 
disease, 
b. QTc (F) prolongation > 480 ms, 
c. arterial thrombosis or pulmonary embolism within ≤ 6 months before the start of 
treatment, 
d. myocardial infarction within ≤ 6 months before the start of treatment, 
e. pericarditis (any NCI-CTCAE grade), pericardial effusion (NCI-CTCAE Grade ≥ 2), 
non-malignant pleural effusion (NCI-CTCAE Grade ≥ 2) or malignant pleural 
effusion (NCI-CTCAE Grade ≥ 3) within ≤ 6 months before the start of treatment, 
f. 
Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart 
Association (NYHA) criteria Class ≥ II within ≤ 6 months before the start of 
treatment. 
16. Patients who have received a live vaccine within 28 days of planned start of trial 
therapy. 

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Other exclusions: 
17. Known hypersensitivity to the active substances or to any of the excipients. 
18. Presence of a severe concurrent illness or other condition (e.g., psychological, family, 
sociological, or geographical circumstances) that does not permit adequate follow-up 
and compliance with the protocol. 
19. Prior treatment with BNT111 and/or with cemiplimab. 
5.1.3 
Inclusion criteria for entering add-on therapy 
1. Patients must have confirmed disease progression on monotherapy in Arm 2 or 3 of 
the trial. 
a. An initial radiological progression needs to be verified by BICR. 
b. Radiological progression to be confirmed by two scans 4 to 12 wks apart unless 
initial progression is accompanied by new symptoms, or deterioration of PS not 
attributed to toxicity, in which case one scan is sufficient. 
2. Patients must sign a new ICF to continue with add-on therapy. Informed consent must 
be documented before any add-on-specific procedure is performed. 
3. WOCBP must have a negative serum (beta-hCG) at baseline. Patients that are post-
menopausal or permanently sterilized can be considered as not having reproductive 
potential. For a definition of WOCBP, see Section 10.4. 
4. Female patients of reproductive potential must agree to use adequate contraception 
during and for 6 months after the last trial drug administration (Section 10.4). 
5. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during trial starting at screening, during the trial and for 6 months after 
receiving the last trial treatment. 
6. A man who is sexually active with a WOCBP 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 trial 
treatment. For a definition of adequate contraception, see Section 10.4. 
 
5.1.4 
Exclusion criteria for entering add-on therapy 
1. Prior toxicity related to trial medication should have resolved to NCI-CTCAE v5.0 
Grade ≤ 1 before the start of add-on treatment and may not have led to permanent 
discontinuation. 
2. The time between confirmed PD on monotherapy and start of add-on therapy shall not 
exceed 6 wks. 
3. Current evidence of new or growing brain or spinal metastases at baseline (lesions that 
remained stable during initial treatment are allowed). 
4. Systemic immune suppression: 

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a. use of chronic systemic steroid medication (up to 5 mg/day prednisolone 
equivalent is allowed); patients using physiological replacement doses of 
prednisone for adrenal or pituitary insufficiency are eligible, 
b. other clinically relevant systemic immune suppression. 
5. Presence of cardiovascular, renal, hepatic or any other disease that in the 
investigator’s opinion, may increase the risks associated with trial participation or 
require treatments that may interfere with the conduct of the trial or the interpretation of 
trial results. 
5.2 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical trial but 
are not subsequently randomized. 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, screen failure details, 
eligibility criteria, and any serious AE (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened once. Rescreened patients should be assigned a new patient number. 
6 TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatments, or marketed products intended 
to be administered to a trial patient according to the trial protocol. 
6.1 
Trial treatments administered 
In all countries participating in the trial, BNT111 and cemiplimab are considered as 
investigational medicinal products (IMPs). An overview of the trial treatments and dosage 
information is shown in Table 2. 
Detailed information on how BNT111 and cemiplimab should be administered is described 
in the current Pharmacy Manual (Appendices 1 and 2). 

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Patients from Arm 2 who continue to add-on therapy should maintain the same dose of 
BNT111 as given during monotherapy treatment, if dose was reduced, this reduction 
should be maintained during combination therapy. 
6.3 
Duration of treatments 
The duration of treatment with BNT111 + cemiplimab (Arm 1) or BNT111 or cemiplimab as 
single agents is up to 24 months and will continue until unacceptable toxicity, withdrawal of 
consent, discontinuation due to investigator’s decision or (confirmed) disease progression. 
Treatment with cemiplimab and/or BNT111 may be continued through initial radiological 
disease progression if the patient derives clinical benefit, e.g., until symptomatic disease, 
confirmation of progression, or unacceptable toxicity (whatever comes first). 
Patients in Arm 2 (BNT111 monotherapy) or Arm 3 (cemiplimab monotherapy) may enter 
add-on therapy (addition of the other compound). The start of the add-on therapy should 
be scheduled with as little therapy interruption as possible and at latest start within 6 wks 
after confirmed disease progression. The duration of therapy for patients entering into add-
on therapy is a total of 24 months for both the monotherapy and add-on therapy part. 
If one of the compounds needs to be discontinued, single-agent treatment with the other 
can continue upon investigator’s and sponsor’s agreement. 
6.4 
Preparation/handling/storage/accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all trial intervention received and any discrepancies are 
reported and resolved before use of the IMPs. 
Only patients enrolled in the trial may receive trial treatment and only authorized trial site 
staff may supply or administer these treatments. All IMPs 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 trial 
site staff. 
The investigator or designee, or the head of the trial site (where applicable) is responsible 
for IMP accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
Further guidance and information for trial treatment preparation and final disposition of 
unused IMP are provided in the Pharmacy Manual. 
6.5 
Measures to minimize bias: randomization and blinding 
This is an open-label trial, potential bias in assigning patients to treatment groups will be 
reduced by automated randomization. Information on trial treatment will be inaccessible for 
the radiologists that assess the CT scans by central review (primary analysis, BICR). 

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6.6 
Trial treatment compliance 
Patients will receive trial treatment directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered must be recorded in 
the source documents and recorded in the electronic case report form (eCRF). The dose 
of both trial treatments and trial patient identification will be confirmed by a member of the 
trial site staff other than the person administering the trial treatment. 
6.7 
Concomitant therapy 
6.7.1 
Permitted concomitant therapy 
Any operation, treatment, medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) or other specific categories of interest 
that the patient is receiving at the time of enrollment or receives during the trial must be 
recorded along with: 
• 
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. 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “prohibited” 
(Section 6.7.2). 
• 
Palliative radiotherapy during the trial will be allowed for local symptom control 
(e.g., pain) provided that: 
− 
(i) in the opinion of the investigator, the patient does not have PD AND 
− 
(ii) no more than 10% of the patient’s bone marrow is irradiated AND 
− 
(iii) the radiation field does not encompass a target lesion. 
• 
G-CSF and other hematopoietic growth factors may be used in the management 
of acute toxicity, such as febrile neutropenia, when clinically indicated or at the 
investigator’s discretion. 
• 
Blood cell transfusion or platelet transfusion is allowed during the trial if clinically 
indicated. No transfusion is allowed within 1 wk prior to trial treatment initiation. 
• 
Steroid treatment is permitted to modulate symptoms of an irAE at the discretion 
of the investigator. Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is 
permitted. However, whenever possible corticosteroid treatment (prednisone 

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> 5 mg daily orally [PO] or IV, or equivalent) should be avoided as it counteracts 
with the mechanism of action of the vaccine. 
6.7.2 
Prohibited concomitant therapy 
The following concomitant therapies and medications are not allowed during the treatment 
phase: 
• 
Any concomitant systemic anti-cancer therapy defined as any agent or 
combination of agents with clinically proven anti-neoplastic activity that achieves 
non-negligible systemic bioavailability after being administered by any route for 
affecting the malignancy, either directly or indirectly, including palliative and 
therapeutic objectives. 
• 
Any immunosuppressive therapy including immunosuppressive or maintenance 
therapy with systemic corticosteroids (PO or IV prednisone > 5 mg per day, or 
its equivalent), unless required per investigator’s decision for treatment of 
an AE (maintenance therapy of prednisone > 5 mg should be discussed with the 
medical monitor). 
Note: Replacement therapy (e.g., physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 
and is permitted. 
• 
Immunization with live-attenuated vaccines 28 days prior to the first dose of 
BNT111 and 3 months after the last dose of BNT111. 
• 
Concomitant treatment with interferon is prohibited for all patients included into 
the trial. 
If a patient receives any of these during the trial, the sponsor must be notified for 
evaluation of whether the patient can continue treatment or not. 
6.8 
Dose modifications and interruptions 
6.8.1 
Interruption of the intravenous infusion of cemiplimab 
The infusion of cemiplimab should be interrupted if any of the following AEs are observed: 
• 
sustained/severe cough 
• 
rigors/chills 
• 
rash, pruritus (itching) 
• 
urticaria (hives, welts, wheals) 
• 
diaphoresis (sweating) 
• 
hypotension 
• 
dyspnea (shortness of breath) 

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• 
vomiting 
• 
flushing 
The reaction(s) should be treated symptomatically. The restart of the infusion at an 
infusion rate of 50% on the same day is at the discretion of the investigator if the 
NCI-CTCAE grade of the AE is Grade ≤ 1. For any AE with a NCI-CTCAE Grade ≥ 2, no 
restart of the infusion on the same day is permitted yet continuation of trial therapy may be 
allowed depending of the evolution of the AE. 
6.8.2 
Dose modification for BNT111 
Treatment must be discontinued if any of the following applies: 
• 
First occurrence of anaphylaxis or a Grade 4 injection-related reaction (IRR). 
• 
Second occurrence of Grade ≥ 3 IRR regardless of pre-medication prior to the 
next administration of BNT111. 
• 
Re-treatment at a lower dose leads to a further identical ADR of Grade ≥ 3. 
• 
ADR of Grade ≥ 3 which fails to resolve to Grade ≤ 1 within 21 days after the 
planned dosing date. 
Note: Asymptomatic Grade 3 to 4 elevations of non-hematological laboratory values 
that resolve to NCI-CTCAE Grade ≤ 2 within 14 days (with or without medical 
intervention) do not require treatment discontinuation. 
• 
Dose delay of more than 21 days (longer delays may be permitted after 
consultation with the medical monitor). 
The dose should be reduced or withdrawn if at least one of the following ADRs occurred in 
a given patient receiving BNT111 vaccinations, regardless of pre-medication: 
• 
Grade 4 fever. 
• 
Grade 3 fever and Grade 3 hypotension. 
• 
Grade 4 hypotension. 
• 
No dose reduction of BNT111 below
µg total RNA is allowed. 
Further dose modification is outlined in Figure 2. Following dose reduction of BNT111, no 
dose re-escalation is permitted. If the BNT111 dose is not increased from the initial
µg 
to 
µg total RNA due to an AE on C1D8 (or AOC1D8), dose-escalation may be 
considered at C1D15 or during Cycle 2. This should only be carried out following 
consultation with a medical monitor and if the AE has abated and can be controlled 
through supportive medication in the future. 
If the investigator is not able to attribute the toxicity to either cemiplimab or BNT111, 
cemiplimab should be interrupted or discontinued and BNT111 doses to be modified per 
CCI
CCI
CCI

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Figure 2. Further dose modifications should be based on clinical judgment by the 
investigator and after discussion with the sponsor’s medical monitor. 
 
 
 
Figure 2: 
Dose modification for BNT111 
Note: Exceptions can be made for recurrent Grade 3 AEs that do not impact the safety of the patient (e.g., short-lasting 
Grade 3 fever) after discussion with the medical monitor. 
1 Dose delay: Next dose of BNT111 can be delayed by a maximum of 21 days, unless approved otherwise by the 
sponsor’s medical monitor. 
2 No further delay for recovery allowed, unless baseline NCI-CTCAE grade was Grade ≥ 2 and TEAE has resolved to 
baseline grade. 
Abbreviations: G = grade; grading according to NCI-CTCAE v5.0. 
 
6.8.3 
Dose modification for cemiplimab 
No dose reductions are recommended. Dosing delay or treatment discontinuation may be 
required based on individual safety and tolerability. Recommended modifications to 
manage adverse reactions are provided in Table 3 and in the cemiplimab (LIBTAYO®) 
locally approved label. 
 

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6.8.4 
Mitigation plans for specific AEs 
6.8.4.1 
BNT111 
It is anticipated that patients may experience AEs of flu-like symptoms following the 
administration of BNT111 due to its mechanism of action. This may include, but is not 
limited to fever, tachycardia, arthralgia, myalgia, headache, nausea, chills and rigors. 
Sporadically patients also experienced moderate to severe hypotension that is potentially 
related to the pharmacodynamic effect of BNT111. Treatment of these events is 
dependent on the discretion of the investigators; however, guidance for monitoring and 
suggestions for management are provided below. 
Safety monitoring, prophylaxis, and treatment of fever and associated symptoms 
• 
Vital signs must be monitored prior, during and after injection: 
− 
Within 60 min prior to first injection. 
− 
At 30 min, 60 min, 4 h and 6 h after last injection of BNT111 vaccine. If no 
Grade ≥ 2 in the first cycle (3 vaccinations), 4 h and 6 h post dose may be 
skipped as per investigator’s discretion and as per local clinical standard 
practice in subsequent cycles. 
− 
Optional at 24 h, based on symptomatology, clinical necessity and/or local 
clinical standard practice. 
− 
Observation period should be prolonged in case of Grade ≥ 2 fever and 
Grade ≥ 2 hypotension in the first 6 h until resolution of fever to Grade ≤ 1 and 
full resolution of hypotension. 
− 
Additional time points to be added at investigator's discretion. 
• 
If a patient develops fever of ≥ 38°C after the administration of the BNT111 
vaccine (during the observation period), secondary prophylactic pre-treatment with 
paracetamol and/or NSAIDs prior to all further vaccination cycles is 
recommended, at least 60 min before BNT111 vaccine administration followed by 
a second dose 2 to 8 h after BNT111 vaccine. 
• 
Corticosteroid should be avoided as either prophylaxis or treatment as it 
counteracts the pharmacodynamic effects of BNT111 vaccine. 
 

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radiographic imaging as indicated based on clinical evaluation and managed with 
cemiplimab treatment modifications and corticosteroids (see Table 3). 
Immune-related colitis 
Immune-related diarrhea or colitis, defined as requiring use of corticosteroids with no clear 
alternate etiology, has been observed in patients receiving cemiplimab (see locally 
approved label). Patients should be monitored for signs and symptoms of diarrhea or 
colitis and managed with cemiplimab treatment modifications, anti-diarrheal agents, and 
corticosteroids (see Table 3). 
Immune-related hepatitis 
Immune-related hepatitis, defined as requiring use of corticosteroids with no clear alternate 
etiology, including fatal cases, has been observed in patients receiving cemiplimab (see 
locally approved label). Patients should be monitored for abnormal liver tests prior to and 
periodically during treatment as indicated based on clinical evaluation and managed with 
cemiplimab treatment modifications and corticosteroids (see Table 3). 
Immune-related endocrinopathies 
Immune-related endocrinopathies, defined as treatment-emergent endocrinopathies with 
no clear alternate etiology, have been observed in patients receiving cemiplimab (see 
locally approved label). 
Thyroid disorders (hypothyroidism/hyperthyroidism) 
Immune-related thyroid disorders have been observed in patients receiving cemiplimab. 
Thyroid disorders can occur at any time during the treatment. Patients should be 
monitored for changes in thyroid function at the start of treatment and periodically during 
the treatment as indicated based on clinical evaluation (see locally approved label). 
Patients should be managed with hormone replacement therapy (if indicated) and 
cemiplimab treatment modifications. Hyperthyroidism should be managed according to 
standard medical practice (see Table 3). 
Hypophysitis 
Immune-related hypophysitis has been observed in patients receiving cemiplimab (see 
locally approved label). Patients should be monitored for signs and symptoms of 
hypophysitis and managed with cemiplimab treatment modifications and corticosteroids 
(see Table 3). 
Adrenal insufficiency 
Adrenal insufficiency has been observed in patients receiving cemiplimab (see locally 
approved label). Patients should be monitored for signs and symptoms of adrenal 
insufficiency during and after treatment and managed with cemiplimab treatment 
modifications and corticosteroids (see Table 3). 

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Type 1 Diabetes mellitus 
Immune-related type 1 diabetes mellitus, including diabetic ketoacidosis, has been 
observed in patients receiving cemiplimab (see locally approved label). Patients should be 
monitored for hyperglycaemia and signs and symptoms of diabetes as indicated based on 
clinical evaluation and managed with oral anti-hyperglycaemics or insulin and cemiplimab 
treatment modifications (see Table 3). Cemiplimab should be withheld and anti-
hyperglycemics or insulin should be administered in patients with severe or life-threatening 
(Grade ≥ 3) hyperglycaemia. Cemiplimab should be resumed when metabolic control is 
achieved on insulin replacement or anti-hyperglycemics (see Table 3). 
Immune-related skin adverse reactions 
Immune-related skin adverse reactions, defined as requiring use of systemic 
corticosteroids with no clear alternate etiology, including severe cutaneous adverse 
reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal 
necrolysis (TEN) (some cases with fatal outcome), and other skin reactions such as rash, 
erythema multiforme, pemphigoid, have been reported in association with cemiplimab 
treatment (see locally approved label). 
Patients should be monitored for evidence of suspected severe skin reactions and exclude 
other causes. Patients should be managed with cemiplimab treatment modifications and 
corticosteroids (see Table 3). 
Cases of SJS, fatal TEN and stomatitis occurred following one dose of cemiplimab in 
patients with prior exposure to idelalisib, who were participating in a clinical trial evaluating 
cemiplimab in Non-Hodgkin Lymphoma (NHL), and who had recent exposure to sulfa 
containing antibiotics (see locally approved label). Patients should be managed with 
cemiplimab treatment modifications and corticosteroids as described above (see Table 3). 
Immune-related nephritis 
Immune-related nephritis, defined as requiring use of corticosteroids with no clear 
alternate etiology, has been observed in patients receiving cemiplimab (see locally 
approved label). Patients should be managed with cemiplimab treatment modifications and 
corticosteroids (see Table 3). 
Other immune-related adverse reactions 
Other fatal and life-threatening immune-related adverse reactions have been observed in 
patients receiving cemiplimab including paraneoplastic encephalomyelitis and meningitis 
(see locally approved label for other immune-related adverse reactions). 
Patients should be monitored for signs and symptoms of immune-related adverse 
reactions and managed with cemiplimab treatment modifications and corticosteroids (see 
Table 3). 
Infusion-related reactions 
Cemiplimab can cause severe or life-threatening infusion-related reactions (see locally 
approved label). Patients should be monitored for signs and symptoms of infusion-related 

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reactions and managed with cemiplimab treatment modifications and corticosteroids. 
Cemiplimab should be interrupted or the rate of infusion slowed for mild or moderate 
infusion-related reactions. The infusion should be stopped and cemiplimab should be 
permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) infusion-
related reactions (see Table 3). 
Patients previously treated with idelalisib 
Any patient receiving cemiplimab who was previously treated with a PI3K inhibitor and who 
develops stomatitis or mucositis should suspend trial treatment. If this or any other irAE 
occurs among these patients, the sponsor should be informed about it as soon as possible 
as an AE of special interest (AESI) to discuss further management of the patient. 
6.9 
Treatment after the end of the trial 
Not applicable. 
7 DISCONTINUATION OF TRIAL TREATMENT AND PATIENT 
DISCONTINUATION / WITHDRAWAL 
7.1 
Discontinuation of trial treatment 
Patients must permanently discontinue trial treatment if any of the following applies: 
• 
Patient withdraws his consent to trial participation. 
• 
Any medical condition that the investigator or sponsor determines may 
jeopardize the patient’s safety if he or she continues to receive trial treatment. 
• 
Investigator or sponsor determination that treatment discontinuation is in the 
best interest of the patient. 
• 
Pregnancy. 
• 
Confirmed disease progression, as determined by the investigator after an 
integrated assessment of radiographic data, biopsy sample results (if available), 
and clinical status (patients in Arms 2 and 3 may continue to combination 
therapy). 
• 
Occurrence of new primary tumor, as assessed by the investigator. 
• 
Intolerable toxicity related to trial treatment, determined by the investigator to be 
unacceptable given the individual patient’s potential response to therapy and 
the severity of the event. 
• 
Substantial non-compliance with trial procedures. 
• 
Use of illicit drugs, prohibited concomitant medications, or other substances that 
may, in the opinion of the investigator, have a reasonable chance of contributing 
to toxicity or otherwise confound the results. 

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• 
Patient is lost to follow-up. 
The primary reason for trial treatment discontinuation should be documented in the 
appropriate eCRF. Patients who discontinue trial treatment will not be replaced. 
Patients who discontinue from treatment will return to the trial site for an end of treatment 
(EoT) Visit within 0 to 21 days after the final dose of trial treatment. 
After treatment discontinuation, patients will be followed-up for safety, efficacy (if 
applicable) and survival (unless the patient withdraws consent, is lost to follow-up or the 
sponsor terminates the trial) for up to 48 months. 
See the SoA (Section 1.3) for data to be collected at the time of discontinuation and follow-
up and for any further evaluations that need to be completed. 
7.1.1 
Temporary discontinuation 
• 
Delay of dosing of BNT111 and/or cemiplimab of up to 21 days is allowed 
(longer delays may be permitted after consultation with the medical monitor). 
• 
If one of the compounds needs to be temporarily discontinued, single-agent 
treatment with the other can continue upon investigator’s and sponsor’s 
agreement. 
7.1.2 
Rechallenge 
Once the dose of BNT111 is reduced, it may not be re-escalated. 
Cemiplimab may either be fully dosed, withheld or permanently discontinued as described 
in Section 6.8.3. No cemiplimab dose reductions are allowed. 
7.2 
Patient discontinuation/withdrawal from the trial 
• 
A patient may withdraw from the trial at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, or 
behavioral, compliance. This is expected to be uncommon. 
• 
At the time of discontinuing from the trial, if possible, an EoT visit should be 
conducted, as shown in the SoA (Section 1.3). 
• 
In case of consent withdrawal, the patient will be permanently discontinued both 
from the trial treatment and from the trial at that time. 
• 
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/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the 
trial source data. 

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7.3 
Lost to follow-up 
A patient will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a patient fails to return to the clinic for a required 
trial visit: 
• 
The trial site staff must attempt to contact the patient and reschedule the missed 
visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the trial. 
• 
Before a patient is considered lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, three 
phone calls and, if necessary, a certified letter to the patient’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the patient’s medical record. 
• 
Should the patient continue to be unreachable, they will be considered to have 
withdrawn from the trial. 
7.4 
Discontinuation of trial by the sponsor 
The sponsor may temporarily pause the trial or discontinue the trial in case new safety 
information becomes available. 
In order to protect the safety and integrity of trial participants, the sponsor will engage in 
continuous medical monitoring of eligibility before the start of trial therapy as well as of all 
AEs including SAEs, suspected unexpected serious adverse reactions (SUSARs) and 
irAEs as well as deaths and laboratory values for all patients in the trial through a 
dedicated Medical Monitoring Plan and a Safety Management Plan. In addition, an IDMC 
will receive full safety information for each of the scheduled meetings (three-monthly 
during the first 12 months following the start of treatment of the first patient, six-monthly 
thereafter). Ad hoc meetings of the IDMC are foreseen by the IDMC charter in case 
circumstances like unexpected findings or safety signals would require so. 
After each IDMC meeting, the IDMC will provide a recommendation to the sponsor 
concerning the continuation of the trial. 
In addition to the scheduled IDMC meetings described above, another IDMC meeting will 
occur after the first ten patients in Arm 1 have been treated for at least two cycles (6 wks) 
or discontinued treatment for any reason during the first two cycles. 
Specific stopping criteria will be based on the cumulative incidence of TEs. TEs include all 
related SAEs, related Grade 3 to 5 TEAEs/irAEs except for transient Grade 3 flu-like 
symptoms, clinically insignificant laboratory abnormalities and Grade 3 hypotension lasting 
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throughout the trial. Skin lesions can be followed by photography. At screening, preferably 
an MRI scan should be done to assess presence of brain metastasis (for patients with a 
contra-indication for MRI, a contrast-enhanced CT scan is allowed). If a patient has brain 
metastasis, stability of the lesions should be confirmed and lesions should be followed at 
each tumor assessment. 
All measurable and evaluable lesions should be assessed at screening and target as well 
as non-target lesions identified and documented following RECIST 1.1 criteria. Tumor 
assessments, including brain imaging, performed as standard of care prior to obtaining 
informed consent and within 28 days prior to randomization do not have to be repeated at 
screening. 
Tumor response will be assessed every 6 (±1) wks for the first 3 months, then every 
9 (±1) wks for the next 9 months and every 12 (±2) wks thereafter, regardless of dose 
delays, until (confirmed) disease progression, death, withdrawal of consent, or until the 
start of next-line anti-cancer therapy, whichever occurs earlier (Section 1.3). 
Lesion photography should be performed for cutaneous or palpable lesions at the required 
tumor assessment time points. When possible, the same individual should photograph and 
measure the lesions for a given patient to decrease intra-patient variability. 
Radiological progression should be confirmed by two scans 4 to 12 wks apart. If 
progression is accompanied by new symptoms or deterioration of PS not attributed to 
toxicity one scan is sufficient. 
Tumor responses will be measured by RECIST 1.1 / iRECIST and are to continue 
according to the schedule in patients who undergo complete trial treatment and in patients 
who discontinue treatment for reasons other than disease progression, consent 
withdrawal, or patient’s withdrawal from the trial. 
The same radiographic procedure used to assess disease sites at screening should be 
used for subsequent tumor assessments (e.g., the same protocol for CT scan). An extra 
scan should be scheduled if clinically indicated. 
The investigator will determine the tumor response based on the radiologist’s 
measurement of all anatomic regions involved according to the RECIST 1.1 and iRECIST 
criteria and make treatment decisions. 
After start of add-on therapy 
Patients in Arms 2 and 3, who experience (centrally verified) disease progression under 
single-agent treatment, may be offered addition of the respective other compound to the 
ongoing treatment. In such cases, tumor assessments are to continue, and additional 
images should be collected in accordance with the imaging schedule and modalities 
outlined in Section 1.3.2. 
The CT or MRI scan or photographs that confirmed disease progression after 
monotherapy can be used as baseline scan for the add-on therapy. The scan/photo should 
not be older than 21 days prior to start of the add-on therapy. At baseline, for patients 

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without brain metastasis during initial therapy, a brain MRI – or CT scan should be 
repeated to assess presence of new brain metastasis. 
For the add-on baseline target lesions and non-target lesions can be redefined. These 
lesions should be re-assessed at each subsequent tumor evaluation. 
Tumor response during add-on therapy will be assessed every 6 (±1) wks for the first 
3 months, then every 9 (±1) wks for the next 9 months and every 12 (±2) wks thereafter, 
regardless of dose delays, until (confirmed) disease progression, death, withdrawal of 
consent, or until the start of next-line anti-cancer therapy, whichever occurs earlier 
(Section 1.3). 
Radiological progression during add-on therapy should be confirmed by a second scan 4 
to 12 wks apart. If progression is accompanied by new symptoms or deterioration of PS 
not attributed to toxicity one scan is sufficient. 
Tumor responses will be measured by RECIST 1.1 / iRECIST and are to continue 
according to the schedule in patients who undergo complete trial treatment and in patients 
who discontinue treatment for reasons other than disease progression, consent 
withdrawal, or patient’s withdrawal from the trial. 
The same radiographic procedure used to assess disease sites at screening should be 
used for subsequent tumor assessments (e.g., the same protocol for CT scan). An extra 
scan should be scheduled if clinically indicated. 
The investigator will determine the tumor response based on the radiologist’s 
measurement of all anatomic regions involved according to the RECIST 1.1 and iRECIST 
criteria and will make treatment decisions. 
8.1.3 
Blinded independent central review 
Digital images from all tumor response assessments, including the screening scan(s), 
must be sent to the independent central review service as outlined in the imaging manual. 
Blinded centralized review and response assessment according to RECIST 1.1/iRECIST 
will take place on a continuous basis. The blinded tumor response evaluation will not be 
shared with the trial sites or have an influence on treatment decisions made by the 
investigator. Where patients have central PD verification in Arm 2 or Arm 3 prior to 
switching to add-on therapy, blinded tumor response evaluation will be permitted to be 
shared with trial sites. 
8.1.4 
Survival follow-up 
After the last trial assessment (i.e., safety or efficacy whichever occurs last) information on 
survival status 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). 

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abnormalities should be recorded in patient notes. New or worsened clinically significant 
abnormalities should be recorded as AEs in the AE eCRF. 
• 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. 
• 
A brief (symptom-directed) physical examination includes an overall health 
judgment. In-depth physical examinations are required if obvious pathological 
signs are visible or in the case the patient states any signs or symptoms. 
8.2.2 
Height and body weight 
Height will be measured at screening only and weight will be measured and recorded 
according to the SoA (Section 1.3). 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.3 
Vital signs 
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed at the 
times given in the SoA (Section 1.3). 
All patients will be observed for at least 6 h after the first three administrations of BNT111 
and the first administration of cemiplimab. A decision on a possible extension of the 
observation time to 24 h will be made at the discretion of the investigator at time of 
discharge. 
In case a given patient tolerated the administration of the trial treatment without 
occurrence of significant inflammatory ADRs during the first three vaccinations (or during 
the next treatment cycle) of BNT111, an observation period of 2 to 4 h is acceptable at the 
discretion of the investigator. Prior to the dismissal of the patient, vital signs should be 
measured. From the second administration of cemiplimab, no observation time is 
stipulated with reference to cemiplimab (local protocol should be followed). 
Blood pressure (systolic/diastolic, in mmHg) and pulse (in bpm) measurements will be 
assessed while the trial patient is in a supine position/at rest. If available, a completely 
automated device should be used, otherwise manual techniques can be used. The same 
method of measurement should be used for the trial patient during the course of the trial. 
Blood pressure and pulse measurements should be preceded by at least 5 min of rest for 
the trial patient in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs to be taken before blood collection for laboratory tests. 
Abnormalities observed at screening/baseline should be reported in the General Medical 
History. New or worsened clinically significant abnormalities observed at subsequent visits 
should be recorded in the AE eCRF. 

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8.2.4 
Electrocardiograms 
Single 12-lead electrocardiograms (ECG) will be obtained as outlined in the respective 
SoAs using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc (F) (QT interval corrected for heart rate according to the Fridericia 
formula) intervals. 
The investigator must review the ECG, document this review, and record any clinically 
relevant changes occurring during the trial in the AE section of the eCRF. 
8.2.5 
Safety laboratory assessments 
See Section 10.2 for the list of safety laboratory assessments to be performed and to the 
SoA (Section 1.3) for the timing and frequency. 
All clinical laboratory assessments will be analyzed centrally at the time points outlined in 
the respective SoAs. Local assessments will be carried out in order to make a decision on 
the dosing and as otherwise specified in the SoAs (Section 1.3). Centrally analyzed 
screening laboratory results must be obtained within 10 d prior to initiation of trial 
treatment, if not otherwise specified. 
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 90 days after the last dose of trial intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or the sponsor’s medical monitor. Unscheduled laboratory 
tests can be done locally, or sent to the central laboratory. 
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 local laboratory assessments 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. If both central and local laboratory assessments are 
done at the same time, the highest grade of clinically significant abnormal findings will be 
reported and collected in the eCRF. 
8.2.6 
Viral serology 
Viral serology screening will be performed using a commercially available kit at the times 
given in the SoA (Section 1.3). 

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The screen will test for hepatitis B core antibodies (anti-HBc), hepatitis B surface antigens 
(HBsAg), hepatitis surface antibodies (anti-HBs), HCV antibodies (anti-HCV). Additionally, 
HIV (1/2) testing is required if the patient has never been tested for HIV, or if testing was 
done prior to primary cancer diagnosis or performed ≥ 12 months prior to trial start. 
8.2.7 
Safety follow-up (SFU1 and SFU2) 
Patients will be followed-up for safety assessments at two safety follow-up visits (SFU1 
and SFU2) after last treatment, where all AEs and concomitant medications must be 
reported. If the patient is not able to attend the clinic due to his/her clinical condition, a 
phone call should be done to assess possible AEs. 
The first safety follow-up visit (SFU1) takes place 30 (+ 5) days after last treatment and the 
second safety follow-up visit (SFU2) takes place 90 (±7) days after last treatment. 
8.3 
Adverse events and serious adverse events 
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 all AEs and SAEs. 
8.3.1 
Time period and frequency for collecting adverse event and serious 
adverse event information 
All AEs and SAEs will be collected from the first signing of the ICF until the SFU2 visit 
(90 days after last trial dose or until a new anti-cancer therapy is started) at the time points 
specified in the SoA (Section 1.3). Additionally, in case a new anti-cancer therapy is 
started within 90 days after last treatment, the safety follow-up visit should be performed 
just prior to starting the new anti-cancer therapy. Adverse events after start of new anti-
cancer therapy do not need to be reported unless a causal relationship to BNT111-01 or 
cemiplimab is suspected. 
All SAEs (initial and follow-up reports) will be recorded and reported to the sponsor or 
designee within the appropriate time frame and under no circumstance should this exceed 
24 h after knowledge of the event, as indicated in Section 10.3.1.10. AESIs should also be 
reported within an appropriate time frame (i.e., no more than 24 h after knowledge of the 
event). 
Investigators are not obligated to actively seek AEs or SAEs after a patient has 
discontinued from the trial. However, if the investigator learns of any SAE, including a 
death, at any time after a patient has discontinued 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. 
8.3.2 
Method of detecting adverse events and serious adverse events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 

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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.3 
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 AEs/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 10.3.1.7. 
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 the 90-day safety follow-up period, 
the investigator will provide the sponsor with a copy of any post mortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to the sponsor within 24 h of receipt of 
the information. 
All ongoing AEs/SAEs will be followed until resolution, considered by the investigator to be 
stable or chronic (resolved with sequelae), the patient is lost to follow-up or the patient 
withdraws consent. If no final status is reached at SFU2 (90 days after last trial treatment), 
the investigator must confirm the unavailability of a final status. 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor 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 (IRBs)/independent ethics 
committees (IECs), and investigators. The execution of expedited reporting to the different 
entities may be delegated as detailed in the trial-specific Safety Management Plan. 
Safety reports will be prepared for SUSARs according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
For events related to IMPs, it is the sponsor’s or delegate’s responsibility to perform 
SUSAR reporting to the regulatory authority, the IRB/IEC and the other investigators as 
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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 should 
review it and then file it together with the IB. If required by local requirements, the 
investigator will notify the relevant IRB/IEC. 
8.3.5 
Pregnancy 
Pregnant and breastfeeding women are excluded from participation in the trial. Any 
WOCBP must have a negative pregnancy test (beta-HCG) at baseline and be willing to 
use highly effective methods of contraception (less than 1% of unintended pregnancies per 
year, according to ICH M3) for the duration of trial treatment until 6 months after the last 
administration of the trial drug. Male patients must use an accepted contraceptive method 
for the duration of trial treatment and at least 6 months after the last administration of the 
trial drug. 
If a pregnancy occurs during the trial and within 90 days after the last trial treatment, the 
investigator should inform the sponsor within 24 h of knowledge of the pregnancy and 
should follow the procedures outlined in Section 10.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Death events 
Any death that occurs within the observation period (from the first signing of the ICF until 
90 d after the last trial dose) will be reported as an SAE. A copy of an autopsy report 
should be submitted if available upon request. Date and cause of death will be recorded. 
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 for 
the AE leading to death the outcome “fatal” should be selected. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, the most likely reason for 
death should be documented as event term. 
Deaths due to disease progression occurring within 90 days of the last trial treatment 
must be reported as a Grade 5 SAE. The AE term on the SAE form should be reported as 
“disease progression” of the disease under trial treatment, i.e., “progression of 
advanced/metastatic melanoma”. All deaths due to disease progression occurring after 
90 days from the end of trial treatment will be reported on the trial-specific death page of 
the eCRF. 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as 
AEs or SAEs 
Non-fatal events that are clearly consistent with the expected pattern of progression of the 
underlying disease (e.g., new metastases) should not be recorded as AEs. These data will 
be captured as efficacy assessment data only and will be recorded on the tumor response 
evaluation pages in the eCRF. In most cases, the expected pattern of progression will be 
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based on symptomatic deterioration; however, every effort should be made to document 
progression using objective criteria. 
If there is any uncertainty as to whether an event is due to disease progression, it should 
be reported as an AE. 
Note: Symptoms resulting from the progression and clearly stated as related to the PD will 
not be documented as AEs nor reported as SAEs. However, specific symptoms at time of 
progression that may be caused by other reason and death due to disease progression, 
will have to be documented as AEs and reported as SAEs if applicable. 
8.3.8 
Immune-related adverse events 
irAEs are defined in Appendix 12.1. The investigators are asked to pay special attention to 
the detection and reporting of irAEs and their relationship to either of the treatments. 
8.4 
Adverse events of special interest 
An AESI, serious or non-serious, is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor are appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulators) might 
also be warranted. 
The following AEs should be reported if related to cemiplimab: 
• 
Grade ≥ 2 infusion-related reactions are considered AESIs and must be reported 
within 24 h of identification by the investigator. 
• 
Grade ≥ 3 irAEs are considered AESIs and should be reported within 24 h of 
identification by the investigator. 
 Note: An irAE can occur shortly after the first dose or several months after the last dose of 
treatment. All AEs of unknown etiology associated with drug exposure should be evaluated 
to determine possible immune etiology. If an irAE is suspected, efforts should be made to 
rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an 
AE as an irAE. 
AESI including non-serious AESI should be reported via the SAE Report Form according 
to the timelines and contact details given in Section 10.3.1.10 of this protocol. For non-
serious AESI, the seriousness criterion should not be reported/selected as these non-
serious AESIs are to be reported according to the timelines of SAEs, but mostly do not 
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8.5 
Treatment of overdose 
For this trial, accidental or intentional overdose is defined as at least two times the 
intended dose of trial treatment within the intended therapeutic window, if associated with 
an AE. 
In the event of an overdose, the investigator should: 
• 
Contact the medical monitor immediately (within 24 h). 
• 
Closely monitor the patient for any AE/SAE and laboratory abnormalities. 
• 
Document the quantity of the excess dose as well as the duration of the 
overdose in the eCRF. 
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. 
8.6 
Pharmacokinetics 
Not applicable. 
8.7 
Pharmacodynamic 
Blood samples will be collected from all trial patients at time points shown in the respective 
SoAs (Section 1.3) to characterize pharmacodynamic markers (e.g., IFN-α, IFN-γ, IL-6, IL-
10, IP-10, TNF-α, and IL12p70 cytokine levels) under treatment with BNT111 and 
cemiplimab in combination or as single agents. 
Detailed information about the handling, labeling, and shipment of samples for 
pharmacodynamic analysis will be provided in a separate document (i.e., Laboratory 
Manual). 
8.8 
Genetics 
Tumor tissue will be collected from all trial patients in order to retrospectively evaluate 
tumor mutational burden as potential outcome-predictive biomarker. Mutational analysis 
will be performed by use of predefined gene panels addressing only somatic mutations. 
An optional whole blood sample will be collected in order to perform pharmacogenomics 
analyses if the patient has consented to this using the ICF. Respective analyses will be 
performed by use of whole exome sequencing, whole genome sequencing and/or 
genotyping analyses of genomic DNA (including germline variants). Detailed information 
about the handling, labeling, and shipment of samples for genetic analysis will be provided 
in a separate document (i.e., Laboratory Manual). 
8.9 
Biomarkers 
Participation in the biomarker sub-study is possible even if no paired biopsies are feasible. 
Tumor tissue will be collected from all trial patients in order to retrospectively test BNT111 

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target antigen expression, and potential outcome-predictive biomarkers and immune 
signature molecules (e.g., PD-L1 expression) at screening. 
For patients in Arms 1 or 2, or add-on treatment at selected trial sites: 
Blood samples will be collected from trial patients after randomization to Arm 1, 2, or add-
on treatment, at subsequent time points shown in the respective SoAs (Section 1.3) in 
order to isolate PBMCs for analysis of cellular immune responses. 
In addition, when feasible and consented, paired biopsies will be performed at screening 
and approximately 6 to 8 wks after treatment start (and optionally at progression) to collect 
fresh tumor tissue. The fresh tumor tissue (non-FFPE material) will be collected in order to 
investigate anti-tumor specific activity within the tumor under treatment compared to before 
treatment by e.g., functional T cell tests (e.g., enzyme-linked immunospot [ELISpot], 
cytotoxicity assays with autologous tumor cell lines), phenotypic characterization of TILs 
and analysis of TCR repertoire (by e.g., RNA sequencing). The tumor sample can be from 
a core biopsy or from resected tumor tissue. Fine needle aspirates and cytological 
specimens are not acceptable. In patients who have had biopsies taken during BNT111 
monotherapy, the number of biopsies during add-on is to be adjusted as appropriate (up to 
three in total during the duration of the trial). For patients who are part of the biomarker 
sub-study (Arms 1 or 2, or add-on treatment), if a biopsy is not taken at baseline prior to 
the first dose of BNT111, no subsequent biopsies are to be taken during the trial as part of 
the biomarker sub-study procedures. It is recommended to perform the biopsy on 
progression only if 4 wks or more have elapsed since the last biopsy (on-treatment 
biopsy). If the time is shorter, no biopsy on progression should be taken. 
For all trial sites, if any biopsies or resections are to be performed as part of standard 
clinical care, tissue samples from such procedures should be provided (if feasible) for the 
sponsor for biomarker testing. 
The biomarker parameters will be analyzed by different laboratories (central laboratory and 
specialty laboratories). Detailed information about the handling, labeling, and shipment of 
samples and biomarker analysis will be provided in separate documents (i.e., Laboratory 
Manual). Samples for future research purposes will be retained for use for up to 5 years 
after the end of this clinical trial. 
8.10 Immunogenicity assessments 
Analysis of cellular immune responses in peripheral blood under treatment compared to 
the response at screening will be performed by functional T cells tests (e.g., ELISpot) and 
phenotypic characterization of tumor-antigen-specific T cells (e.g., flow cytometry). For the 
latter, an additional blood sample will be collected for characterization of the respective 
HLA types. For detailed information about the handling, labeling, and shipment of samples 
and biomarker analysis will be provided in separate documents (i.e., Laboratory Manual). 
8.11 Blood collection 
The blood volumes taken per patient are described below: 

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This trial will investigate an experimental medicine; therefore, the sponsor may decide to 
draw up to five additional blood samples for explorative biomarker/immunogenicity 
research purposes. Blood draw volumes may vary, but the total blood volume drawn at 
any single time point will not exceed 200 mL. 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical hypotheses 
The primary endpoint is ORR and the primary statistical objective is to demonstrate that 
the ORR of BNT111 + cemiplimab is greater than 
using an overall significance level 
of
 
 
Regarding Arms 2 and 3, i.e., single-agent BNT111 and cemiplimab, respectively, the 
primary endpoint ORR will be analyzed descriptively in a non-confirmatory sense in order 
to obtain an estimate for the single-agent anti-cancer activity. No formal statistical 
comparisons between treatment groups will be performed and no statistical hypothesis is 
defined. Hence, no further adjustments are required to control the overall type I error. 
9.2 
Sample size determination 
The original sample size calculation for the BNT111 + cemiplimab group (Arm 1) is based 
on the following specifications and assumptions: 
Based on these specifications, at least
patients are planned to be randomized into the BNT111 + cemiplimab 
group. The assumed true effect size for ORR is based on preliminary data of the ongoing 
Phase I Lipo-MERIT trial with a selected population of patients with melanoma. 
After the originally planned interim analysis (IA1), where there were
patients in the BNT111 + cemiplimab group, one additional interim analysis (IA2) will be 
performed. IA2 will assess efficacy after
of the planned number of
patients 
are response evaluable (i.e., having at least two post-screening tumor assessments or 
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All safety analyses will be based on the treatment actually taken by the patient (‘as 
treated’). All other analyses will be based on the treatment the patient was randomized to 
(‘as randomized’), unless stated otherwise. 
9.4 
Statistical analyses 
Statistical analyses will be performed by 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 SAP will be finalized prior to database snapshot for the primary analysis and before a 
substantial amount of data have been collected (within approximately 3 months after first 
patient in). The SAP will include a more technical and detailed description of the statistical 
analyses described in this section. Any deviations from the planned analyses described in 
the final SAP will be described and justified in the clinical trial report. This section is a 
summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1 
General considerations 
In general, the statistical analysis will be performed by treatment group. Additionally, for 
each calibrator arm the secondary analyses will be performed based on subsequent 
single-agent treatment following progression. 
Continuous variables will be summarized by treatment group using the following 
descriptive statistics: number of patients (n), mean, standard deviation, median, minimum 
and maximum. 
Categorical variables will be summarized by treatment group presenting absolute and 
relative frequencies (n and %) of patients in each category. 
Time-to-event-endpoints will be analyzed using Kaplan-Meier methodology by treatment 
group 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 anticancer medicinal products in man”. Censoring rules will be defined in the 
SAP. 
The median survival time including two-sided 95% confidence limits according to 
(Brookmeyer and Crowley 1982) and the first and third quartile will be presented for each 
treatment group. Survival rates including two-sided 95% confidence interval based on 
Greenwood’s formula (Greenwood 1926) 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 by treatment group 
and strata. 
Baseline is defined as last available value prior to the first dose. 

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Regarding the calibrator arms (i.e., single-agent BNT111 and cemiplimab, respectively) 
the primary endpoint ORR will be analyzed descriptively in a non-confirmatory sense in 
order to obtain an estimate for the single-agent anti-cancer activity. No formal statistical 
comparisons between treatment groups will be performed. Hence, no further adjustments 
are required to control the overall type I error. 
9.4.3 
Secondary endpoints 
The secondary analyses will be performed using the 
set. 
The secondary endpoints related to tumor assessments (e.g., DCR, DOR, PFS) are based 
on independent read using RECIST 1.1 criteria. The endpoints based on iRECIST criteria 
will be evaluated as exploratory analysis. The endpoints based on investigator’s criteria 
will be evaluated as exploratory analysis. 
Disease control rate 
DCR is defined as the proportion of patients in whom a CR or PR or SD (SD assessed at 
least 6 wks [+/- 1 wk] after first dose) is observed as best overall response. Patients not 
meeting the criteria for CR or PR or SD, including those without any post-randomization 
tumor assessments, will be considered as non-responders. 
DCR will be summarized with absolute and relative frequencies along with two-sided 
Clopper-Pearson 95% confidence intervals by treatment group. 
Time to response 
TTR is defined as the time from randomization to first objective response (CR or PR). Only 
patients in whom a CR or PR is observed will be analyzed for TTR. 
TTR will be analyzed using summary statistics by treatment group. 
Duration of response 
DOR is defined as the time from first objective response (CR or PR) to first occurrence of 
objective tumor progression (PD), or death from any cause, whichever occurs first. Only 
patients in whom a CR or PR is observed will be analyzed for DOR. 
DOR will be analyzed using Kaplan-Meier methodology by treatment group. Patients alive 
and without disease progression at data cut-off date or patients lost to follow-up will be 
censored at the day of their last tumor assessment. Additional censoring rules will be 
defined in the SAP. 
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Progression-free survival 
PFS is defined as the time from randomization to first objective tumor progression (PD 
according to RECIST 1.1), or death from any cause, whichever occurs first. 
PFS will be analyzed using Kaplan-Meier methodology by treatment group/cohort. Patients 
alive and without disease progression or patients lost to follow-up at data cut-off date will 
be censored at the day of their last tumor assessment. Additional censoring rules will be 
defined in the SAP. 
Overall survival 
OS is defined as the time from randomization to death from any cause. 
OS will be analyzed using Kaplan-Meier methodology by treatment group. Patients alive or 
patients lost to follow-up at date of analysis cut-off will be censored at the day of their last 
date known to be alive. Additional censoring rules will be defined in the SAP. 
Health-related quality of life 
HRQoL will be measured by EORTC QLQ-C30 using PGIS and PGIC for calibration 
HRQoL will be assessed through changes from baseline in the global health status score 
and individual scores of the EORTC QLQ-C30 as well as first clinically meaningful 
deterioration in global health status score and individual scores of the EORTC QLQ-C30. 
9.4.4 
Exploratory endpoints 
The exploratory analyses will be detailed in the SAP. 
9.4.5 
Safety analyses 
Safety data that will be summarized includes AEs, safety laboratory parameters, vital signs 
and ECGs. All safety analyses will be based on the safety set and will be summarized 
descriptively by treatment group unless otherwise stated. 
Adverse events 
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 

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• 
related SAE 
• 
SAE leading to death 
• 
AEs leading to dose reduction 
• 
AE leading to permanent discontinuation of treatment 
• 
any irAE (listed in Appendix 12.1) 
Moreover, the number and percentage of patients with any AE will be summarized by 
worst NCI-CTCAE grade by PT nested within SOC. 
Laboratory parameters 
Safety laboratory assessments to be summarized include hematology, blood chemistry, 
and urinalysis. The safety laboratory parameters to be assessed are listed in Section 10.2 
and the scheduled time points for assessment are outlined in the SoAs (Section 1.3). 
Safety laboratory parameters at each time point and change from baseline to each post-
baseline time point will be summarized using descriptive summary statistics for each 
parameter by treatment group. 
Safety laboratory results will be classified according to the most recent version of 
NCI-CTCAE. Shift tables from baseline to worst grade on treatment will be provided for 
each laboratory parameter by treatment group. 
Additionally, the occurrence of clinically significant abnormal laboratory results within a 
patient will be analyzed using descriptive summary statistics for each parameter and visit 
by treatment group. 
Laboratory results will be listed along with the normal ranges and NCI-CTCAE grade. 
Laboratory values that are below or above the normal ranges will be flagged. 
Vital signs 
Vital sign parameters and the scheduled time points for assessment are presented 
Section 8.2.3 and Section 1.3. 
Vital sign parameters at each time point and change from baseline to each post-baseline 
time point will be summarized using descriptive summary statistics for each parameter by 
treatment group. 
Additionally, the occurrence of abnormal vital sign results within a patient will be analyzed 
using descriptive summary statistics for each parameter and visit by treatment group. 
ECG 
ECG parameters and the scheduled time points for assessment are presented in 
Section 8.2.4 and Section 1.3. 

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ECGs will be judged by the investigator as clinically significant (yes/no). The number and 
percentage of patients with clinically significant ECG findings will be summarized by 
treatment group for each visit. 
9.4.6 
Other analyses 
Other analyses including treatment exposure will be detailed in the SAP. 
9.5 
Interim analyses and analysis sequence 
The IA1 for efficacy has been performed after there were
of the planned number of 
patients in Arm 1.  
The IA2 for efficacy will be performed after
of the planned number of
 patients 
in Arm 1 are response evaluable (i.e., having at least two post-baseline tumor 
assessments or discontinued before). 
The primary analysis of the trial will be performed based on all available data from a 
clinical data cut-off that will occur when all the planned
patients in Arm 1 are 
response evaluable (i.e., having at least three post-baseline tumor assessments or 
discontinued before). 
An analysis update will be performed when the last patient discontinued from the trial and 
once all patients have been randomized and have been followed-up for at least 24 months. 
An analysis update may be subsequently performed. 
Further details will be specified in a separate IDMC Charter. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 Regulatory, ethical, and trial oversight considerations 
This trial will be conducted in according to this protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, GCP, and applicable regulatory requirements. 
10.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable ICH GCP Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) will be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the trial is initiated. 
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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: 
• 
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. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• 
Providing oversight of the conduct of the trial at the trial site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 (if applicable), and all other applicable local regulations. 
The principal investigator, any investigator(s), the sponsor, or personnel at other 
establishments, must cooperate with any inspection of the documents, facilities, records, 
and other resources considered appropriate by the inspecting authorities to be related to 
the trial and that may be located at the trial site, at the sponsor, or at other establishments. 
The sponsor must be notified as soon as possible about any upcoming regulatory authority 
inspection. 
10.1.2 
Financial disclosure 
All 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 local regulations (e.g., 21 CFR 50), ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/IEC or trial site. 
The ICF must be signed prior to performance of any trial-related activity. The ICF that is 
used must be approved both by the sponsor and by the reviewing IRB/IEC. 
The medical record must include a statement that written informed consent was obtained 
using the ICF before the patient was enrolled in the trial and the date the written consent 

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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 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 must sign a new ICF. 
Patients will be informed in their native language, comprehensive, concise, clear, relevant, 
and understandable to a layperson, that their participation is voluntary and that they are 
free not to participate in the trial and may withdraw consent to participate at any time. They 
will be told which alternative treatments are available if they refuse to take part and that 
such refusal will not prejudice future treatment. Finally, they will be told that their records 
may be examined by competent authorities and authorized persons but that their personal 
data will be treated as strictly confidential and will not be publicly available. Patients must 
be given the opportunity to ask questions. 
10.1.4 
Data protection 
Patients will be assigned a unique identifier by the investigator according to the sponsor 
specifications on unique identifier assignment. 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 laws. 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 their medical records may be examined by sponsor 
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 
Committee’s structure (IDMC) 
An IDMC will be established to review the interim efficacy and safety results. The 
frequency will be based on the number of enrolled patients and will occur at least once 
every 3 months for the first year and every 6 months thereafter. In addition, an ad hoc 
IDMC meeting will be performed once the first ten patients in Arm 1 have been treated for 
at least two cycles or discontinued treatment for any reason during the first two cycles. 
The board will act according to its own written rules described in a charter and will prepare 
written minutes of its meetings including the recommendations of the IDMC, that will be 
provided to the sponsor for evaluation. 

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10.1.6 
Dissemination of clinical trial data 
A final report integrating all trial results will be prepared by the sponsor. 
This trial will be registered and the trial results will be posted on publicly accessible trial 
registries (e.g., ClinicalTrials.gov) in accordance with the applicable regulations. 
10.1.7 
Data quality assurance 
All patient data relating to the trial will be recorded on the 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 physically or 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. 
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 non-
compliance 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 parties (e.g., CRO). 
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized trial site staff 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 15 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. 
10.1.8 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. At a minimum, source documentation must be available to 
substantiate proper informed consent procedures, adherence to protocol procedures, 
adequate reporting and follow-up of AEs, administration of concomitant medications, drug 
receipt/dispensing/return records, and trial drug administration information. 

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Source data are all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
Source documents are original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, patient diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, patient files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical trial). 
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. 
10.1.9 
Trial and site start and closure 
The trial start date is the date on which the clinical trial starts recruitment of patients. 
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. 
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 CROs 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. 
10.1.10 
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 

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A 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 with an onset date more than 90 days after the 
last administration of trial treatment will be considered as treatment-emergent only if 
assessed as related to IMP by the investigator. 
10.3.1.1 
Events meeting the AE definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator. 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
New conditions or worsening of pre-existing conditions detected or diagnosed after signing 
ICF. 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
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. 
10.3.1.2 
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 expected 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.  
Exceptions: All deaths due to disease progression occurring within 90 days of the last trial 
treatment must be reported as SAEs. Specific symptoms at time of progression that may 
be caused by other reason (unrelated to progression) have to be documented as AEs and 
reported as SAEs, if applicable.  
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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10.3.1.3 
Suspected adverse reaction (suspected AR) 
All untoward and unintended responses related to any of the IMPs or their administered 
dose solutions. 
The definition covers also medication errors and uses outside what is foreseen in the 
protocol, including misuse and abuse of the product. 
The definition implies a reasonable possibility of a causal relationship between the event 
and the IMP. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
10.3.1.4 
Definition of a serious adverse event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under trial). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
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. 
• 
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. 
• 
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. 
• 
Is a congenital anomaly/birth defect. 

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• 
Other situations: 
− 
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. 
10.3.1.5 
Suspected unexpected serious adverse reactions 
All suspected ARs related to an IMP that occur in this trial, and that are both unexpected 
and serious are ‘suspected unexpected serious adverse reactions’ or SUSARs. SUSARs 
are subject to expedited reporting. 
10.3.1.6 
Use of the terms “severe” and “serious” 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
AE (e.g., rated as mild, moderate, or severe, or according to NCI-CTCAE); see 
Section 10.3.1.7 for guidance on the assessment of intensity; the event itself may be of 
relatively minor medical significance (such as severe headache without any further 
findings). 
Severity and seriousness need to be assessed independently for each AE recorded on the 
eCRF. 
SAEs must be reported by the investigator to the sponsor within 24 h after knowledge of 
the event; see Section 10.3.1.10 for reporting instructions). 
10.3.1.7 
Recording and follow-up of adverse events and/or serious adverse 
events 
AE and SAE recording 
The investigator needs to assess and document any AE regardless of association with the 
use of the trial treatment during the period of observation (refer to Section 8.3.1). 
• 
Data pertaining to AEs will be collected during each trial visit either based on the 
patient’s spontaneous description or investigator’s inquiry or discovered in the 
course of examinations done during the visit, clinical significance of any sign or 
symptom needs to be evaluated by the investigator. 
• 
Clinically significant findings need to be documented as AEs in the source data 
and eCRF. Findings that are evaluated and documented in the source data as not 

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clinically significant (e.g., an abnormal laboratory value without any clinical 
manifestation), should not be documented as AE. 
• 
The investigator will then record all relevant AE information in the eCRF and 
perform an assessment on: 
− 
Intensity according to NCI-CTCAE v5.0 
− 
Seriousness 
− 
Outcome 
− 
Causal relationship of the AE to the trial treatment/trial procedure 
− 
Any trial treatment action and/or any other action taken 
• 
All assessments as well as AE term (diagnosis/description), start date and time of 
onset, end date and time need to be documented in the eCRF. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all patient identifiers, with the exception of 
the patient number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
• 
To avoid colloquial expressions, the AE should be reported in standard medical 
terminology. 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. If 
a definitive diagnosis is not possible, the individual signs and symptoms should be 
recorded. 
Assessment of intensity 
The intensity of an AE (i.e., severity of organ toxicity) will be graded according to the 
NCI-CTCAE v5.0. 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. 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the trial and assign it to one of the following categories: 
• 
Grade 1 – Mild 
• 
Grade 2 – Moderate 
• 
Grade 3 – Severe 
• 
Grade 4 – Life-threatening consequences; urgent intervention indicated 
• 
Grade 5 – Death related to AE 

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With regards to the intensity of an AE the following needs to be documented in the 
patient’s notes and recorded in the eCRF: 
• 
Initial intensity of the AE 
• 
For each change of intensity: 
− 
New grade of intensity 
− 
Date of change (= start of new grade of intensity) 
− 
Time of change (only if relevant) 
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 v5.0 criteria). 
• 
An event is defined as “serious” when it meets at least one of the predefined 
seriousness criteria as described in the definition of an SAE, NOT when it is rated 
as severe. 
Actions taken by the investigator 
Actions taken by the investigator as a result of an AE have to be documented. 
Action(s) taken with trial treatment (prepared from IMPs) by the investigator: 
• 
Dose not changed (= continuation of trial treatment administration according to the 
trial protocol) 
• 
Dose reduced 
• 
Drug interrupted: 
− 
Delayed administration of trial treatment within one cycle 
− 
Delayed start of the next treatment cycle 
− 
Cancellation of administration at a given visit 
− 
Interruption of trial treatment administration during a given visit 
• 
Drug withdrawn (= discontinuation) 
• 
Unknown (e.g., in case the patient 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 medication for the treatment of the AE 

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• 
Termination of a concomitant medication (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 the SAE Form) 
• 
Initiation/termination of a non-drug therapy 
Outcome 
The investigator has to assess the outcome of an AE (and not the patient’s outcome) at 
the time of documentation based on the following criteria: 
• 
Recovered/resolved* (= complete resolution of the AE) 
• 
Recovering/resolving (= AEs which are improving but not yet resolved completely, 
e.g., decrease in an intensity grade) 
• 
Not recovered/not resolved (= AEs which are ongoing without improving or still 
present when the patient deceases due to another cause) 
• 
Recovered/resolved with sequelae* (= patient recuperated but retained 
pathological conditions resulting from the AE; the sequelae should be indicated) 
• 
Fatal** (= death due to the AE) 
• 
Unknown (e.g., in case the patient is lost to follow-up) 
* Generally, an AE is defined as recovered/resolved if all symptoms have ceased, no 
medication for treatment of the event is taken anymore and no other measures (e.g., 
hospitalization) are ongoing. 
If the patient has developed permanent or chronic symptoms or if the event requires long-
term medication(s), the AE is defined as recovered/resolved with sequelae as soon as no 
changes of symptoms and/or medication(s) are expected anymore. 
An AE that is documented as a worsening of a medical condition already known at 
baseline, is defined as recovered as soon as the medical condition has returned to 
baseline status. 
** 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”. All other AEs ongoing at the 
time of death will be attributed with the outcome “not recovered/not resolved”. A copy of an 
autopsy report should be submitted if available. 
Assessment of causality 
The investigator is obligated to assess the relationship between trial treatment/trial 
procedure and each occurrence of each AE/SAE. 

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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. 
It is sufficient to document the causality in the source data and eCRF as: 
• 
Related (= there is a reasonable possibility of a causal relationship) or 
• 
Not related (=there is no reasonable possibility of a causal relationship) 
Relationship to trial treatment 
The relationship or association of an AE or SAE should be assessed separately for each of 
the trial drugs by the investigator after having evaluated all accessible data and, if 
necessary, he/she will re-evaluate the case as new information becomes available. 
If the investigator feels that the event cannot be firmly attributed to one of the trial drugs, 
then the same assessment should be documented for each trial drug. 
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 suspected ARs but not events caused by 
procedure of trial treatment administration. 
Relationship to trial procedures 
In this trial, it cannot be excluded that during the course of the trial some procedures give 
rise to AEs which are related to the trial procedure and not to the trial treatment. Procedure 
related AE can occur on the site of injection of the trial treatment e.g., redness, swelling, 
hematoma or itching or during or after trial-specific procedure, e.g., discomfort after blood 
drawing. These events have to be reported in the eCRF on AE pages as “related to trial 
procedure” with the causing procedure specified. The intensity of these AEs will be 
characterized according to the NCI-CTCAE v5.0. 
Applicable for all categories 
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 makes 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. 

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10.3.1.8 
Serious adverse event exemptions 
In general, SAEs are defined according to ICH Topic E2A (CPMP/ICH/377/95), EU 
Directive 2001/20/EC and ENTR/CT-3 (see Section 10.3.1.4). In the present trial, some 
events are excluded from the SAE definition. The following events do not need to be 
reported as SAEs: 
• 
SAEs occurring later than the SFU2 visit (see Section 1.3) must only be 
reported by the investigator to the sponsor if a relationship to trial treatment or 
trial procedure is suspected. 
• 
Hospitalizations for respite care will not be considered as reportable SAE. 
• 
Hospitalizations solely for coordination of care, including hospice arrangements, 
will not be considered as reportable SAE. 
• 
Hospitalizations that were necessary solely because of patient requirement for 
outpatient care outside of normal outpatient clinic operating hours will not be 
considered as reportable SAE. 
• 
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 SAE. 
• 
Hospitalization of a patient for monitoring and symptomatic treatment for up to 
24 h due to a transient inflammatory reaction of Grade 1 or 2 will not be 
considered as an SAE (but needs to be documented as AE). 
• 
Hospitalizations for procedures or interventions of a pre-existing condition of the 
patient (elective surgery = planned, non-emergency surgical procedure) will not 
be considered as a reportable SAE (unless the intervention/procedure is not 
caused by an acute worsening of the pre-existing condition during the time trial 
participation). 
− 
if it was planned and documented in patient record before the trial-specific 
patient informed consent was signed (ICF for trial participation, see 
Section 10.1.3, or 
− 
if it was scheduled during the trial when elective surgery became necessary 
and the patient has not experienced an AE. 
Nevertheless, this kind of hospitalization should be avoided during trial treatment. 
• 
The progression of underlying disease (e.g., new metastases) during trial 
participation is not considered as AE. However, specific symptoms at time of 
progression that may be caused by other reason, and fatal cases where other 
reason rather than the PD may not be discarded, have to be documented as 
AEs and reported as SAEs if applicable. 
• 
Routine treatment or monitoring of the underlying disease not associated with 
any deterioration in the patient’s condition. 

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10.3.1.9 
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 source data and 
eCRF. For example: 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be documented as AE. 
If vomiting results in severe dehydration, both events should be documented as AEs 
separately. 
Abnormal laboratory results and vital signs values 
Not every laboratory or vital signs abnormality needs to be documented as AE. For 
clinically significant laboratory/vital signs abnormalities the following definitions and 
documentation rules apply: 
• 
If a laboratory/vital signs abnormality is a sign of a disease or syndrome, the 
laboratory/vital signs abnormality is clinically significant and only the diagnosis of 
the causing disease or syndrome needs to be documented as AE. 
• 
If a laboratory/vital signs abnormality results in specific symptoms but no diagnosis 
of a disease or syndrome can be made, the laboratory/vital signs abnormality is 
clinically significant and only the symptoms need to be documented as AEs. 
• 
If a laboratory/vital signs abnormality 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, the laboratory/vital signs abnormality is clinically significant 
and must be documented as AE. 
AEs 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 the trial treatment) 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. 
All AEs associated with an overdose or incorrect administration should be documented as 
AE in source data and eCRF and reported as SAE if applicable. 
10.3.1.10 
Reporting of serious adverse events 
All SAEs which occur in a patient during the observation period, whether considered to be 
associated with trial treatment or not, must be reported by the investigator to the sponsor 
within 24 h following knowledge of the event. 

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All SAEs occurring after the end of the period of observation only have to be reported to 
the sponsor within the appropriate time frame if the investigator suspects a relationship to 
trial treatment or the trial procedure. 
SAE reporting to the sponsor using a paper (SAE report) form 
For the period of observation please refer to Section 8.3.1. 
The investigator needs to complete the paper Serious Adverse Event Form which must be 
sent to the sponsor via one of the following reporting lines: 
• 
Safety report fax no.:   
• 
Safety report E-mail address:
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 patient (patient number) 
• 
A suspected medicinal product 
• 
An identifiable reporting source (investigator/trial site identification) 
• 
An event or outcome that can be identified as serious 
SAE follow-up information should be sent to the sponsor (indicating that this is a “follow-
up” report using the SAE Form or the Additional Information and Follow-Up Form) without 
delay as described above and accompanied by appropriate anonymous supporting 
documentation (e.g., discharge letters, medical reports or death certificates), until a final 
outcome and date are available. All confidential information (name, address, full day of 
birth) needs to be blackened before sending. In addition to a medical record, the 
investigator should complete an Additional Information and Follow-Up Form, which 
contains the SAE term and patient number. 
A copy of the submitted SAE report must be retained on file by the investigator. If explicitly 
required according to national legislation, the investigator must submit copies of the SAEs 
to the IRB/IEC or authority and retain documentation of these submissions in the Site Trial 
File. 
In case an investigator or any other trial team member has questions on safety reporting 
the sponsor may be contacted via: 
• 
E-mail:
For medical questions, the medical monitor for this trial should be contacted. 

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10.4 Contraceptive guidance and collection of pregnancy information 
10.4.1 
Definitions 
Definition of reproductive potential and measures of contraception for BNT111 are detailed 
below. Further guidance for other trial treatments should be according to the authorized 
product information (for approved concomitant medications). 
Female patients 
In this trial, female patients are considered to be WOCBP, unless they are post-
menopausal or permanently sterile: 
• 
A post-menopausal 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 post-menopausal 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 
BNT111. 
Female patients of reproductive potential must agree to use adequate contraception during 
and for 6 months after the last BNT111 administration. Adequate contraception is defined 
as highly effective methods of contraception (Table 15). Birth control methods are 
considered highly effective if they have a failure rate of less than 1% per year, when used 
consistently and correctly. 
The investigator or delegate should advise the patient how to achieve effective 
contraception as outlined in Table 15. 
 
Table 15: 
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 

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1. Hormonal contraception may be susceptible to interaction with some concomitant medications, which may reduce the 
efficacy of the contraception method. 
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 childbearing 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 Clinical Trial Facilitation Group (CTFG)-meeting in Rome 2014 (CTFG 2014). 
 
Male patients 
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 BNT111. 
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 BNT111. For a non-pregnant WOCBP partner, contraception 
recommendations should also be considered. 
Male patients must also not donate sperm during the trial and for 6 months after receiving 
the last dose of BNT111. 
10.4.2 
Collection of pregnancy information 
Pregnancy information will only be collected after obtaining written informed consent from 
the pregnant female patient (or if a male patients’ partner becomes pregnant, written 
informed consent from both). 
Pregnancy information will be collected for pregnancies that occurred after the start of trial 
intervention and until 90 days after the last trial treatment for pregnant patients (or until 
28 days after the last dosing of the male patient for pregnant female partners). 
The initial and follow-up information must be documented on the paper-based Pregnancy 
Reporting Form and submitted to the sponsor within 24 h of knowledge of a patient’s 
pregnancy/partner’s pregnancy. The completed form needs to be sent to the Safety Report 
Fax number or E-mail given in Section 10.3.1.10. Completed pregnancy forms must 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 
investigator’s site file (ISF). 
The investigator will collect follow-up information on the patient/patient’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 

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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 IMPs. 
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 within the appropriate time 
frame. While the investigator is not obligated to actively seek this information in former trial 
patients, he or she may learn of an SAE through spontaneous reporting. 
10.5 Genetics 
Genetic analyses will be performed as outlined in Section 8.8. 
10.6 Liver safety: suggested actions and follow-up assessments 
Based upon data from other studies using RNA-LPX formulations (refer to the BNT111 IB), 
the sponsor does not expect to encounter any liver safety issues. 
For cemiplimab, please refer to the locally approved label. 
10.7 Investigators and trial administrative structure 
10.7.1 
Investigators and trial site personnel 
There must be an investigator at each trial site. 
If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator. 
All persons assigned responsibility as principal investigator must sign a declaration of their 
responsibilities and their agreement to this protocol before any trial-related procedure is 
performed. 
Curriculum vitae and/or other relevant documents confirming the current qualification of 
the investigators must be provided to the sponsor. This should include any previous 
training in the principles of GCP, experience obtained from work with clinical trials, and 
experience with patient care. 
Documentation of all involved investigators must be maintained according to GCP and 
applicable regulatory requirements. 
10.7.2 
Trial site personnel assigned trial-related duties 
The principal investigator may define appropriately qualified personnel at a trial site to 
perform significant trial-related procedures and/or to make trial-related decisions under 

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his/her supervision. In this case, the principal investigator must maintain a signed list of the 
persons to whom they delegate significant trial-related duties/responsibilities; the 
delegated trial-related duties/responsibilities must be specified in the list. 
When personnel or responsibility changes are made, the principal investigator must 
ensure that the relevant documentation is updated before any trial-related activities are 
performed. 
Documentation of all involved trial site personnel performing significant trial-related 
procedures and/or making trial-related decisions must be maintained according to GCP 
and applicable regulatory requirements. 
10.7.3 
Contract research organizations 
Documentation of all involved CRO must be maintained according to GCP and applicable 
regulatory requirements. This includes documentation of any delegation of responsibilities 
to CROs. 
10.7.4 
The sponsor and sponsor’s personnel 
The trial sponsor listed on the title page accepts the responsibilities of the sponsor 
according to GCP and applicable regulatory requirements. 
The sponsor must designate appropriately qualified personnel to advise on trial-related 
topics. The trial site will be provided with contact details for these personnel before any 
trial-related procedure is performed. 
A list of key sponsor personnel involved in the preparation of this protocol and the conduct 
of the trial, including their full names, titles, roles, and responsibilities, must be maintained. 
10.8 Country-specific requirements 
Country-specific requirements will be met; specific information is not available as the sites 
have not yet been defined. 
 

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10.10 Protocol amendments 
Changes made to the protocol using the protocol amendments are described in detail in 
the document Protocol Amendment History which is available upon request. This Protocol 
Amendment History is filed together with the protocol in the TMF. 
10.10.1 
Protocol amendment no. 01 
Amendment rationale 
The trial protocol was amended on 03 NOV 2020. The key changes were: 
• 
Clarification of secondary endpoint on PRO/QoL measurements 
• 
Clarification on the add-on therapy (requirement for central verification of 
radiological progression prior to inclusion to add-on treatment) 
• 
Addition and clarification of inclusion and exclusion criteria: exclusion criterion 
on prior malignancy added and criteria for add-on treatment further specified 
• 
Specific TEs and an additional IDMC review after 10 patients (after 
two treatment cycles) in Arm 1 added to Section 7.4 
This amendment was issued before any trial subjects were enrolled into the trial. 
10.10.2 
Protocol amendment no. 02 
Amendment rationale 
This amendment implements changes that were required based on comments from the 
Medicines and Healthcare products Regulatory Agency (MHRA). The key changes were: 
• 
Wording in Sections 4.1.1 and 4.1.3 regarding sponsor involvement in 
determination of trial eligibility in removed 
• 
Amendment of inclusion criterion 10 in regard to patients with BRAF-V600-
positive tumor(s) 
• 
Amendment of exclusion criterion 10 in regard to Grade 2 neuropathy 
• 
Table 3 in Section 6.8.3 updated to align with current version of the cemiplimab 
SmPC 
This amendment was issued before any trial subjects were enrolled into the trial. 
10.10.3 
Protocol amendment no. 03 
Amendment rationale 
The trial protocol was amended on 03 MAR 2021. This amendment implements changes 
that were required based on comments from the Paul-Ehrlich-Institute (PEI) on 
16 FEB 2021. The key changes were: 

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• 
Amendment of key exclusion criterion in Section 1.1 and exclusion criterion #8 
in Section 5.1.2 to define the time-span of prior/concomitant therapy 
• 
Amendment of Sections 1.3.1 and 1.3.2 which now requires for WOCBP to have 
a pregnancy test at each cycle (every three weeks) before the application of trial 
treatment 
This amendment was issued before any trial subjects were enrolled into the trial. 
10.10.4 
Protocol amendment no. 04 
Amendment rationale 
This amendment was generated in order to incorporate changes made in the country-
specific clinical trial protocols (as described above) to a global protocol amendment. 
Additional changes also included: 
• 
Patient randomization number increased and statistics amended (Sections 1.1 
and 9) 
• 
Benefits/risk section added in relation to COVID-19 vaccination 
• 
Amendment of inconsistencies 
10.10.5 
Protocol amendment no. 05 
Amendment rationale 
This amendment was generated in order to incorporate the following substantial changes: 
• 
Change in inclusion criterion 5 and removal of inclusion criterion 6 to make 
patients eligible if they have confirmed disease progression with an approved 
anti-PD-L1 regimen as an alternative to anti-PD-1 
• 
Change in inclusion criterion 17 to make biopsies no longer mandatory for 
patients who are part of the biomarker sub-study 
• 
Addition of a new row to SoA 1 to clarify that pharmacogenomic analyses 
should be carried out at screening 
• 
Correction of some inconsistencies/additions of clarification to some sections 
10.10.6 
Protocol amendment no. 06 
Amendment rationale 
This amendment was generated in order to incorporate the following substantial changes: 
• 
Sections 4.1.4, 8.3.1, SoA 1 footnote c, and SoA 2 footnote b was revised to 
include information on the safety follow-up in case a new anti-cancer therapy is 
started within 90 days after last treatment. 

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• 
Text was added to Section 8.9 to indicate optional biopsies in biomarker 
substudy. 
10.10.7 
Protocol amendment no. 07 
This amendment was generated in order to incorporate the following substantial changes: 
• 
A second interim analysis (IA2) which will be performed after approximately 
of the planned number of
 patients are response evaluable. 
• 
Updates to allow that patients in Arm 3 who have entered add-on treatment are 
eligible to take part in the biomarker sub-study. 
• 
Additional exclusion criterion (criterion 19). 
• 
Dose modification schema for BNT111 was changed. 
• 
Non-substantial updates throughout the CTP for clarity / further information or 
correction of inconsistencies were also implemented. 
10.11 Data collection and management 
The trial documentation must be adequate for the reconstruction of the trial. 
10.11.1 
Case report forms 
eCRFs will be completed through use of an electronic data capture (EDC) system. Trial 
site personnel will receive training and have access to a manual for appropriate eCRF 
completion. The eCRFs will be submitted electronically to the sponsor via the system and 
should be handled in accordance with instructions from the sponsor. 
All eCRFs should be completed by designated, trained trial site personnel. eCRFs should 
be reviewed, verified, and then electronically signed and dated by the investigator or a 
designee. 
At the end of the trial, the investigator will receive trial patient data for his/her trial site in a 
readable format that must be kept with the trial records. Acknowledgment of receipt of the 
trial patient data will be required. 
10.11.2 
Patient-reported outcomes 
PROs will be collected after randomization as outlined in the SoAs (see Section 1.3). 
PROs will be provided to the trial site as printed copies as part of the ISF or electronically. 
At the given time points each patient has to complete all PROs by him/herself. PROs 
completed by the patient are considered as source documents. The investigator or 
designee must transfer the PROs data to the eCRF if provided on paper. 
10.11.3 
Data management 
The data management activities of this trial, including quality checking of the data will be 
performed by the CRO (see the title page). 
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Data entered manually will be submitted to the sponsor through use of an EDC system, 
data extracts and reports. Trial sites will be responsible for data entry into the EDC 
system. In the event of discrepant data, the data management service provider will request 
data clarification from the trial sites, which the trial sites will resolve electronically in the 
EDC system. 
The data management service provider will produce a Trial Data Validation Specification 
document that describes the quality checking to be performed on the data. eCRF entries 
and corrections will be documented and maintained in the EDC system's audit trail. 
Central laboratory data will be sent directly to the data management service provider. 
System backups for data stored by the sponsor and records retention for the trial data will 
be in accordance with regulatory requirements. 
10.11.4 
Investigator’s Site File and the Trial Master File 
The principal investigator is responsible for the filing of all essential documents in an ISF. 
The sponsor is responsible for the timely filing of all essential documents in the TMF. As 
applicable, these files must be available at monitoring visits and during audits or regulatory 
inspections. 
After trial completion, the principal investigator must ensure that all source 
data/documentation related to the trial is recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation and verification. The principal investigator must 
take measures to prevent accidental or premature destruction of these documents. 
The principal investigator must keep the ISF, the source data/documentation arising from 
the trial according to the prescribed record retention period in the country and/or according 
to the hospital policy, but at least until informed by the sponsor that the trial-related records 
are no longer required. 
10.12 Other data 
10.12.1 
Demographic data 
At screening, the following demographic data will be recorded for all trial patients: 
• Age (in years/months) 
• Sex (male/female) 
• Ethnic group 
10.12.2 
Medical history and underlying disease history 
Medical history information will be recorded for at the times given in the SoA (Section 1.3). 
Medical history includes clinically significant diseases, surgeries, previous medical 
procedures, smoking history, use of alcohol and/or drugs of abuse, reproductive status, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 

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homeopathic remedies, and nutritional supplements) used by the patient within 7 d prior to 
treatment start. 
Underlying disease history should include histology, tumor, node, metastasis at diagnosis, 
prior anti-neoplastic therapies/procedures. 
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