Phase I/IIa, First-in-human, Open-label, Dose Escalation Trial With Expansion Cohorts to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of BNT151 as a Monotherapy and in Combination With Other Anti-cancer Agents in Patients With Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: BioNTech SE

 
Page 1 of 150 
 
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 
BNT151-01 
 
Version: 
8.0 
Date: 
13 DEC 2023 
Sponsor: 
BioNTech SE 
 
 
 
Trial title: 
Phase I/IIa, first-in-human, open-label, dose escalation trial with 
expansion cohorts to evaluate safety, pharmacokinetics, 
pharmacodynamics, and preliminary efficacy of BNT151 as a 
monotherapy and in combination with other anti-cancer agents in 
patients with solid tumors 
Brief title: 
BNT151 as a monotherapy and in combination with other anti-
cancer agents in patients with solid tumors 
Trial phase: 
I/IIa 
Indication: 
Solid tumors 
Product: 
BNT151 
Principal/Coordinating 
investigator: 
Aung Naing, MD, FACP 
The University of Texas MD Anderson Cancer Center 
Department of Investigational Cancer Therapeutics 
1515 Holcombe Blvd. 
77030 Houston TX 
USA 
Sponsor’s responsible person: 
Goran Babić, MD, Director Clinical Development, BioNTech SE 
Regulatory identifier(s): 
EudraCT number: 2019-003572-39 
IND number: 023301 
Medical monitor: 
See Section 8.12 
 
Document history 
Date 
Version number 
Valid for  
First submitted version 
16 JUN 2020 
3.0 
All countries 
Second submitted version 
11 AUG 2020 
4.0 
All countries 
Third submitted version 
06 AUG 2021 
6.0 
All countries 
Fourth submitted version 
21 DEC 2021 
7.0 
All countries 
Fifth submitted version 
13 DEC 2023 
8.0 
All countries 
 

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Exploratory objectives 
Endpoints 
Evaluate efficacy of IMP in terms of PFS 
and OS. 
• 
PFS defined as the time from first dose of IMP to first 
objective tumor progression, or death from any cause, 
whichever occurs first. 
• 
OS defined as the time from first dose of IMP to death 
from any cause. 
Characterize the PK profile of translated IL-
2 variant. 
• 
PK parameters (including but not limited to AUC, Cmax, 
tmax, and t1/2). 
Identify potentially predictive or other 
exploratory PD markers. 
• 
Changes in selected cytokines and other soluble innate 
and adaptive immune system activation markers 
compared to baseline. 
• 
Changes in systemic and intra-tumoral immune 
response in blood and tumor tissue compared to 
baseline (e.g., immunophenotyping of immune cells and 
tumor microenvironment analysis). 
• 
Correlate potential predictive biomarkers in tumor and 
periphery with antitumor response. 
Examine potential incidence of 
immunogenicity by measuring ADAs 
against translated proteins derived from the 
IMPs or against PEG lipids. 
• 
Evaluate pre-existing (pre-treatment) and post-
treatment ADAs and examine the immunogenicity 
incidence with treatment. 
ADAs = anti-drug antibodies; AUC = area-under-the-concentration-time curve; Cmax = maximum observed serum 
concentration; CR = complete response; DCR = disease control rate; DLTs = dose limiting toxicities; DOR = duration of 
response; IL = interleukin; IMP = investigational medicinal product; MTD = maximal tolerated dose; ORR = objective 
response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic; 
PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended Phase II dose; 
SD = stable disease; t1/2 = half-life; tmax = time to Cmax; TEAE = treatment emergent adverse event. 
 
Trial design 
This is an open-label, multicenter Phase I/IIa dose escalation, safety, pharmacokinetic 
(PK) and PD trial of BNT151 with expansion cohorts in various solid tumor indications. 
The monotherapy dose escalation, (Part 1) of this clinical trial will enroll patients with 
various solid tumors that are metastatic or of advanced unresectable stage for whom there 
is no available standard therapy likely to confer clinical benefit, or patients who are not 
candidates for such available therapy. During combination dose escalation (Part 2A), 
patients with squamous cell carcinoma of head and neck (SCCHN), and hepatocellular 
carcinoma (HCC) will be enrolled and treated with a combination of BNT151 and 
pembrolizumab. Once Part 2A of SCCHN and HCC is completed, patients with renal cell 
carcinoma (RCC), non-small cell lung cancer (NSCLC), and triple negative breast cancer 
(TNBC) will be enrolled and treated with a combination of BNT151 with the respective 
standard of care (SoC). 
The trial consists of Part 1, Part 2A and Part 2B with adaptive design elements:  
• 
Part 1 will be a monotherapy dose escalation in patients with advanced solid 
malignancies until the maximum tolerated dose (MTD) and/or recommended 
Phase II dose (RP2D) of BNT151 as monotherapy are defined. Dose escalation 
and RP2D regimen may include a pre˗conditioning dose, which would be 

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implemented under the rules defined in Section 4.1.4 Adaptive trial design 
elements. 
The Part 1 of the trial also plans to implement a dedicated biomarker cohort in BNT151 
monotherapy: 
• 
The Biomarker Cohort will recruit patients at selected sites in the US only. The 
objective of the cohort is to observe PD activity and drug-induced changes in the 
blood and tumor. The gathered data are expected to inform on the drugs 
mechanism of action and further refine selection of monotherapy dose. This cohort 
will only enroll patients that are capable and willing to donate serial biopsies. 
Patients will only be dosed at dose levels at the RP2D level or lower, which have 
been cleared safe in the monotherapy dose escalation, and where 
pharmacodynamics activity is expected. Approximately, 20 patients will be enrolled 
in this cohort. 
• 
Part 2 will start once Part 1 monotherapy dose escalation is completed (exception: 
Biomarker Cohort in Part 1 can continue enrolling as long as a BNT151 
monotherapy dose is established in the dose escalation). It consists of 5 expansion 
cohorts starting with BNT151 in combination with pembrolizumab in patients with 
SCCHN (Cohort 1) and HCC (Cohort 2). Safety evaluation of BNT151 in 
combination with pembrolizumab in Cohorts 1 and 2 will be done at the same time, 
and data generated in both patient populations will be used to assess safety. Once 
the safety of the combination is confirmed by the safety review committee (SRC) 
(for details see the SRC Charter), the 2 cohorts will then enroll independently in 
expansion and a further 3 cohorts evaluating BNT151 in combination with SoC will 
be opened for enrollment: RCC (Cohort 3), NSCLC (Cohort 4), and TNBC 
(Cohort 5). Further cohorts may be opened based on sponsor’s decision. 
Each Part 2 cohort will consist of 2 sub-parts: 
• 
Part 2A where the dose of BNT151 will be established for each combination using 
either a safety run-in or abbreviated dose finding based on predefined criteria. 
Part 2B where a predefined number of patients will be treated with the confirmed 
RP2D of BNT151 in combination with respective SoC. In case the same dosing 
regimen is used in Parts 2A and 2B (i.e., in case option of safety run-in is adopted), 
the patients enrolled in Part 2A are eligible for efficacy evaluation in Part 2B. In 
case a different dosing regimen is used for Part 2A compared to Part 2B (i.e., in 
case option of abbreviated dose finding is adopted), efficacy generated in Part 2A 
will be used as supporting data. 
In all parts, efficacy will be assessed by on-treatment imaging at Week 6 (+7 days), every 
6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) thereafter until disease 
progression is assessed by the investigator (unless the investigator elects to continue 
treatment), withdrawal of consent, trial termination by the sponsor, or death, whichever 
occurs first. 
Safety will be assessed on a regular basis by means of clinical and laboratory parameters. 

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Pharmacokinetics (PK) of translated interleukin-2 (IL-2) variant and various PD markers, 
which may act as indicators of safety and activity of BNT151 monotherapy and in 
combination with SoC, will be evaluated. 
Brief description of the sequence and duration of all trial periods 
The Part 1, monotherapy part of the trial will be preceded by an enrollment and screening 
period of 13 months. Patients are screened at a Screening Visit within 3 weeks prior to the 
beginning of treatment. During the treatment and dose limiting toxicity (DLT) observation 
period, patients will be treated with treatment cycles lasting 21 days until progression, or 
treatment discontinuation of BNT151 due to other factors. Following discontinuation, and a 
safety follow-up period of 60 days, patients will be followed up for survival every 12 weeks 
until death. 
Part 2, combination therapy expansion will be detailed in a protocol amendment following 
review of the Part 1 data. 
Population 
In Part 1, the sample size will be up to 54 DLT-evaluable patients depending on the 
number of dose limiting toxicities (DLTs) which may occur, with the possible enrollment of 
up to 10 additional patients if efficacy is seen in a specific tumor type. In addition, 
approximately 20 patients will be enrolled in the Biomarker Cohort. 
The objective for the trial Part 2A and 2B is to further investigate the safety profile and to 
assess the efficacy of the investigational medicinal product (IMP) in different indications in 
combination with other approved anti-cancer agents. The design in Part 2A can either be a 
safety run-in of 6 patients or a short escalation at 2 dose levels according to the 3+3 trial 
design, therefore the sample size in Part 2A will range from 6 to 12 patients per cohort. 
The sample size in Part 2B may be based on either Simon two-stage design or one-stage 
design. The final sample size calculations will be introduced through protocol amendment. 
Key inclusion criteria 
Patients who meet the following inclusion criteria will be eligible for trial entry: 
For all Parts: 
1. Histological documentation of the original primary tumor via a pathology report. 
2. Measurable disease per response evaluation criteria in solid tumors (RECIST) 
version 1.1. 
For Part 1: 
3. Histologically confirmed solid tumor that is metastatic or of advanced unresectable 
stage and for whom there is no available standard therapy likely to confer clinical 
benefit, or patient who is not a candidate for such available therapy. If there is no 
contraindication, patients should have exhausted all SoC therapies before entering 
the trial. 

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For Part 2 (including 2A and 2B): 
Cohort 1: SCCHN 
4. Histologically confirmed, recurrent or metastatic (R/M) SCCHN with disease 
progression on or after a platinum-based therapy.  
Cohort 2: Hepatocellular carcinoma (HCC) 
5. Histologically confirmed unresectable or metastatic HCC who have been previously 
treated with a first-line systemic treatment. 
Cohort 3: Renal cell carcinoma (RCC) 
6. Histologically confirmed RCC eligible for pembrolizumab in combination with 
axitinib, for the first-line treatment of patients with advanced RCC. 
Cohort 4: Non-small cell lung cancer (NSCLC) 
7. Histologically or cytologically confirmed NSCLC eligible for pembrolizumab in 
combination with pemetrexed and platinum chemotherapy for the first-line treatment 
of patients with metastatic non-squamous NSCLC, with no epidermal growth factor 
receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. 
Cohort 5: Triple negative breast cancer (TNBC) 
8. Histologically confirmed TNBC eligible for atezolizumab in combination with 
paclitaxel protein-bound for the treatment of unresectable locally advanced or 
metastatic TNBC whose tumors express programmed death-ligand (PD-L1 stained 
tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as 
determined by a Food and Drug Administration (FDA) approved test. 
Other inclusion criteria 
For all parts: 
9. ≥18 years of age. 
10. Must sign an informed consent form (ICF) indicating that he or she understands the 
purpose and procedures required for the trial and are willing to participate in the trial 
prior to any trial-related assessments or procedures.  
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
12. Adequate coagulation function at screening as determined by: 
− 
International normalized ratio (INR) or prothrombin time ≤1.5 × upper limit 
normal (ULN; unless on therapeutic anticoagulants with values within 
therapeutic window). 
− 
Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless on therapeutic 
anticoagulants with values within therapeutic window). 
13. Adequate hematologic function at screening as determined by: 
− 
White blood cell (WBC) count ≥3 × 109/L. 
− 
Absolute neutrophil count (ANC) ≥1.5 × 109/L (patient may not use granulocyte-
colony stimulating factor (G-CSF) or granulocyte-macrophage colony 

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stimulating factor (GM-CSF) in the past 7 days to achieve these WBC and ANC 
levels). 
− 
Platelet count ≥100 × 109/L. 
− 
Hemoglobin (Hgb) ≥9.0 g/dL. 
14. Adequate hepatic function at screening as determined by: 
− 
Total bilirubin (TBili) ≤1.5 mg/dL (or ≤2.0 mg/dL for patients with known 
Gilbert’s syndrome or liver metastasis). 
− 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × ULN; ≤3 × ULN for patients with liver metastasis. 
15. Adequate renal function at screening as determined by: 
− 
Glomerular filtration rate (GFR) 45 mL/min/1.73 m² – 
According to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation, expressed as a single equation: 
 
GFR = 141 × min(Scr/κ,1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
 
Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 
for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max 
indicates the maximum of Scr/κ or 1. 
− 
For creatinine assays using methods traceable to isotope dilution mass 
spectrometry (IDMS) assigned National Institute of Standards and Technology 
(NIST) certified reference materials (Levey et al. 2009). 
16. Able and willing to attend trial visits as required by the protocol. 
17. Women of childbearing potential (WOCBP) must have a negative serum (beta-
human chorionic gonadotropin [β-hCG]) test/value at screening. Patients who are 
postmenopausal or permanently sterilized can be considered as not having 
reproductive potential. 
18. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the entire trial, until 6 months after last BNT151 treatment. 
19. 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 
dose of BNT151. 
20. WOCBP must agree to use highly effective contraception during the trial and for 
6 months after receiving the last dose of BNT151. Birth control methods are 
considered highly effective if they have a failure rate of less than 1% per year, when 

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used consistently and correctly. Further guidance on contraceptive measures for 
female patients can be found in Section 10.4. 
For the Biomarker Cohort: 
21. At selected US sites only: at enrollment patients must agree to have one pre-dose 
biopsy and lesion that is deemed accessible by the investigator. If possible, at least 
one on-treatment biopsy should be accessible from same tumor lesion. 
Key exclusion criteria 
Patients who meet at least one of the following exclusion criteria will not be eligible for trial 
entry: 
Prior and concomitant therapy: 
1. Use of any IMP or device within 28 days before administration of first dose of trial 
treatment. 
2. Has been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or 
tyrosine kinase inhibitors within 2 weeks or 5 half-lives (whichever is longer) of the 
start of trial treatment; immunotherapy/monoclonal antibodies within 3 weeks of the 
start of trial treatment; any live vaccine within 4 weeks of the start of trial treatment; 
nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the 
start of trial treatment. 
3. Ongoing participation in the active treatment phase of interventional clinical trial. 
4. Receives concurrent systemic (oral or intravenous [IV]) steroid therapy >10 mg 
prednisone daily or its equivalent for an underlying condition. 
5. Has had major surgery within the 4 weeks before the first dose of BNT151. 
6. Ongoing or active infection requiring IV treatment with anti-infective therapy that 
has been administered less than 2 weeks prior to the first dose of BNT151. 
7. Has ongoing side effects to any prior therapy or procedures for any medical 
condition not recovered to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v5.0 Grade ≤1. 
Note: Peripheral neuropathy Grade ≤2 is allowed; alopecia of any Grade is allowed. 
Medical conditions: 
8. Current evidence of new or growing brain or leptomeningeal metastases during 
screening. Patients with known brain metastases may be eligible if they:  
− 
had radiotherapy, surgery or stereotactic surgery for the brain metastases;  
− 
have no neurological symptoms (excluding Grade ≤2 neuropathy); 
− 
have stable brain metastasis on the computed tomography (CT) or magnetic 
resonance imaging (MRI) scan within 4 weeks before signing the informed 
consent; and 
− 
are not undergoing acute corticosteroid therapy or steroid taper. 

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Notes: Patients with central nervous system (CNS) symptoms should undergo a 
CT-scan or MRI of the brain to exclude new or progressive brain metastases. Spinal 
bone metastases are allowed, unless imminent fracture with cord compression is 
anticipated. 
9. Has a history of a cerebrovascular accident or had transient ischemic attack less 
than 6 months ago. 
10. Effusions (pleural, pericardial, or ascites) requiring drainage. 
11. History of autoimmune disease active or past including but not limited to 
inflammatory bowel disease, systemic lupus erythematosus (SLE), ankylosing 
spondylitis, scleroderma, or multiple sclerosis. Has any active immunologic disorder 
requiring immunosuppression with steroids or other immunosuppressive agents 
(e.g., azathioprine, cyclosporine A) with the exception of patients with isolated 
vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism 
or hypopituitarism, and patients with a history of Grave's disease with stable thyroid 
function. Patients with controlled hyperthyroidism must be negative for 
thyroglobulin, thyroid peroxidase antibodies, and thyroid stimulating immunoglobulin 
prior to administration of trial treatment. 
12. Known history of seropositivity for human immunodeficiency virus (HIV) with cluster 
of differentiation 4 positive (CD4+) T˗cell (CD4+) counts <350 cells/µL and with a 
history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic 
infections. 
13. Known history/positive serology for hepatitis B requiring active antiviral therapy 
(unless immune due to vaccination or resolved natural infection or unless passive 
immunization due to immunoglobulin therapy). Patients with positive serology must 
have hepatitis B virus (HBV) viral load below the limit of quantification. 
14. Active hepatitis C virus (HCV) infection; patients who have completed curative 
antiviral treatment with HCV viral load below the limit of quantification are allowed. 
Note: Country-specific criteria for Germany: To confirm that a patient would be 
eligible, an active infection with HIV/hepatitis B or C should be ruled out by serum 
blood test at screening. 
15. Any contraindication to the combination therapies as per United States prescribing 
information (USPI) or summary of product characteristics (SmPC) for patients 
receiving BNT151 in combination with other systemic anticancer agent(s). 
16. Another primary malignancy that has not been in remission for at least 2 years, with 
the exception of those with a negligible risk of metastasis or death (including but not 
limited to adequately treated carcinoma in situ of the cervix, basal or squamous cell 
skin cancer, localized prostate cancer, or ductal carcinoma in situ). 
Note: In case of uncertainties it should be discussed with the medical monitor. 
 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 1 0  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
Ot h er c o m or bi diti e s  
1 7.  A b n or m al el e ctr o c ar di o gr a m s ( E C G s) t h at ar e cli ni c all y si g nifi c a nt, s u c h a s 
Fri d eri ci a -c orr e ct e d Q T pr ol o n g ati o n > 4 8 0  m s . 
1 8.  I n t h e o pi ni o n of t h e tr e ati n g i n v e sti g at or, h a s a n y c o n c urr e nt c o n diti o n s t h at c o ul d 
p o s e a n u n d u e m e di c al h a z ar d or i nt erf er e wit h t h e i nt er pr et ati o n of t h e tri al r e s ult s; 
t h e s e c o n diti o n s i n cl u d e, b ut ar e n ot li mit e d t o:  
− O n g oi n g or a cti v e i nf e cti o n r e q uiri n g a nti bi oti c/ a nti vir al/ a ntif u n g al t h er a p y  
− C o n c urr e nt c o n g e sti v e h e art f ail ur e ( N e w Y or k H e art A s s o ci ati o n [ N Y H A] 
F u n cti o n al Cl a s sifi c ati o n Cl a s s III or I V)  
− C o n c urr e nt u n st a bl e a n gi n a  
− C o n c urr e nt c ar di a c arr h yt h mi a r e q uiri n g tr e at m e nt ( e x cl u di n g a s y m pt o m ati c 
atri al fi brill ati o n)  
− A c ut e c or o n ar y s y n dr o m e wit hi n t h e pr e vi o u s 6  m o nt h s  
− P ul m o n ar y e m b oli s m wit hi n t h e pr e vi o u s 3  m o nt h s  
− S i g nifi c a nt p ul m o n ar y di s e a s e ( s h ort n e s s of br e at h at r e st or o n mil d e x erti o n) 
f or e x a m pl e d u e t o c o n c urr e nt s e v er e o b str u cti v e p ul m o n ar y di s e a s e.  
1 9.  C o g niti v e, p s y c h ol o gi c al or p s y c h o s o ci al i m p e di m e nt t h at w o ul d i m p air t h e a bilit y of 
t h e p ati e nt t o r e c ei v e t h er a p y a c c or di n g t o t h e pr ot o c ol or a d v er s el y aff e ct t h e a bilit y 
of t h e p ati e nt t o c o m pl y wit h t h e i nf or m e d c o n s e nt pr o c e s s, pr ot o c ol, or pr ot o c ol -
r e q uir e d vi sit s a n d pr o c e d ur e s. 
2 0.  I s pr e g n a nt or br e a stf e e di n g. 
Tri al tr e at m e nt s  
T h e I M P i n all p art s of t h e tri al i s B N T 1 5 1. T h e I M P i s a pr e s er v ati v e -fr e e, st eril e ri b o n u cl ei c 
a ci d ( R N A) -li pi d n a n o p arti cl e ( L N P) di s p er si o n i n a n a q u e o u s cr y o pr ot e ct a nt b uff er f or I V 
a d mi ni str ati o n. F or f urt h er i nf or m ati o n o n t h e I M P, r ef er t o t h e p h ar m a c y 
m a n u al  f or 
B N T 1 5 1 -0 1 . 
I n P art  1 , B N T 1 5 1 will b e a d mi ni st er e d I V o n D a y 1 of e a c h 3-w e e k tr e at m e nt c y cl e ( 2 1  d a y s ) 
aft er all r e q uir e d pr o c e d ur e s a n d a s s e s s m e nt s b ef or e a d mi ni str ati o n h a v e b e e n c o m pl et e d. 
O n c e eli gi bilit y i s c o nfir m e d, a d mi ni str ati o n of B N T 1 5 1 c a n b e d el a y e d  f or u p t o 7 d a y s 
u nl e s s  ot h er wi s e a p pr o v e d b y t h e s p o n s or m e di c al m o nit or.  
P ati e nt s will b e a d mi ni st er e d B N T 1 5 1 a c c or di n g t o d o s e l e v el s ( 0. 4  µ g/ k g  st arti n g d o s e t o 
b e e s c al at e d t o 
 µ g/ k g ). B N T 1 5 1 will b e a d mi ni st er e d a s a b o d y w ei g ht-b a s e d d o si n g. 
A c a p of d o si n g f or p ati e nt s w ei g hi n g 1 2 0  k g  a n d m or e will b e i m pl e m e nt e d i n t h e 
pr o p o s e d cli ni c al tri al.   
 
C CI

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 1 1  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
Tr e at m e nt n a m e  
B N T 1 5 1  
T y p e  
Bi ol o gi c  
D e si g n ati o n  
A d v a n c e T h er a p y ( F D A)/ A d v a n c e T h er a p y M e di ci n al Pr o d u ct ( E M A)  
D o s e f or m ul ati o n  
A m p ul e  
U nit d o s e str e n gt h( s)  
I M P c o n c e ntr ati o n ( 0. 0 4 m g/ m L). R ef er t o t h e P h ar m a c y M a n u al f or 
f urt h er i nf or m ati o n 
D o s a g e l e v el( s)  
0. 4  µ g/ k g  R N A f or t h e fir st d o s e, i n cr e m e nt s u p t o 
 µ g/ k g  
R o ut e of a d mi ni str ati o n  
I V b ol u s i nj e cti o n/I V i nf u si o n ( d e p e n di n g o n t h e a d mi ni st er e d 
v ol u m e)  
U s e  
E x p eri m e nt al (I M P)  
S o ur ci n g  
Pr o vi d e d c e ntr all y b y t h e s p o n s or  
P a c k a gi n g a n d l a b eli n g  
I M P will b e pr o vi d e d i n a f ol di n g b o x. E a c h f ol di n g b o x a n d e a c h vi al 
will b e l a b el e d a s r e q uir e d p er c o u ntr y r e q uir e m e nt  
I M P =  i n v e sti g ati o n al m e di ci n al pr o d u ct; I V =  i ntr a v e n o u s; R N A =  ri b o n u cl ei c a ci d. 
 
F or P art  2 , C o h ort s 1 a n d 2 i n c o m bi n ati o n wit h S o C tr e at m e nt s, a d mi ni str ati o n s c h e d ul e s 
a n d i nf or m ati o n a b o ut t h e  c o m bi n ati o n tr e at m e nt s  will b e s u b mitt e d b y a m e n d m e nt.  
St ati sti c s  
T h e pri m ar y o bj e cti v e s of t hi s tri al P art  1  ar e t o a s s e s s t h e s af et y pr ofil e a n d t o i d e ntif y t h e 
M T D a n d/ or R P 2 D. T h e Bi o m ar k er C o h ort  e x a mi n e s  t h e e x pl or at or y m ar k er s f or t h e 
m e c h a ni s m of a cti o n  i n t h e t u m or a n d p eri p h er y. H e n c e, n o st ati sti c al h y p ot h e si s i s u n d er 
t e st f or tri al P art  1 . F or tri al P art  2 A a n d 2 B h y p ot h e si s t e sti n g f or e a c h e x p a n si o n c o h ort 
m a y b e i ntr o d u c e d t hr o u g h pr ot o c ol a m e n d m e nt.  
T h e s a m pl e si z e f or tri al P art  1  i s dri v e n b y a c c el er at e d titr ati o n d e si g n of si n gl e-p ati e nt 
c o h ort s wit h a s wit c h t o t h e 3 + 3  tri al d e si g n . I n P art  1 , t h e s a m pl e si z e will b e u p t o 
5 4  D L T -e v al u a bl e  p ati e nt s  d e p e n di n g o n t h e n u m b er of D L T s w hi c h m a y o c c ur  ( wit h t h e 
p o s si bl e e nr oll m e nt of u p t o 1 0 a d diti o n al p ati e nt s if effi c a c y i s s e e n i n a s p e cifi c t u m or 
t y p e). 
I n a d diti o n, a p pr o xi m at el y 2 0 p ati e nt s will b e e nr oll e d i n t h e Bi o m ar k er C o h ort wit h p air e d 
bi o p si e s. T hi s s a m pl e si z e i s b a s e d o n t h e pr o p orti o n of p ati e nt s w h o h a v e a c hi e v e d at 
l e a st 5 0 % i n cr e a s e fr o m b a s eli n e i n l y m p h o c yt e s (t ot al l y m p h o c yt e s, C D 4 +, C D 8 +, Tr e g s, 
a n d N K c ell s) u p o n tr e at m e nt wit h B N T 1 5 1. T w e nt y p ati e nt s ar e e sti m at e d t o h a v e > 8 0 % 
c h a n c e t o r ul e o ut a pr o p orti o n of 1 0 % if t h e tr u e pr o p orti o n i s 4 0 % at a 2-si d e d 
si g nifi c a n c e l e v el of 0. 0 5 . 
T h e o bj e cti v e f or t h e tri al P art  2 A a n d 2 B i s t o f urt h er i n v e sti g at e t h e s af et y pr ofil e a n d t o 
a s s e s s t h e effi c a c y of t h e I M P i n diff er e nt i n di c ati o n s i n c o m bi n ati o n wit h ot h er a p pr o v e d 
a nti -c a n c er a g e nt s. T h e d e si g n i n P art  2 A c a n eit h er b e a s af et y r u n -i n of 6 p ati e nt s  or a 
s h ort e s c al ati o n at 2  d o s e l e v el s a c c or di n g t o t h e 3 + 3  tri al d e si g n , t h er ef or e t h e s a m pl e 
si z e i n P art  2 A will r a n g e fr o m 6 t o 1 2  p ati e nt s  p er c o h ort. T h e s a m pl e si z e i n P art  2 B m a y 
b e b a s e d o n eit h er Si m o n t w o -st a g e d e si g n or o n e -st a g e d e si g n . T h e fi n al s a m pl e si z e 
c al c ul ati o n s will b e i ntr o d u c e d t hr o u g h pr ot o c ol a m e n d m e nt.  
C CI

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The statistical analysis plan (SAP) will be finalized prior to database lock for the main 
analysis and it will include a more technical and detailed description of the statistical 
analyses. Any deviations from the planned analyses described in the final SAP will be 
described and justified in the clinical trial report. 
Safety Review Committee (SRC) 
A data monitoring committee (DMC) is not planned. An SRC, composed of the 
investigators and the sponsor’s representatives will assess the cumulative safety data 
(e.g., serious AEs [SAEs], AEs, laboratory data and DLTs where applicable) collected 
during the trial to help ensure patient’s safety.  
The SRC will make recommendations for the adaptive trial design as well as for the 
recommended dose for pre-conditioning if needed and for Parts 2A and 2B and will 
recommend whether to activate the Expansion Phase (Part 2). 

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1.3 
Schedule of activities 
According to the adaptive trial design of this trial, Part 1 of the trial will start without a 
pre-conditioning dosing schedule. The schedule of activities (SoA) and procedures for 
Part 1 with and without a pre-conditioning dosing scheme is shown in Table 1a and 
Table 1b, with the schedule of PK, exploratory PD, cytokines/chemokines and 
immunogenicity shown in Table 2a and Table 2b. In case the SRC recommend pre-
conditioning, all newly enrolled patients will be treated with the pre-conditioning cycle. 
The SoA and procedures for the Biomarker Cohort with and without pre-conditioning is 
shown in Table 3a and Table 3b, with the schedule of PK, exploratory PD, 
cytokines/chemokines and immunogenicity shown in Table 4a and Table 4b. 
Assessments should be performed before trial treatment administration (on the applicable 
days) or any planned intervention, with the exception of post-dose blood sampling for 
exploratory PD, PK, immunogenicity assessments and any samples required for 
supplementary biomarker assessments. On the days of tumor imaging, blood sampling 
can be before or after imaging assessments. 
In the dosing scheme, one cycle is defined as 21 days. The length of the pre-conditioning 
cycle is 7 days. 
The SoA for the expansion cohorts in Part 2 will be submitted by amendment. 
 

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12 Imaging at screening, on-treatment imaging at Week 6 (+7 d), every 6 weeks (±7 d) for 48 weeks, and every 12 weeks (±7 d) thereafter until disease progression is assessed by the investigator 
(unless the investigator elects to continue treatment [see below for conditions of continued treatment]), withdrawal of consent, trial termination by the sponsor, or death, whichever occurs first. The 
RECIST 1.1 criteria will be used for secondary endpoint response evaluation including PFS (Eisenhauer et al. 2009). All images obtained must be submitted to the central imaging vendor. At 
screening a head and neck imaging is required for patients with SCCHN. Imaging of the pelvis is not required for those patients but is strongly recommended. 
13 During screening ECOG performance status should be assessed no later than 7 days prior to the planned visit C1D1/if applicable planned pCD1. 
14 Evaluation of left ventricular function by ECHO scan will be performed during screening, and if clinically indicated at other time points. 
15 Adverse events (AEs) and serious adverse events (SAEs) should be reported from the time of signing the informed consent to 60 days after the patient receives the last dose of BNT151. 
16 Suspected BNT151-related AEs only. 
17 Prior/Concomitant medications and non-drug therapies include all anti-cancer pre-treatments and all previous and on-trial COVID-19 vaccinations. 
18 Only medications and non-drug therapies related to “Suspected BNT151-related AEs” need to be documented. 
19 Patients who experience a delay in the administration of BNT151 should return to the clinic at least every 2 weeks (±3 d) after onset of the delay and assessments listed under ad hoc visit should be 
performed and reported in the eCRF. Ad hoc visit assessments should be performed at the investigator’s discretion. 
20 Cycle 2 dose should not be given during DLT observation period, which lasts for 21 days.  
21 Hematology includes platelet count, red blood cell (RBC) count, RBC indices, white blood cell count with differential, hemoglobin, hematocrit (for details, see Table 13). 
22 All labs (hematology, blood chemistry, coagulation factors) at the screening visit must be obtained within 7 days prior to the planned C1D1 (if applicable planned pCD1) and again on C1D1 (if 
applicable pCD1). The following samples will be analyzed locally at the site the patient was enrolled: hematology, blood chemistry, coagulation factors, endocrine, pregnancy test, urinalysis, and 
serum autoantibody sample (see Table 13). All other laboratory samples will be analyzed centrally. 
23 Blood chemistry panel for the screening and D1 of each cycle sample includes sodium, potassium, magnesium, chloride, bicarbonate or carbon dioxide, glucose, BUN or urea, creatinine, total 
protein, albumin, pre-albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, ferritin, and C-reactive 
protein. For all subsequent sampling, only a reduced panel will be assessed (see Footnote 24). 
24 Reduced blood chemistry panel includes sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, 
alanine aminotransferase, and aspartate aminotransferase, lactate dehydrogenase. 
25 TSH, free-T3 and free-T4 will only be measured at screening, pCD1 (if applicable), C1D1, C2D1, on Day 1 of every evenly numbered cycle thereafter (e.g., Cycle 4, 6, 8…), SFU-1, SFU-2, and at 
EoT. 
26 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The frequency of testing during treatment phase may depend on clinical 
indication per investigator's assessment and may also depend on the local guidelines and regulations. 
27 Includes specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick. Microscopic examination (if blood or protein is abnormal). 
28 Country-specific procedure for Germany: To confirm that a patient would be eligible to participate in the trial, an active infection with HIV/hepatitis B or C should be ruled out by serum blood test of 
hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against 
HIV-1 and -2 (anti-HIV 1/2). 
29 Autoantibody analysis includes anti-nuclear antibody, anti-double-stranded-DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. For patients 
who show evidence of immune-mediated toxicity, additional time points may be considered. 
30 If feasible, patients should provide a fresh biopsy (aspirates are not acceptable) performed at screening and treatment discontinuation in the trial. Further serial biopsy during treatment and/or at 
progression will be performed in the same patients if feasible. The trial site should either provide FFPE (block/slides) or provide fresh formalin fixed tumor biopsy for sponsor processing into FFPE. In 
case the site and the patients are willing to provide biopsies on-treatment but cannot provide fresh biopsy during screening, archived material is allowed to be used as a screening sample. 
AE = adverse event; BUN = blood urea nitrogen; C = cycle; CT = computed tomography; D,d = day; DLT = dose limiting toxicity; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EoT = end of treatment; FFPE = formalin fixed paraffin embedded; FU = Follow-up; 
MRI = magnetic resonance imaging; pC = pre-conditioning cycle; PFS = progression-free survival; RECIST = Response Evaluation Criteria Solid Tumors; SFU = Safety Follow-up; SCCHN = squamous 
cell carcinoma of head and neck; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; wks = weeks. 

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20 Cycle 2 dose should not be given during DLT observation period, which lasts for 21 days.  
21 Hematology includes platelet count, red blood cell (RBC) count, RBC indices, white blood cell count with differential, hemoglobin, hematocrit (for details, see Table 13). 
22 All labs (hematology, blood chemistry, coagulation factors) at the screening visit must be obtained within 7 days prior to the planned C1D1 (if applicable planned pCD1) and again on C1D1 (if 
applicable pCD1). The following samples will be analyzed locally at the site the patient was enrolled: hematology, blood chemistry, coagulation factors, endocrine, pregnancy test, urinalysis, and 
serum autoantibody sample (see Table 13). All other laboratory samples will be analyzed centrally. 
23 Blood chemistry panel for the screening and D1 of each cycle sample includes sodium, potassium, magnesium, chloride, bicarbonate or carbon dioxide, glucose, BUN or urea, creatinine, total 
protein, albumin, pre-albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, ferritin, and C-reactive 
protein. For all subsequent sampling, only a reduced panel will be assessed (see Footnote 24). 
24 Reduced blood chemistry panel includes sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, 
alanine aminotransferase, and aspartate aminotransferase, lactate dehydrogenase. 
25 TSH, free-T3 and free-T4 will only be measured at screening, pCD1 (if applicable), C1D1, C2D1, on Day 1 of every evenly numbered cycle thereafter (e.g., Cycle 4, 6, 8…), SFU-1, SFU-2, and at 
EoT. 
26 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The frequency of testing during treatment phase may depend on clinical 
indication per investigator's assessment and may also depend on the local guidelines and regulations. 
27 Includes specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick. Microscopic examination (if blood or protein is abnormal). 
28 Country-specific procedure for Germany: To confirm that a patient would be eligible to participate in the trial, an active infection with HIV/hepatitis B or C should be ruled out by serum blood test of 
hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against 
HIV-1 and -2 (anti-HIV 1/2). 
29 Autoantibody analysis includes anti-nuclear antibody, anti-double-stranded-DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. For patients 
who show evidence of immune-mediated toxicity, additional time points may be considered. 
30 If feasible, patients should provide a fresh biopsy (aspirates are not acceptable) performed at screening and treatment discontinuation in the trial. Further serial biopsy during treatment and/or at 
progression will be performed in the same patients if feasible. The trial site should either provide FFPE (block/slides) or provide fresh formalin fixed tumor biopsy for sponsor processing into FFPE. In 
case the site and the patients are willing to provide biopsies on-treatment but cannot provide fresh biopsy during screening, archived material is allowed to be used as a screening sample. 
AE = adverse event; BUN = blood urea nitrogen; C = cycle; CT = computed tomography; D,d = day; DLT = dose limiting toxicity; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EoT = end of treatment; FFPE = formalin fixed paraffin embedded; FU = Follow-up; 
MRI = magnetic resonance imaging; PFS = progression-free survival; RECIST = Response Evaluation Criteria Solid Tumors; SFU = Safety Follow-up; SCCHN = squamous cell carcinoma of head and 
neck; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; wks = weeks 
 
 
 

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RECIST 1.1 criteria will be used for secondary endpoint response evaluation including PFS (Eisenhauer et al. 2009). All images obtained must be submitted to the central imaging vendor. At 
screening a head and neck imaging is required for patients with SCCHN. Imaging of the pelvis is not required for those patients but is strongly recommended. 
13 During screening ECOG performance status should be assessed no later than 7 days prior to the planned visit C1D1/if applicable planned pCD1. 
14 Evaluation of left ventricular function by ECHO scan will be performed during screening, and if clinically indicated at other time points. 
15 Adverse events (AEs) and serious adverse events (SAEs) should be reported from the time of signing the informed consent to 60 days after the patient receives the last dose of BNT151. 
16 Suspected BNT151-related AEs only. 
17 Prior/Concomitant medications and non-drug therapies include all anti-cancer pre-treatments and previous and on-trial COVID-19 vaccinations. 
18 Only medications and non-drug therapies related to “Suspected BNT151-related AEs” need to be documented. 
19 Patients who experience a delay in the administration of BNT151 should return to the clinic at least every 2 weeks (±3 d) after onset of the delay and assessments listed under ‘ad hoc visit’ should be 
performed and reported in the eCRF. Ad hoc visit assessments should be performed at the investigator’s discretion. 
20 Cycle 2 dose should not be given during DLT observation period, which lasts for 21 days. 
21 Hematology includes platelet count, red blood cell (RBC) count, RBC indices, white blood cell count with differential, hemoglobin, hematocrit (for details, see Table 13). 
22 All labs (hematology, blood chemistry, coagulation factors) at the screening visit must be obtained within 7 days prior to the planned C1D1 (if applicable planned pCD1) and again on C1D1 (if 
applicable pCD1). The following samples will be analyzed locally at the site the patient was enrolled: hematology, blood chemistry, coagulation factors, endocrine, pregnancy test, urinalysis, and 
serum autoantibody sample (see Table 13). All other laboratory samples will be analyzed centrally. 
23 Blood chemistry panel for the screening and D1 of each cycle sample includes sodium, potassium, magnesium, chloride, bicarbonate or carbon dioxide, glucose, BUN or urea, creatinine, total 
protein, albumin, pre-albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, ferritin, and C-reactive 
protein. For all subsequent sampling, only a reduced panel will be assessed (see Footnote 24). 
24 Reduced blood chemistry panel includes sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, 
alanine aminotransferase, and aspartate aminotransferase, lactate dehydrogenase. 
25 TSH, free-T3 and free-T4 will only be measured at screening, pCD1 (if applicable), C1D1, C2D1, on Day 1 of every evenly numbered cycle thereafter (e.g., Cycle 4, 6, 8…), SFU-1, SFU-2, and at 
EoT. 
26 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The frequency of testing during treatment phase may depend on clinical 
indication per investigator's assessment and may also depend on the local guidelines and regulations. 
27 Includes specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick. Microscopic examination (if blood or protein is abnormal). 
28 Country-specific procedure for Germany: To confirm that a patient would be eligible to participate in the trial, an active infection with HIV/hepatitis B or C should be ruled out by serum blood test of 
hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against 
HIV-1 and -2 (anti-HIV 1/2). 
29 Autoantibody analysis includes anti-nuclear antibody, anti-double-stranded-DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. For patients 
who show evidence of immune-mediated toxicity, additional time points may be considered. 
30 The mandatory fresh pre-treatment biopsy must be between signature of informed consent and before the first dose, the on-treatment biopsy should be taken post-dose, preferred on C2D5-12, and 
an optional biopsy can be taken at disease progression or EoT.  
AE = adverse event; BUN = blood urea nitrogen; C = cycle; CT = computed tomography; D,d = day; DLT = dose limiting toxicity; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EoT = end of treatment; FFPE = formalin fixed paraffin embedded; FU = Follow-up; 
MRI = magnetic resonance imaging; pC = pre-conditioning cycle; PFS = progression-free survival; RECIST = Response Evaluation Criteria Solid Tumors; SFU = Safety Follow-up; SCCHN = squamous 
cell carcinoma of head and neck; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; wks = weeks. 
 

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20 Cycle 2 dose should not be given during DLT observation period, which lasts for 21 days. 
21 Hematology includes platelet count, red blood cell (RBC) count, RBC indices, white blood cell count with differential, hemoglobin, hematocrit (for details, see Table 13). 
22 All labs (hematology, blood chemistry, coagulation factors) at the screening visit must be obtained within 7 days prior to the planned C1D1 (if applicable planned pCD1) and again on C1D1 (if 
applicable pCD1). The following samples will be analyzed locally at the site the patient was enrolled: hematology, blood chemistry, coagulation factors, endocrine, pregnancy test, urinalysis, and 
serum autoantibody sample (see Table 13). All other laboratory samples will be analyzed centrally. 
23 Blood chemistry panel for the screening and D1 of each cycle sample includes sodium, potassium, magnesium, chloride, bicarbonate or carbon dioxide, glucose, BUN or urea, creatinine, total 
protein, albumin, pre-albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, ferritin, and C-reactive 
protein. For all subsequent sampling, only a reduced panel will be assessed (see Footnote 24). 
24 Reduced blood chemistry panel includes sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, 
alanine aminotransferase, and aspartate aminotransferase, lactate dehydrogenase. 
25 TSH, free-T3 and free-T4 will only be measured at screening, pC1D1 (if applicable), C1D1, C2D1, on Day 1 of every evenly numbered cycle thereafter (e.g., Cycle 4, 6, 8…), SFU-1, SFU-2, and at 
EoT 
26 Serum pregnancy test is performed at screening. Thereafter, urine pregnancy test is sufficient unless indicated otherwise. The frequency of testing during treatment phase may depend on clinical 
indication per investigator's assessment and may also depend on the local guidelines and regulations. 
27 Includes specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick. Microscopic examination (if blood or protein is abnormal). 
28 Country-specific procedure for Germany: To confirm that a patient would be eligible to participate in the trial, an active infection with HIV/hepatitis B or C should be ruled out by serum blood test of 
hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), antibody against hepatitis C virus (anti-HCV), antibody against 
HIV-1 and -2 (anti-HIV 1/2). 
29 Autoantibody analysis includes anti-nuclear antibody, anti-double-stranded-DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. For patients 
who show evidence of immune-mediated toxicity, additional time points may be considered. 
30 The mandatory fresh pre-treatment biopsy must be between signature of informed consent and before the first dose, the on-treatment biopsy should be taken post-dose, preferred on C2D5-12, and 
an optional biopsy can be taken at disease progression or EoT.  
AE = adverse event; BUN = blood urea nitrogen; C = cycle; CT = computed tomography; D,d = day; DLT = dose limiting toxicity; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EoT = end of treatment; FFPE = formalin fixed paraffin embedded; FU = Follow-up; 
MRI = magnetic resonance imaging; PFS = progression-free survival; RECIST = Response Evaluation Criteria Solid Tumors; SFU = Safety Follow-up; SCCHN = squamous cell carcinoma of head and 
neck; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; wks = weeks 
 
 
 
 

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4 
Cytokines/chemokines which will be analyzed including but not limited to IFN-α, IP-10, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, TNF-α, IL-12p70, IL-13, and IL-18. 
5 
Cell pellet to support the genetic analysis by next generation sequencing should be generated from the spin down of whole blood for lipid PK plasma. 
6 
Extra sample for retesting if required. 
7 
The mandatory fresh pre-treatment biopsy must be between signature of informed consent and before the first dose, and the on-treatment biopsy should be taken post-dose, preferred on C2D5-12, 
and an optional biopsy can be taken at disease progression or EoT. 
Investigators must adhere to the given time points. However, due to possible time deviations that may occur in clinical practice, those will not be reported as protocol deviations. 
ADAs = anti-drug antibodies; Anti-PEG = Anti-Polyethylene glycol; C = cycle; D,d = day; EoT = end of treatment; IFN = interferon; IL = interleukin; IP = interferon-gamma induced protein; SFU = Safety 
Follow-up; sCD25 = soluble interleukin-2 receptor; TNF = tumor necrosis factor; pC = pre-conditioning cycle; PK = pharmacokinetics. 
. 
 

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7 
The mandatory fresh pre-treatment biopsy must be between signature of informed consent and before the first dose, and the on-treatment biopsy should be taken post-dose, preferred on C2D5-12, 
and an optional biopsy can be taken at disease progression or EoT. 
Investigators must adhere to the given time points. However, due to possible time deviations that may occur in clinical practice, those will not be reported as protocol deviations. 
ADAs = anti-drug antibodies; Anti-PEG = Anti-Polyethylene glycol; C = cycle; D,d = day; EoT = end of treatment; IFN = interferon; IL = interleukin; IP = interferon-gamma induced protein; SFU = Safety 
Follow-up; sCD25 = soluble interleukin-2 receptor; TNF = tumor necrosis factor; PK = pharmacokinetics. 
 
 

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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY 
2 
1.1 
Trial synopsis 
2 
1.2 
Schema (graphical representation of the trial) 
13 
1.3 
Schedule of activities 
14 
TABLE OF CONTENTS 
33 
LIST OF TABLES 
37 
LIST OF FIGURES 
38 
TRIAL-SPECIFIC ABBREVIATIONS 
39 
2 
INTRODUCTION 
42 
2.1 
Trial rationale 
42 
2.2 
Background 
43 
2.2.1 
Overview of the disease(s) 
43 
2.2.2 
Introduction to the investigational treatment 
49 
2.3 
Benefit/risk assessment 
52 
2.3.1 
Risk assessment as a monotherapy (for Part 1) 
52 
2.3.2 
Potential risks associated with BNT151 in combination with pembrolizumab, 
axitinib, carboplatin, pemetrexed, atezolizumab, and nab-paclitaxel 
54 
2.3.3 
Benefit assessment as a monotherapy (for Part 1) 
55 
2.3.4 
Benefit assessment in combination with SoC (for Part 2) 
56 
2.3.5 
Overall benefit/risk conclusion 
56 
3 
OBJECTIVES AND ENDPOINTS 
56 
4 
TRIAL DESIGN 
58 
4.1 
Overall design 
58 
4.1.1 
MTD and RP2D definitions 
59 
4.1.2 
Dose escalation Part 1 - Monotherapy dose escalation 
60 
4.1.3 
Expansion Part 2 - Expansion Phase 
62 
4.1.4 
Adaptive trial design elements 
63 
4.1.5 
Planned number of patients 
66 
4.1.6 
Replacement of patients 
67 
4.2 
Scientific rationale for the trial design 
67 
4.2.1 
Option of monotherapy dose escalation with pre-conditioning 
68 
4.2.2 
Part 2A: Combination dose finding 
68 
4.2.3 
Part 2B: Expansion Phase 
69 
4.3 
Justification for dose 
70 
4.4 
End of trial definition 
71 
5 
TRIAL POPULATION 
72 

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5.1 
Inclusion criteria 
72 
5.1.1 
Disease-specific inclusion criteria 
72 
5.1.2 
Other inclusion criteria 
73 
5.2 
Exclusion criteria 
74 
5.3 
Lifestyle considerations 
77 
5.4 
Screen failures 
77 
6 
TRIAL TREATMENTS 
77 
6.1 
Trial treatments administered 
77 
6.2 
Preparation/handling/storage/accountability 
78 
6.3 
Measures to minimize bias: randomization and blinding 
78 
6.4 
Trial treatment compliance 
79 
6.4.1 
Concomitant medication and non-drug therapies 
79 
6.4.2 
Premedication 
80 
6.4.3 
Rescue medication 
80 
6.5 
Dose modifications 
80 
6.5.1 
Dose limiting toxicity 
80 
6.5.2 
DLTs for Part 1 and Part 2A (dose escalation) 
81 
6.5.3 
Dose modification guidance/rules 
81 
6.5.4 
Mitigation plans for specific AEs 
84 
6.5.5 
Safety stopping criteria 
85 
6.6 
Treatment after the end of the trial - New anti-cancer treatment 
86 
7 
DISCONTINUATION OF TRIAL TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
86 
7.1 
Discontinuation of trial treatment 
86 
7.1.1 
Temporary discontinuation 
86 
7.1.2 
Rechallenge (if applicable) 
86 
7.2 
Patient discontinuation/withdrawal from the trial 
86 
7.2.1 
Safety follow-up evaluations 
87 
7.3 
Lost to follow-up 
87 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
87 
8.1 
Efficacy assessments 
88 
8.1.1 
Anti-tumor activity assessment – CT/MRI imaging 
88 
8.1.2 
Survival follow-up 
89 
8.2 
Safety assessments 
89 
8.2.1 
Physical examinations including height and body weight 
89 
8.2.2 
Vital signs 
89 
8.2.3 
Electrocardiograms (ECGs) 
90 
8.2.4 
Clinical safety laboratory assessments 
91 

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8.2.5 
Eastern Cooperative Oncology Group (ECOG) 
91 
8.2.6 
Echocardiogram (ECHO) 
91 
8.2.7 
Pregnancy testing 
92 
8.3 
Adverse events (AEs) and serious adverse events (SAEs) 
92 
8.3.1 
Time period and frequency for collecting AE and SAE information 
92 
8.3.2 
Method of detecting AEs and SAEs 
92 
8.3.3 
Follow-up of AEs and SAEs 
92 
8.3.4 
Regulatory reporting requirements for SAEs 
93 
8.3.5 
Pregnancy 
93 
8.3.6 
Death events 
94 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs 
or SAEs 
94 
8.3.8 
Adverse events of special interest 
94 
8.4 
Treatment of overdose 
94 
8.5 
Pharmacokinetics 
95 
8.6 
Exploratory pharmacodynamics 
95 
8.7 
Genetics 
95 
8.8 
Biomarkers 
95 
8.8.1 
Tumor tissue 
96 
8.8.2 
Pharmacodynamic biomarkers 
96 
8.8.3 
Screening for predictive biomarkers 
97 
8.8.4 
Additional biomarkers 
97 
8.9 
Supplementary biomarker assessments 
97 
8.10 
Immunogenicity assessments 
97 
8.11 
Blood collection 
98 
8.12 
Medical monitor contact information 
98 
8.13 
24/7 coverage for urgent protocol-related medical questions 
98 
8.14 
Collection of demographic and other baseline characteristics 
98 
8.14.1 
Demographic data 
98 
8.14.2 
Medical history 
99 
9 
STATISTICAL CONSIDERATIONS 
99 
9.1 
Statistical hypotheses 
99 
9.2 
Sample size determination 
99 
9.3 
Analysis sets 
99 
9.4 
Statistical analyses 
100 
9.4.1 
General considerations 
100 
9.4.2 
Primary endpoints 
101 
9.4.3 
Secondary endpoints 
101 

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9.4.4 
Exploratory endpoints 
102 
9.4.5 
Safety analyses 
102 
9.4.6 
Other analyses 
103 
9.5 
Interim analyses 
103 
9.6 
Data Monitoring Committee 
103 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
 
 
103 
10.1 
Regulatory, ethical, and trial oversight considerations 
103 
10.1.1 
Regulatory and ethical considerations 
103 
10.1.2 
Financial disclosure 
104 
10.1.3 
Informed consent process 
104 
10.1.4 
Data protection 
105 
10.1.5 
Committees structure – SRC 
105 
10.1.6 
Dissemination of clinical trial data 
106 
10.1.7 
Data quality assurance 
106 
10.1.8 
Source documents 
107 
10.1.9 
Trial and site start and closure 
107 
10.1.10 
Publication policy 
108 
10.1.11 
Protocol preparation and approval 
108 
10.2 
Clinical laboratory tests 
109 
10.3 
Adverse events: Definitions and procedures for recording, evaluating, follow-up, 
and reporting 
110 
10.3.1 
Definition of AE 
110 
10.4 
Contraceptive guidance and collection of pregnancy information 
120 
10.4.1 
Female patients 
120 
10.4.2 
Male patients 
121 
10.4.3 
Collection of pregnancy information 
121 
10.5 
Genetics 
122 
10.6 
Liver safety: Suggested actions and follow-up assessments 
122 
10.7 
Investigators and trial administrative structure 
124 
10.7.1 
Investigators and trial site personnel 
124 
10.7.2 
Trial site personnel assigned trial-related duties 
124 
10.7.3 
Contract research organizations 
124 
10.7.4 
The sponsor and sponsor’s personnel 
125 
10.8 
Country-specific requirements 
125 
10.9 
Other standard abbreviations and definitions 
125 
10.10 
Protocol amendments 
126 
10.10.1 
Update to protocol version 8.0 (from version 7.0) 
126 

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10.10.2 
Update to protocol version 7.0 (from version 6.0) 
126 
10.10.3 
Update to protocol version 6.0 (from version 5.0) 
127 
10.10.4 
Update to protocol version 5.0 (from version 4.0) 
132 
10.11 
Data collection and management 
135 
10.11.1 
Case report forms (CRFs) 
135 
10.11.2 
Data management 
135 
10.11.3 
Investigator’s Site File (ISF) and the Trial Master File (TMF) 
136 
11 
REFERENCES 
136 
12 
APPENDICES 
144 
12.1 
Appendix 1: Response evaluation criteria in solid tumors version 1.1 
(RECIST 1.1) 
144 
12.2 
Appendix 2: Country-specific information 
146 
12.2.1 
Germany 
146 
12.3 
Appendix 3: Management recommendations in case of a potential cytokine 
release syndrome (CRS) 
146 
12.4 
Appendix 4: Risk-benefit assessment of COVID-19 vaccination in BNT151-01 
trial  
148 
12.5 
Appendix 5: COVID-19 vaccination in BNT151-01 trial during the pandemic 150 
LIST OF TABLES 
Table 1a: Schedule of activities and procedures – Part 1: Monotherapy with and without 
pre-conditioning - Screening, treatment cycles, and end of treatment 
15 
Table 1b: Schedule of activities and procedures – Part 1: Monotherapy with and without 
pre-conditioning – Safety follow-up, survival follow-up, and ad hoc visits 
18 
Table 2a: Schedule of PK, exploratory PD, cytokines/chemokines and immunogenicity for 
Part 1: Monotherapy with and without pre-conditioning – Cycle 1 to 4 inclusive
 
 
21 
Table 2b: Schedule of PK, exploratory PD, cytokines/chemokines and immunogenicity for 
Part 1: Monotherapy with and without pre-conditioning – Every 4th cycle 
thereafter, end of treatment, and safety follow-up visits 
22 
Table 3a: Schedule of activities and procedures – Part 1: Biomarker Cohort with and 
without pre-conditioning – Screening, treatment cycles, and end of treatment 23 
Table 3b: Schedule of activities and procedures – Part 1: Biomarker Cohort with and 
without pre-conditioning – Safety follow-up visits, survival follow-up, and ad hoc 
visits  
26 
Table 4a: Schedule of PK, exploratory PD, cytokines/chemokines and immunogenicity and 
biopsies for the Biomarker Cohort with and without pre-conditioning in selected 
US sites only – Screening, treatment cycles 1 to 2 inclusive 
29 
Table 4b: Schedule of PK, exploratory PD, cytokines/chemokines and immunogenicity and 
biopsies for the Biomarker Cohort with and without pre-conditioning in selected 

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US sites only – Cycles 3- 4, Every 4th cycle thereafter, end of treatment, and 
safety follow-up visits 
31 
Table 5: 
Objectives and endpoints 
56 
Table 6: 
Dose escalation table 
61 
Table 7: 
BNT151 dose increments 
61 
Table 8: 
Dose escalation in monotherapy with pre-conditioning 
64 
Table 9: 
Trial treatments to be administered in Part 1 
78 
Table 10: Vital signs during Part 1 (administration days) 
90 
Table 11: ECOG performance status scale 
91 
Table 12: Analysis sets 
100 
Table 13: Protocol-required safety laboratory assessments 
109 
Table 14: Highly effective methods of contraception 
121 
Table 15: Evaluation of overall response 
146 
Table 16: CRS grading per NCI CTCAE v5.0 
147 
Table 17: American Society for Transplantation and Cellular Therapy CRS consensus 
grading 
147 
Table 18: Guidelines for management of cytokine release syndrome 
148 
 
LIST OF FIGURES 
Figure 1: Trial design 
13 
Figure 2: Decision for safety run-in versus abbreviated dose escalation 
66 
Figure 3: Lymphoproliferation-based MABEL projection 
70 
Figure 4: IL-2R activation-based MABEL projection 
71 
Figure 5: Handling of Grade 3 BNT151-related AEs outside of DLT periods 
82 
 
 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 4 2  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
2  
I N T R O D U C TI O N 
2. 1  
Tri al r ati o n al e  
O ut c o m e s r e m ai n p o or for p ati e nt s  wit h r el a p s e d or r efr a ct or y a d v a n c e d s oli d t u m or s. 
Tr e at m e nt o pti o n s i n cl u d e f urt h er p alli ati v e c h e m ot h er a p y, w hi c h mi g ht b e l e s s w ell 
t ol er at e d aft er pr e vi o u s r e p e at e d e x p o s ur e t o c yt ot o xi c c o m p o u n d s, or b e st s u p p orti v e 
c ar e, a n d tri al tr e at m e nt s wit h o ut  pr o v e n b e n efit. T h er a p y i n t hi s p o p ul ati o n i s n ot c ur ati v e, 
wit h a n e x p e ct e d o v er all s ur vi v al ( O S ) of a f e w  m o nt h s . I m m u n ot h er a p y h a s e m er g e d a s 
a n eff e cti v e tr e at m e nt o pti o n i n s o m e c a n c er s wit h hi g h, u n m et m e di c al n e e d s.  
S p e cifi c all y, i m m u n e c h e c k p oi nt i n hi bit or s ( C PI s ) ar e a p pr o v e d a cr o s s v ari o u s c a n c er 
i n di c ati o n s a n d a ct b y i n vi g or ati n g pr e-e xi st e nt a nti -t u m or-s p e cifi c T  c ell s . E v e n t h o u g h 
C PI s ar e pr o vi di n g cl e ar cli ni c al b e n efit, t h e m e di c al n e e d i s still hi g h f or v ari o u s c a n c er 
t y p e s a n d 
. 
R e c o m bi n a nt I L -2, al d e sl e u ki n, w a s t h e fir st a p pr o v e d c a n c er i m m u n ot h er a p y a n d h a s 
b e e n u s e d f or d e c a d e s i n t h e tr e at m e nt of l at e st a g e m ali g n a nt m el a n o m a a n d r e n al c ell 
c a n c er ( At ki n s et al. 1 9 9 9 , R o s e n b er g 2 0 0 7 , Kl a p p er et al. 2 0 0 8 ). T h e t h er a p e uti c eff e ct of 
I L-2 pri m aril y d e p e n d s o n it s p ot e nti al t o a cti v at e a n d e x p a n d t u m or s p e cifi c cl u st er of 
diff er e nti ati o n 8 p o siti v e ( C D 8 + ) eff e ct or T  c ell s . R e c o m bi n a nt I L-2 h a s a v er y s h ort h alf -lif e 
i n t h e r a n g e of mi n  a n d t h er ef or e r e q uir e s hi g h a n d fr e q u e nt d o si n g, w hi c h i n t ur n 
p ot e nti at e s it s si d e eff e ct s ( L ot z e et al. 1 9 8 6 ). A p arti c ul ar c h all e n g e of I L-2 f or c a n c er 
tr e at m e nt i s t h e pr ef er e nti al sti m ul ati o n of r e g ul at or y T  c ell s  (T r e g) w hi c h d a m p e n a nti -
t u m or i m m u n e r e s p o n s e s alr e a d y at l o w I L-2 d o s e s. A cti v ati o n of C D 8 + eff e ct or T  c ell s  o n 
t h e ot h er h a n d r e q uir e s hi g h er I L-2 a m o u nt s d u e t o t h e e x pr e s si o n of a n I L -2 r e c e pt or of 
l o w er affi nit y. T h e c a n di d at e tr e at m e nt B N T 1 5 1 e n c o d e s a n I L -2 v ari a nt, w hi c h w a s 
d e si g n e d t o f a cilit at e s u st ai n e d d eli v er y of t h e e n c o d e d I L -2 v ari a nt wit h pr ol o n g e d h alf -lif e 
a n d t o di s pl a y m ar k e dl y r e d u c e d T r e g a cti v ati o n. B y i n cr e a si n g a cti v ati o n of eff e ct or T  c ell s  
a s w ell a s d e cr e a si n g a cti v ati o n of c o u nt er a cti n g T r e g, B N T 1 5 1 a d mi ni str ati o n i s b eli e v e d t o 
yi el d hi g h er effi c a c y a s c o m p ar e d t o r e c o m bi n a nt I L -2 w hil e a m eli or ati n g p e a k d o s e 
m e di at e d t o xi citi e s. F urt h er m or e, d u e t o it s b e n efi ci al p h ar m a c o ki n eti c pr o p erti e s, B N T 1 5 1 
s h o ul d r e q uir e l e s s fr e q u e nt d o si n g, c o m p ar e d t o al d e sl e u ki n wit h s h ort h alf-lif e, w hi c h 
r e q uir e s fr e q u e nt d o si n g w hi c h t h e n i n cr e a s e s t h e ri s k s of t o xi citi e s. 
A s B N T 1 5 1 pr o vi d e s a n e s s e nti al T -c ell gr o wt h a n d s ur vi v al f a ct or, 
 
 
 T u m or c ell br e a k d o w n b y s u c h a g e nt s r e s ult s i n r el e a s e of 
t u m or a nti g e n s i n c o nj u n cti o n wit h i m m u n e m o d ul ati o n (i m m u n o g e ni c c ell d e at h) 
pr o m oti n g a cti v ati o n of T  c ell s  r e c o g ni zi n g s u c h a nti g e n s. 
 
 
 
 
T h e m ai n p ur p o s e of t h e tri al i s t o d et er mi n e s af et y, e x pl or at or y P D, P K, a n d pr eli mi n ar y 
effi c a c y of B N T 1 5 1 a s a m o n ot h er a p y a n d i n c o m bi n ati o n wit h ot h er a nti -c a n c er a g e nt s. 
T hi s will b e a c hi e v e d b y r u n ni n g a P h a s e  I d o s e e s c al ati o n i n b ot h m o n ot h er a p y a n d i n 
c o m bi n ati o n  wit h ot h er a nti -c a n c er a g e nt s .  
C CI
C CI
C CI

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mRNA underlies an innovative and sophisticated drug platform to deliver a protein-based 
therapy but, ongoing data do potentially suggest an occurrence of interpatient variability 
especially in translation that can affect correct determination of effective dose, as well as 
establishing a confident safety profile of the product. Therefore, the implementation of the 
Biomarker Cohort to further elucidate the differences and understand the variabilities is 
justified. Dose levels that have been cleared by the SRC in the dose escalation will be 
investigated in the monotherapy Biomarker Cohort, in order to further investigate the mode 
of action of BNT151, to allow optimization of future combinations with other anti-cancer 
agents, and to assess the interpatient variability. The RP2D of BNT151 monotherapy and 
in combination with other anti-cancer agents will then be tested further in the Expansion 
Phase to seek a preliminary signal of efficacy/anti-tumor activity. Establishing a safe and 
efficacious dose is crucial for successful development of new anti-cancer therapy, which 
will ultimately benefit the patients.  
The IL-2 variant-encoding BNT151 provides an innovative new approach for the treatment 
of solid tumors, especially in combination with existing SoC. 
2.2 
Background 
2.2.1 
Overview of the disease(s) 
Cancer is the second leading cause of death globally and is expected to be responsible for 
an estimated 9.6 million deaths in 2018 (Bray et al. 2018). In general, metastasis of a solid 
tumor is associated with a poor prognosis. 
2.2.1.1 
Treatment of advanced and metastatic solid tumors 
Refinements in conventional therapies such as chemotherapy, radiotherapy, surgery, and 
targeted therapies and recent advances in immunotherapies have improved outcomes in 
patients with advanced solid tumors. In the last few years, the FDA and European 
Medicines Agency (EMA) have approved 6 CPIs: one monoclonal antibody targeting the 
cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathway, ipilimumab, and 6 antibodies 
targeting PD-L/PD-L1, including atezolizumab, avelumab, durvalumab, nivolumab, 
cemiplimab and pembrolizumab, in various cancer indications, mainly solid tumors 
(Gentzler et al. 2016, Ribas and Wolchok 2018). While these approvals have dramatically 
changed the landscape of cancer treatment, the majority of cancer patients, including 
those with tumors considered CPI-‘sensitive’ (e.g., melanoma, NSCLC, urothelial 
carcinoma, kidney cancer) either do not respond or become resistant to these agents 
(Arora et al. 2019). In addition, some of the most prevalent tumors, colorectal, breast 
cancer (BC) and prostate cancer, are largely refractory to checkpoint inhibition 
(Borcherding et al. 2018). 
Many immunotherapies have demonstrated efficacy in only a selected subgroup of 
cancers, such as those expressing PD-L1 (Tecentriq® US Prescribing Information), with 
microsatellite instability (MSI)/mismatch repair (MMR) deficiency or high tumor mutational 
burden (TMB) (Luchini et al. 2019), and even novel targeted agents only address very 
small sub-populations across tumor types (Vitrakvi® US Prescribing Information). Indeed, 
despite considerable early success and relatively fewer side effects compared to other 

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systemic therapies, the majority of cancer patients do not respond to CPIs or novel 
targeted therapies (Arora et al. 2019). 
With cures remaining scarce in patients with advanced solid tumors, there is an unmet 
medical need for more effective and less toxic therapies, in particular those that have 
synergistic mechanisms of action with the CPIs. 
2.2.1.2 
Squamous cell carcinoma of the head and neck 
Globally, over 600,000 patients are diagnosed with SCCHN annually (Bray et al. 2018), 
with approximately 65,000 patients diagnosed and approximately 14,000 deaths occurring 
annually in the US secondary to SCCHN (Siegel et al. 2019). Infection with human 
papillomavirus (HPV), specifically HPV-16 and 18, are risk factors for developing SCCHN, 
particularly oropharyngeal cancers involving the tonsils or the base of the tongue 
(Chaturvedi et al. 2011). Approximately 25,000 SCCHN patients per year in the US 
develop locally R/M disease. Once patients reach this advanced state, SCCHN remains 
essentially incurable and 5-year survival is less than 50% (American Cancer Society 
2019a). 
2.2.1.2.1 
Treatment of advanced/metastatic SCCHN 
Treatments with anti-PD-1 antibody have recently demonstrated substantial anti-tumor 
activity in patients with advanced SCCHN. Pembrolizumab received accelerated approval 
in the US based on response rate (18%) and modest durability of response in patients with 
R/M SCCHN whose disease had progressed after platinum-containing chemotherapy 
(second-line therapy), irrespective of HPV status (Chow et al. 2016). 
Pembrolizumab also recently demonstrated substantial anti-tumor activity in a Phase III 
trial relative to SoC (EXTREME: cetuximab + cisplatin or carboplatin + fluorouracil), first-
line in patients with R/M SCCHN (Burtness et al. 2019, Rischin et al. 2019). Patients with a 
high (≥20) or any level (≥1) of combined positive score (CPS) (Burtness et al. 2019) who 
received pembrolizumab had a statistically significant improvement in OS vs. EXTREME 
alone: Hazard ratio (HR) 0.61 (0.45-0.83); P = 0.0007 and HR 0.78 (0.64-0.96); 
P = 0.0086, respectively. The overall response rates (ORRs) with pembrolizumab in the 
CPS ≥20 and ≥1 groups were 31% and 49%, respectively, though response rates with 
EXTREME were higher in the respective cohorts. Pembrolizumab has recently been 
approved by the FDA for monotherapy or combination use in the first-line setting based on 
improvements in OS and is likely to become the global standard (Keytruda® US 
Prescribing Information, Taberna et al. 2019). 
Taken together, these data demonstrate that strong anti-tumor activity against SCCHN can 
be achieved by stimulating T cells targeting tumor antigens. In fact, with pembrolizumab 
moving into first-line SCCHN treatment, the role of chemo-based regimens such as 
EXTREME is in flux, as such therapies have not been evaluated after failure with anti-PD-
(L)1 therapy. 
Although the recent advances in therapy for advanced SCCHN have increased OS, the 
disease remains incurable, and pembrolizumab did not increase the response rate over 
EXTREME, only the duration of response (DOR). Furthermore, less than half of all 
SCCHN patients have a CPS score ≥20, implying that the majority of these patients will 

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not obtain benefits from pembrolizumab therapy. Treatments that not only enhance activity 
among high PD-L1 expressing SCCHN patients but also those that have low expression 
are needed to improve outcomes for this unmet patient population. The mechanism of 
action of BNT151 and strong anti-tumor activity of therapies that enhance T-cell activity 
make SCCHN a highly suitable candidate to target with this novel immunotherapy 
combined with CPI. 
2.2.1.3 
Hepatocellular carcinoma (HCC) 
HCC results in up to 1 million deaths annually worldwide, making it the second leading 
cause of cancer-related death in the world (Kim and El-Serag 2019); it is diagnosed in just 
over 40,000 patients in the US per year, resulting in approximately 30,000 deaths. Five-
year survival is very poor, at 18% overall and 2% for metastatic disease (American Cancer 
Society 2019c). The incidence of liver cancer in the US has more than doubled in the last 
two decades (Bray et al. 2018, White et al. 2017). Most patients are diagnosed with 
incurable disease. Besides stage at diagnosis, hepatic reserve per Child-Pugh 
classification is a major determinant of treatment. 
2.2.1.3.1 
Treatment of unresectable HCC 
Select patients with advanced, unresectable HCC may benefit from liver-directed non-
surgical therapies. For most other patients, systemic therapy is considered, but cytotoxic 
chemotherapy has modest efficacy, with no clear impact on OS (NCCN Guidelines® 
Hepatobiliary Cancers 2020). In patients with Child-Pugh A/B7, the multi-kinase inhibitor 
sorafenib represents the current SoC in first-line, improving OS compared to placebo (10.7 
vs. 7.9 months), with an ORR of 2% (Llovet et al. 2008). Lenvatinib has been shown to be 
non-inferior to sorafenib in Child-Pugh A disease only, with a longer time to treatment 
failure (7.4 vs. 3.7 months) and an increased ORR of 24% (Cheng et al. 2017). 
Regorafenib was superior to placebo after progression on first-line therapy with sorafenib, 
with an improvement in median OS (10.6 vs. 7.8 months) (Bruix et al. 2017). Other kinase 
inhibitors have shown similar results (NCCN Guidelines® Hepatobiliary Cancers 2020). 
The role of sorafenib as SoC in first-line will be challenged by the recent FDA decision to 
grant approval to atezolizumab in combination with bevacizumab for patients with 
unresectable or metastatic HCC who have not received prior systemic therapy, due to 
superiority in OS (median OS not reached vs 13.2 months) and progression-free survival 
(PFS) (6.8 vs 4.3 months) in the IMbrave150 trial (Cheng et al. 2019). 
A Phase I/II trial of nivolumab in patients with Child-Pugh A or B demonstrated a median 
OS of 15 months, with ORR of 23% in the sorafenib-naïve cohort and 19% in the 
sorafenib-experienced cohort (El-Khoueiry et al. 2017). These results led to accelerated 
approval by the FDA for nivolumab as second-line therapy for patients who have been 
previously treated with sorafenib. Nivolumab was safe in patients with underlying HBV and 
HCV. More recently, pembrolizumab reported an ORR of 17%, including one complete 
response (CR) in Child-Pugh A, sorafenib pre-treated patients. Pembrolizumab was 
approved by the FDA for a second-line indication in late 2018. 
The Phase III studies of both pembrolizumab vs. placebo in second-line therapy and 
nivolumab vs. sorafenib in first-line therapy recently reported no significant improvement in 

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OS, putting into question the role of these agents in HCC (Finn et al. 2020, Yau et al. 
2019). While the approval of atezolizumab in combination with bevacizumab in first-line 
represents progress, HCC remains an indication of high medical need. Agents that could 
improve upon the rather low response rates and impact long term outcomes are 
desperately needed in first and later lines of therapy. 
2.2.1.4 
Renal cell carcinoma (RCC) 
Renal cell carcinoma (RCC) denotes cancer originating from kidney epithelium and 
accounts for >90% of cancers in the kidney. The disease encompasses >10 histological 
and molecular subtypes, of which clear cell RCC is the most common, accounting for most 
cancer-related deaths (Hsieh et al. 2017). RCC is diagnosed in over 70,000 people 
annually in the US, and just under 15,000 die of their disease (around 300,000 cases and 
134,000 deaths worldwide) (Hsieh et al. 2017). Despite recent advances in systemic 
treatment, the 5-year survival rate for patients with distant metastases is only 12% and 
median OS remains around 2.5 years in studies where maximum systemic treatment is 
given (Hsieh et al. 2017, American Cancer Society 2019e). The incidence of RCC has 
been rising in the last few years, most likely due to increased incidental findings of early 
stage tumors with the increased use of CT and MRI scanning (American Cancer Society 
2019e). 
2.2.1.4.1 
Treatment of metastatic RCC 
Resection of the primary tumor in patients with RCC is recommended since it appears to 
confer a survival advantage, although recent data is challenging that paradigm (Méjean et 
al. 2018). Prior standard systemic therapies, cytokines (interferon) interferon alpha (IFN-α) 
and IL-2, are now only used in selected patients, based on incremental improvements with 
other agents in terms of response, PFS and OS (NCCN Guidelines® Kidney Cancer 2020). 
Vascular endothelial growth factor receptors (VEGF)-targeted kinase inhibitors dominate 
the SoC for metastatic disease in both first and second-line. Overall, sorafenib has a broad 
label, sunitinib, pazopanib and the combination of bevacizumab and IFN-α are approved 
as first-line options whereas axitinib and cabozantinib are approved in the second-line 
(Hsieh et al. 2017). Indeed, arguably, the landmark trial of first-line systemic therapy of 
metastatic RCC was the Phase III trial of sunitinib versus IFN-α reported in 2007 in which 
the superiority of sunitinib in terms of response rate, PFS and OS was reported (Motzer et 
al. 2007). This trial established sunitinib as the SoC, and the drug remains the comparator 
for Phase III studies of new drugs. The mammalian/mechanistic target of rapamycin 
(mTOR) inhibitors everolimus and temsirolimus are approved as single agents in the 
second-line setting and in the first-line in patients with poor-risk status (Motzer et al. 2008, 
Hudes et al. 2007). 
More recent is the data with CPIs, with nivolumab monotherapy in second-line and the 
nivolumab-ipilimumab combination in first-line. The first-line trial in more than 
1,000 patients showed worse outcomes for the combination in favorable-risk patients and 
significantly improved results for the intermediate and poor-risk patients. ORR and CR 
rates were 42% vs. 27% and 9% vs. 1%, both p<0.001, respectively, with the CPI 
combination vs. sunitinib. Although OS was significantly improved in the intermediate and 
poor-risk patients (HR 0.63; p<0.001), the median PFS was essentially identical in both 

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arms (NCCN Guidelines® Kidney Cancer 2020, Motzer et al. 2019). Given the substantial 
toxicity of this combination, and because the survival benefit appears to be restricted to 
poor/intermediate risk patients, especially among those who express PD-L1 (about 26% of 
patient population), it is not clear that combination CPIs will become a first-line standard 
therapy in practice, despite the recent FDA and EMA approvals (Yervoy® US Prescribing 
Information and EU Summary of Product Characteristics). 
After immune CPIs and antiangiogenic targeted therapies were found to improve 
outcomes, the combination of these 2 approaches has been studied in clinical trials and 
shown to result in longer OS when compared with monotherapy. An open-label, Phase III 
randomized controlled trial comparing sunitinib with the combination of pembrolizumab 
and axitinib enrolled 861 patients who had received no previous systemic therapy for 
metastatic disease. With 12.8 months median follow-up, 1-year OS was 90% in the 
pembrolizumab plus axitinib arm compared with 78% in the sunitinib arm (HR 0.53; 95% 
confidence interval (CI), 0.38˗0.74; P <0.0001) (Rini et al. 2019). This has led to recent 
FDA approval for the combination of pembrolizumab and axitinib in first-line setting of 
RCC. 
In the second-line setting, after VEGF-targeted therapy, nivolumab showed a significant 
improvement in OS versus everolimus (25 vs. 19.6 months at the median, HR 0.73, 
P = 0.0018) with a substantial improvement in both response rate and DOR (21.5 vs. 3.9% 
with a median duration of 23 vs. 13.7 months) (Opdivo® US Prescribing Information and 
Summary of Product Characteristics). Nivolumab monotherapy is, therefore, now a 
recommended option in second-line therapy (NCCN Guidelines® Kidney Cancer 2020, 
Motzer et al. 2019). 
Despite these advances, it is clear that the majority of patients still do not benefit from 
systemic checkpoint therapy. The medical need remains in this non-responder majority 
and also in those who do initially respond but then progress on CPI. 
2.2.1.5 
Triple negative breast cancer 
There is still a substantial unfulfilled medical need in advanced and metastatic BC and 
TNBC, in particular. Of the over one-quarter of a million cases of BC diagnosed annually in 
the US, over 40,000 die of their disease. The 5-year survival rate for women with BC is 
27% (American Cancer Society 2019b) and median survival (OS) remains around 
2.5 years in studies where maximum systemic treatment is given (Zielinski et al. 2016). 
Median OS varies by type of disease, with bone-only metastatic disease survival topping 
7 years for some subgroups, while metastatic TNBC, which represents 10-20% of cases, 
has the worst prognosis and a median OS of less than 1 year (Parkes et al. 2018, Dent et 
al. 2007). 
2.2.1.5.1 
Treatment of advanced/metastatic TNBC 
Hormone-receptor positive BC has proven largely refractory to PD-1 and PD-L1 inhibition 
(Gentzler et al. 2016), and clinical trials of checkpoint inhibition have focused on TNBC, 
where response rates appear to be between 5-20% in a selected PD-L1-positive patient 
population (Nanda et al. 2016, Lyons et al. 2019) or around 60% in first-line combination 
with nab-paclitaxel (Schmid et al. 2018). The first Phase III trial to report in this setting 

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showed that atezolizumab significantly improves PFS in both the overall and 
PD-L1-selected population (with approx. 2 months improvement), but only improves OS in 
PD-L1-positive disease (from 15.5 to 25 months) (Schmid et al. 2018). Atezolizumab has 
obtained approval in the US and approval in the EU, but only in the <20% of patients 
whose tumors overexpress PD-L1 >1% (European Medicines Agency Tecentriq 
(atezolizumab), Summary of opinion, Mittendorf et al. 2014, Sun et al. 2016, Tecentriq® US 
Prescribing Information). The advent of atezolizumab in first-line also leaves an open 
question as to an appropriate second-line treatment for these patients. Thus, despite 
recent advances, metastatic TNBC remains an area of high medical need in three specific 
patient populations: 
• 
The 40% of PD-L1 positive patients whose tumors do not respond to the 
atezolizumab combination. 
• 
The PD--L1-non-expressing tumors, which do not respond to CPIs at all and 
progress rapidly, irrespective of treatment. 
• 
Patients who may have originally responded to first-line treatment, but whose 
disease has progressed on atezolizumab. 
2.2.1.6 
Non-small cell lung cancer (NSCLC) 
In the US in 2019, it is estimated that approximately 228,000 patients were diagnosed with 
lung cancer and 80 to 85% of these cases were of NSCLC histology (American Cancer 
Society 2019d). In 2019, lung cancer accounted for approximately 24% of all cancer-
related deaths in the US, remaining the leading cause of cancer deaths worldwide (Bray et 
al. 2018). 
The etiologic association of NSCLC with exposure to tobacco carcinogens is of particular 
relevance for cancer immunotherapy, as current approaches targeting immune 
checkpoints exhibit increased responses in tumors with a high number of somatic 
mutations, as is the case in smoking induced NSCLC. Conversely, immune checkpoint 
blockade (ICB) has been significantly less successful in never-smokers, including a 
majority of ALK-rearranged or EGFR-mutated NSCLC (Garassino et al. 2018). 
2.2.1.6.1 
Treatment of metastatic NSCLC 
Most patients with NSCLC present at an advanced stage of the disease and are 
symptomatic at the time of diagnosis, with a related poor prognosis and no curative 
options. In Stage IV, systemic palliative treatment is recommended, including cytotoxic 
chemotherapy, immune CPIs, and a series of targeted agents in selected molecularly-
defined subsets of NSCLC patients.  
The approved anti-PD-(L)1 inhibitors nivolumab, pembrolizumab, durvalumab and 
atezolizumab have demonstrated substantial anti-tumor activity, and are changing the 
treatment paradigm in driver mutation-negative NSCLC. Anti-PD-(L)1 therapies are now 
approved as monotherapy or combination therapy with chemotherapy in first-line, and as 
monotherapy in second-line (Imfinzi® US Prescribing Information, Keytruda® US 
Prescribing Information, Opdivo® US Prescribing Information and Summary of Product 
Characteristics, Tecentriq® US Prescribing Information). 

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Pembrolizumab has demonstrated an OS benefit over cisplatin-based doublet 
chemotherapy in NSCLC patients with high PD-L1 (>50% on tumor cell [TC]) expression in 
the front-line setting (Reck et al. 2016). Furthermore, consolidation therapy with 
durvalumab delays tumor progression or death after chemoradiation of locally advanced 
NSCLC (Antonia et al. 2017). Studies of adjuvant therapy of early disease with CPIs are 
ongoing. 
Clearly, CPIs have improved survival in many of these NSCLC patient populations, but 
few patients are obtaining long term cures. Patients progressing on or after CPIs have few 
therapeutic options. Although salvage cytotoxic chemotherapy, docetaxel monotherapy in 
particular, is commonly used in this setting, outcomes remain poor. Median OS in the 
second-line setting ranges from 7.5 months with docetaxel monotherapy to 10.5 months 
with docetaxel and ramucirumab (Garon et al. 2014). There is sparse clinical data on the 
efficacy of cytotoxic chemotherapy after failure of ICB; cohort studies suggest an improved 
ORR in patients pre-treated with ICB compared to ICB-naïve patients, but this has yet to 
be described in a prospective study. 
ICB is rapidly becoming the SoC in all patients with NSCLC in the front-line, either as 
monotherapy, or in combination with chemotherapy. All these patients will relapse with few 
effective therapies available to them. Thus, NSCLC patients previously treated with CPI 
represents a population of unmet medical need for whom novel approaches are needed. 
Unlike SCCHN, EGFR mutations play a significant role in driving tumor development and 
progression in approximately 20% of NSCLC adenocarcinomas (mutant NSCLC: 
mNSCLC). Unlike driver mutation-negative NSCLC, mNSCLC does not respond well to 
checkpoint inhibition after anti-EGFR therapy, for unclear reasons. One explanation for the 
lack of anti-PD-L1 efficacy in this large subgroup is that mNSCLC does not carry as high a 
mutational load as driver mutation-negative NSCLC, making these tumors less amenable 
to native adaptive immune attack by T cells (Miura et al. 2018). There is, thus, also a need 
to explore novel agents in combination with CPIs in EGFR-positive tumors, to find out 
whether they can be rendered immune responsive. 
Despite the significant advances in NSCLC treatment with anti-PD-L1 therapy, advanced 
disease remains largely incurable. NSCLC is a very good candidate for evaluation of novel 
approaches, with a demonstrated susceptibility to immune modulation with monotherapy 
CPIs and sub-populations of less sensitive tumors. 
2.2.2 
Introduction to the investigational treatment 
The IMP under evaluation in this trial is BNT151. Further information on combination 
therapies in Part 2 will be done by protocol amendment. 
2.2.2.1 
Investigational medicinal product (IMP) 
2.2.2.1.1 
BNT151 
The active pharmaceutical ingredient of BNT151 is a single stranded, pharmacologically 
optimized, 5′-capped messenger RNA coding for an IL-2/serum albumin fusion construct. 
The RNA is formulated as LNPs for IV administration and for selective delivery of the RNA 
to the liver. Upon entering liver cells, the RNA is translated into the encoded 

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cytokine/albumin fusion construct, which is then secreted and becomes systemically 
available to act on T cells in the tumor, in lymphoid compartments and in the periphery to 
potentiate their anti-tumor efficacy. 
IL-2 is a key cytokine in T-cell homeostasis and pivotal for the differentiation, proliferation, 
survival and effector functions of T cells (Bamford et al. 1994, Blattman et al. 2003, Gillis 
and Smith 1977, Kamimura and Bevan 2007). The RNA in BNT151 encodes an IL˗2 
variant that is modified such that it (1) stimulates effector T cells and natural killer (NK) 
cells with higher potency than its wild type counterpart and (2) displays markedly reduced 
stimulation of T regulatory (Treg) cells, hence limiting their counter-regulatory immune 
suppressive function. 
Fusion of the IL-2 variant to the human serum albumin sequence in the encoding RNA 
contributes to a favorable PK in 2 ways. First, the molecular size of the fusion protein is 
well above the threshold for renal clearance. Second, albumin fusion proteins are taken up 
via micropinocytosis into cells, but instead of undergoing lysosomal degradation are 
salvaged by the membrane-bound neonatal Fc receptor (FcRn), and are reshuttled back 
into the circulation. Both mechanisms are expected to significantly prolong the plasma 
half-life (Kontermann 2011). 
2.2.2.2 
Potential combination therapies in Part 2 
2.2.2.2.1 
Pembrolizumab (Keytruda®) 
Pembrolizumab, a PD-1-blocking antibody, is an approved marketed product both in 
Europe and the US for various solid tumors. Pembrolizumab is a humanized monoclonal 
immunoglobulin G4 (IgG4) kappa antibody. Pembrolizumab is a monoclonal antibody that 
binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-
1 pathway-mediated inhibition of the immune response, including the anti-tumor immune 
response. 
Please refer to United States Prescribing Information (USPI) or Summary of Product 
Characteristics (SmPC) for further information on pembrolizumab. 
2.2.2.2.2 
Atezolizumab (Tecentriq®) 
Atezolizumab is a monoclonal antibody that binds to PD-L1 and is an approved marketed 
product both in Europe and in the US for various solid tumors. It blocks PD-L1 interactions 
with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of 
the immune response, including activation of the anti-tumor immune response without 
inducing antibody dependent cellular cytotoxicity. 
Please refer to USPI or SmPC for further information on atezolizumab. 
2.2.2.2.3 
Axitinib (Inlyta®) 
Axitinib inhibits receptor tyrosine kinases including vascular endothelial growth factor 
receptors VEGFR-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. 
These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer 
progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by 

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axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and 
phosphorylation of VEGFR-2 in tumor xenograft mouse models. 
Please refer to USPI or SmPC for further information on axitinib. 
2.2.2.2.4 
Nab-paclitaxel (Abraxane®) 
Nab-paclitaxel is an albumin-bound form of paclitaxel with a mean particle size of 
approximately 130 nanometers. It is a microtubule inhibitor that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and mitotic 
cellular functions. Paclitaxel induces abnormal arrays or ‘bundles’ of microtubules 
throughout the cell cycle and multiple asters of microtubules during mitosis. 
Please refer to USPI or SmPC for further information on nab-paclitaxel. 
2.2.2.2.5 
Carboplatin 
Carboplatin is a platinum coordination compound. Carboplatin, like cisplatin, produces 
predominantly interstrand desoxyribonucleic acid (DNA) cross-links rather than DNA-
protein cross-links. This effect is apparently cell cycle nonspecific. The aquation of 
carboplatin, which is thought to produce the active species, occurs at a slower rate than in 
the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin 
induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological 
effects. The differences in potencies for carboplatin and cisplatin appear to be directly 
related to the difference in aquation rates. 
Please refer to USPI or SmPC for further information on carboplatin. 
2.2.2.2.6 
Pemetrexed 
Pemetrexed is a folate analog metabolic inhibitor that exerts its action by disrupting folate-
dependent metabolic processes essential for cell replication. In vitro studies have shown 
that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and 
glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent 
enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. 
Pemetrexed is taken into cells by membrane carriers, such as the reduced folate carrier 
and membrane folate binding protein transport systems. Once in the cell, pemetrexed is 
converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The 
polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. 
Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells 
and is thought to occur (to a lesser extent) in normal tissues. Polyglutamated metabolites 
are thought to have an increased intracellular half-life resulting in prolonged drug action in 
malignant cells. 
Please refer to USPI or SmPC for further information on pemetrexed. 

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2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks, and 
reasonably expected adverse event (AE) for this trial are given in the investigator’s 
brochure (IB). 
2.3.1 
Risk assessment as a monotherapy (for Part 1) 
As this trial is the first to test BNT151 in humans, all precautions indicated when testing a 
new systemically active compound in a first-in-human (FIH) trial will be taken, including 
choosing a high medical need patient population. The trial will be conducted at centers 
experienced in FIH trials, and trial-related procedures will only be performed by qualified 
physicians and trained nurses. The sponsor also prepares and trains the investigator to 
closely monitor, dose delay, dose-reduce or withdraw patients based on AEs that may 
occur with BNT151. 
Furthermore, there will be regular safety data review by the sponsor and the SRC for 
identification and evaluation of potential safety concerns. All patients enrolled in this trial 
will be monitored by qualified health care professionals who will provide care and evaluate 
the patient’s response to the trial drug in terms of its safety and efficacy. 
Beyond that, the sponsor went through an exercise to identify and assess risks specific to 
BNT151 related to either the translated protein, i.e., an IL-2 variant, or to the formulation of 
the RNA drug substance with LNPs. In particular, the following data sources were used: (i) 
the preclinical data package obtained for BNT151 monotherapy and in combination with 
several other agents in development (e.g., RNA-encoded cancer vaccine, anti-PD-1/PD-
L1); and (ii) nonclinical and (iii) clinical literature data published on other IL-2-based 
therapies either still in development or approved. This group of compounds encompasses, 
for example, recombinant IL-2 (aldesleukin) approved for the treatment of adults with 
metastatic RCC and metastatic melanoma; bempegaldesleukin (NKTR-214; Nektar 
Therapeutics) in clinical trials across a few cancer indications; anti-fibroblast activation 
protein (FAP)/IL-2 fusion protein RO6874281/ RG-7461 (Roche); an engineered fusion 
protein comprised of a circularly permuted IL-2 and IL-2 Receptor (IL-2R) α, ALKS-4230 
(Alkermes); a variant of recombinant human IL-2 that is PEGylated at one specific site, 
THOR-707 (Synthorx); an enhanced version of IL-2 that preferentially binds to IL-2Rβ, 
MDNA-109 (Medicinna); and a recombinant fusion protein comprised of cergutuzumab, a 
genetically engineered human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody 
directed against carcinoembryonic antigen linked to amunaleukin, an engineered, mutated 
variant form of interleukin-2 (IL-2v), RG-7813 (Roche).  
One identified risk with high-dose IL-2 therapy (aldesleukin) is capillary leak syndrome 
(CLS). CLS begins immediately after aldesleukin treatment starts and is marked by 
increased capillary permeability to protein and fluids and reduced vascular tone. In 
most patients, this results in a concomitant drop in mean arterial blood pressure within 2 to 
12 hours after the start of treatment. With continued therapy, clinically significant 
hypotension (defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop 
from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of 
protein and fluids into the extravascular space will lead to the formation of edema and 
creation of new effusions. The exact cause of CLS is only partially understood. It is 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 5 3  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
b eli e v e d t h at pr o -i nfl a m m at or y c yt o ki n e s fr o m I L-2 a cti v at e d N K c ell s pl a y a n e s s e nti al 
r ol e. T h e s p o n s or a s s e s s e s t hi s ri s k a s s o ci at e d wit h B N T 1 5 1 t o b e l o w t o m e di u m: d u e t o 
t h e n e e d of tr a n sl ati o n of t h e a cti v e pr ot ei n fr o m R N A, s er u m l e v el s of h u m a n al b u mi n -I L 2 
v ari a nt ( h Al b -hI L 2 v ar ) ri s e sl o wl y o v er s e v er al h o ur s , a n d r e m ai n el e v at e d f or a pr ol o n g e d 
p eri o d of ti m e. T h e s e c h ar a ct eri sti c s e n a bl e tr e at m e nt wit h a r e d u c e d n u m b er of d o s e s a s 
w ell a s wit h a l o w er d o s e, miti g ati n g t h e ri s k a s s o ci at e d wit h r e pe at e d hi g h -d o s e I L -2 
a d mi ni str ati o n a s r e q uir e d f or al d e sl e u ki n.  
T h e a b o v e m e nti o n e d si d e eff e ct s of hi g h -d o s e I L -2 t h er a p y ar e al s o ri s k s of a t h er a p y 
wit h B N T 1 5 1. A s B N T 1 5 1 i s a p ot e nt v ari a nt of t h e k e y T -c ell h o m e o st ati c c yt o ki n e I L -2 
t h at m e di at e s t h e diff er e nti ati o n, pr olif er ati o n, s ur vi v al a n d eff e ct or f u n cti o n s of T  c ell s , 
e x a g g er at e d p h ar m a c ol o g y a n d o v er -a cti v ati o n of t h e i m m u n e s y st e m i s a n i d e ntifi e d 
p ot e nti al ri s k . O v er all, B N T 1 5 1 t h er a p y w a s w ell t ol er at e d i n n o n cli ni c al t o xi c ol o g y a n d P D 
st u di e s i n mi c e a n d c y n o m ol g u s m o n k e y s at d o s e s r a n gi n g fr o m 
 µ g/ k g  aft er 
r e p e at e d a d mi ni str ati o n a n d n o cl e ar si g n s of a C L S s y n dr o m e w er e a p p ar e nt . 
H e m at ol o g y d at a di d s h o w a tr a n si e nt d e cr e a s e of w hit e bl o o d c ell s ( W B C s), m ai nl y 
l y m p h o c yt e s, w hi c h mi g ht b e r el at e d t o t h e h o mi n g t o l y m p h oi d or g a n s, e xtr a v a s ati o n or 
i n cr e a s e d a d h er e n c e t o v e s s el w all s wit h a s u b s e q u e nt l y m p h o pr olif er ati o n. A n i m m e di at e 
a n d tr a n si e nt i n d u cti o n of i nt erf er o n g a m m a-i n d u c e d pr ot ei n 1 0 (I P-1 0 ), I F N-γ a n d t o a 
l e s s er e xt e nt I L-6 w a s o b s er v e d. A sli g ht i n cr e a s e i n li v er e n z y m e s w a s o b s er v e d a s 
d e s cri b e d i n t h e lit er at ur e f or I L -2 (N a k a g a w a et al. 1 9 9 6 ). Hi st o p at h ol o g y d at a fr o m a 
g o o d l a b or at or y pr a cti c e ( G L P ) t o xi cit y st u d y i n mi c e di d o nl y r e v e al sli g ht c h a n g e s i n li v er 
( K u pff er c ell h y p ertr o p h y/ h y p er pl a si a) a n d s pl e e n (l y m p h oi d h y p er pl a si a of t h e 
p eri art eri ol ar l y m p h oi d s h e at h). N e v ert h el e s s, fr e q u e nt l a b or at or y m o nit ori n g i s pl a n n e d t o 
o b s er v e t h e bi o c h e mi c al a n d h e m at ol o gi c al eff e ct. F or t h e cli ni c al m a nif e st ati o n s of 
c yt o ki n e el e v ati o n, t h e tri al pr ot o c ol i m pl e m e nt s m a n a g e m e nt wit h a n al g e si c s or 
a nti p yr eti c s at r e c o m m e n d e d c o m m o nl y u s e d d o s e s.  
A s s u m m ari z e d, d at a fr o m t h e t o xi c ol o g y st u d y i n mi c e di d n ot i n di c at e str o n g eff e ct s fr o m 
B N T 1 5 1 tr e at m e nt. O n t h e ot h er h a n d , P D d at a i n cl u di n g a d e di c at e d n o n -G L P st u d y i n 
mi c e p oi nt t o w ar d s a str o n g a cti v ati o n of N K c ell s aft er B N T 1 5 1 tr e at m e nt, e s p e ci all y i n 
c o m bi n ati o n wit h a n a d diti o n al a cti v ati o n b y t y p e I I F N r el e a s e ( i. e., b y t h e R N A li p o pl e x 
[R N A -L P X ] v a c ci n e). It i s h y p ot h e si z e d t h at t h e e x p a n si o n a n d a cti v ati o n of N K c ell s b y 
B N T 1 5 1 c a n l e a d t o a d v er s e eff e ct s b y r el e a s e of pr o -i nfl a m m at or y c yto ki n e s s u c h a s 
I F N-γ. T h e d etri m e nt al eff e ct s w er e a m eli or at e d b y d o s e r e d u cti o n, w hi c h c orr el at e s t o 
l o w er d o s e s t o b e a d mi ni st er e d i n t h e cli ni c al tri al. F urt h er m or e, t h e s p o n s or s h o w e d t h at 
a n i niti al tr e at m e nt wit h a l o w er d o s e of B N T 1 5 1 l e a v e s t h e N K c ell s i n a r efr a ct o r y st at e 
t h at a b oli s h e s t h e B N T 1 5 1-m e di at e d a d v er s e eff e ct s f or c o n s e c uti v e hi g h er d o s e s i n mi c e. 
T h e pl a n n e d FI H a d dr e s s e s t hi s p ot e nti al p h e n o m e n o n b y a p o s si bilit y t o p erf or m d o s e 
e s c al ati o n wit h a l o w er l e a d -i n d o s e. I n a d diti o n, a no n -G L P st u d y i n mi c e c o m bi ni n g 
B N T 1 5 1 wit h a n a nti -P D -1 tr e at m e nt di d n ot r e s ult i n e n h a n c e d s af et y -r el at e d fi n di n g s. 
F urt h er m or e,  p ati e nt s  i n t h e cli ni c al tri al s h o ul d h a v e n or m al c ar di a c, p ul m o n ar y, h e p ati c, 
a n d C N S f u n cti o n at t h e st art of t h er a p y. C ar ef ul m o nit ori n g of t h e p ati e nt’ s fl ui d a n d or g a n 
p erf u si o n st at u s i s pl a n n e d b y fr e q u e nt d et er mi n ati o n of bl o o d pr e s s ur e a n d h e art r at e , 
a n d b y m o nit ori n g or g a n f u n cti o n, w hi c h i n cl u d e s a s s e s s m e nt of m e nt al st at u s a n d uri n e 
o ut p ut.  
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Another risk identified with aldesleukin is mental status change and other CNS-related 
changes. Safety pharmacology data from mice with BNT151 do not indicate effects on 
neurological safety. However, as these effects are not easily detected in animals, all 
patients should have thorough evaluation and treatment of CNS metastases, and have a 
scan to show disease control in the brain prior to receiving BNT151. 
Aldesleukin is also shown to exacerbate pre-existing or initial presentation of autoimmune 
disease and inflammatory disorders. The sponsor mitigates this risk by exclusion of 
patients with prior autoimmune or inflammatory disorders. 
Furthermore, the potential risk of IL-2-based therapies and other pro-inflammatory 
cytokines to induce cardiac toxicity such as acute coronary syndrome and heart 
arrhythmias is addressed in the clinical trial by exclusion of high-risk patients. ECG and 
echocardiogram (ECHO) are to be performed at screening and ECG also on Day 1 of each 
cycle. Patients are also closely monitored for such events in the clinic. It is worth 
mentioning that no indications of such potential risks were noted in animals tested with 
BNT151. 
Other AEs most commonly seen with IL-2-based therapies such as mild-to-moderate, 
transient and manageable flu-like symptoms (e.g., arthralgia, body temperature increase, 
chills, dehydration, dizziness, fatigue, feeling cold, headache, hot flush, hyperhidrosis, 
myalgia, nausea, pyrexia, tachycardia, and vomiting) may occur. The systemic effects 
could be PD surrogates caused by cytokine elevation. The trial protocol implements 
management with supportive care drugs, such as analgesics, antipyretics, antiemetics and 
antidiarrheals at recommended commonly used doses. 
A potential risk is the liver-targeting LNP formulation, which contains four synthetic lipids. 
Two of them are used in approved drug products (e.g., Doxil® and Onpattro®). The 
two other lipids are used in products in currently running clinical trials (e.g., NCT03639714 
at clinical trials.gov). Formulation-related toxicities were assessed in nonclinical studies in 
mice and cynomolgus monkeys. The animals were treated with the LNP formulation 
without RNA payload (empty LNPs). Overall, no findings including histopathology 
assessment were reported compared to the control group treated with saline in the 
different studies. Frequent laboratory monitoring including liver parameters is planned. 
In conclusion, the nonclinical and literature data collected so far do not show any potential 
unacceptable toxicities that cannot be mitigated or managed in the clinical setting. The 
anticipated benefits of BNT151 in patient populations with high, unmet medical needs 
outweigh the potential risks with the compound. 
2.3.2 
Potential risks associated with BNT151 in combination with 
pembrolizumab, axitinib, carboplatin, pemetrexed, atezolizumab, 
and nab-paclitaxel 
This part of the clinical trial protocol (CTP) will be updated by amendment when the profile 
of BNT151 is better understood from Part 1. The decision to expand is based on the 
totality of data generated in Part 1. All decisions for expansion should be endorsed by the 
SRC. 

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Once the monotherapy RP2D is established the trial will proceed with the Part 2 
Expansion, where BNT151 will be used in combination therapy in various Cohorts.  
As this is the first trial in humans, the risk of synergistic and/or potentiating toxicities when 
BNT151 is combined with pembrolizumab, axitinib, carboplatin, pemetrexed, atezolizumab, 
and nab-paclitaxel cannot be completely ruled out. Therefore, the trial seeks to mitigate 
this risk by implementing a safety run in trial if no potential overlapping toxicities between 
BNT151 and SoC are anticipated based on the BNT151 monotherapy safety profile. If 
overlapping toxicity is expected based on the data in the monotherapy part, an abbreviated 
dose escalation of BNT151 in combination with SoC will be performed. 
The combination dose escalation will only occur after reasonable data for BNT151 are 
generated in monotherapy dose escalation. Additionally, the dose level to start the 
combination dose level and at any given time thereafter will always be one dose level 
lower than the monotherapy MTD and/or RP2D. If safe, the BNT151 dose will be escalated 
to monotherapy MTD and/or RP2D. If the starting dose is declared too toxic, dose levels 
with PK/PD activity below the starting dose can be explored in the combination. This 
should mitigate such a potential risk for unknown synergistic and/or potentiating toxicities.  
Supporting data from preclinical studies of BNT151 in combination with PD-1 blockade 
also do not suggest any additional toxicity beyond that of BNT151 alone. For this reason, 
we will start the combination part with two cohorts treated with BNT151 and 
pembrolizumab to generate sufficient safety data before BNT151 is combined with cancer 
therapies other than pembrolizumab. 
This section will be expanded by amendment to better address potential risks associated 
with BNT151 in combination treatments (providing a risk assessment for each combination 
treatment in turn) once the BNT151 monotherapy safety profile is better understood from 
Part 1, and the risk of synergistic and/or potentiating toxicities when BNT151 is used in 
combination therapies in Part 2 can be better predicted. 
2.3.3 
Benefit assessment as a monotherapy (for Part 1) 
Preclinical studies demonstrated that monotherapy of tumor-bearing mice with BNT151 
resulted in potent anti-tumor activity with increased rejection rates and significantly 
prolonged survival, which was further augmented by administration of anti-PD-1/PD-L1 
ICB or RNA˗based tumor antigen vaccination in several mouse tumor models.  
Based on preclinical antitumoral activity and mechanistic data, BNT151 is expected to 
mount tumor-targeted, integrated innate and adaptive immune reactions as a 
monotherapy, as well as in combination with other background therapies such as cytotoxic 
therapies, targeted therapies and other cancer immunotherapies in particular in settings 
with large tumor load. There is still a high unmet medical need in patients with advanced or 
metastatic solid tumors and it is planned to evaluate BNT151 in various suitable tumor 
indications and settings. 
For monotherapy, IL-2-based treatments have long been recognized to have moderate 
single˗agent activity in the classically “immune-sensitive” tumors such as melanoma and 
RCC (DeVita et al. 2018). However, the literature also shows anecdotal evidence of 
patients having tumor shrinkage and durable disease control in other tumor types such as 

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4 
TRIAL DESIGN 
4.1 
Overall design 
This is an open-label, multicenter Phase I/IIa dose escalation, safety, PK and PD trial of 
BNT151 with expansion cohorts in various solid tumor indications.  
The monotherapy dose escalation (Part 1) of this clinical trial will enroll patients with 
various solid tumors that are metastatic or of advanced unresectable stage for whom there 
is no available standard therapy likely to confer clinical benefit, or patients who are not 
candidates for such available therapy. During combination dose escalation 
(Part 2A), patients with SCCHN, and HCC will be enrolled and treated with a combination 
of BNT151 and pembrolizumab. Once Part 2A of SCCHN and HCC is completed, patients 
with RCC, TNBC, and NSCLC will be enrolled and treated with a combination of BNT151 
with the respective SoC. 
The trial consists of Part 1, Part 2A and Part 2B with adaptive design elements:  
• 
Part 1 will be a monotherapy dose escalation in patients with advanced solid 
malignancies until the MTD and/or RP2D of BNT151 as monotherapy are defined. 
Dose escalation and RP2D regimen may include a pre˗conditioning dose, which 
would be implemented under the rules defined in Section 4.1.4 Adaptive trial 
design elements. 
The Part 1 of the trial also plans to implement a dedicated biomarker cohort in BNT151 
monotherapy: 
• 
The Biomarker Cohort will recruit patients at selected sites in the US only. The 
objective of the cohort is to observe PD activity and drug-induced changes in the 
blood and tumor. The gathered data are expected to inform on the drugs 
mechanism of action and further refine selection of monotherapy dose. This cohort 
will only enroll patients that are capable and willing to donate serial biopsies. 
Patients will only be dosed at dose levels at the RP2D level or lower, which have 
been cleared safe in the monotherapy dose escalation, and where 
pharmacodynamics activity is expected. Approximately, 20 patients will be enrolled 
in this cohort. 
• 
Part 2 will start once Part 1 monotherapy dose escalation is completed (exception: 
Biomarker Cohort in Part 1 can continue enrolling as long as a BNT151 
monotherapy dose is established in the dose escalation). It consists of 5 expansion 
cohorts starting with BNT151 in combination with pembrolizumab in patients with 
SCCHN (Cohort 1) and HCC (Cohort 2). Safety evaluation of BNT151 in 
combination with pembrolizumab in Cohorts 1 and 2 will be done at the same time, 
and data generated in both patient populations will be used to assess safety. Once 
the safety of the combination is confirmed by the SRC (for details see the SRC 
Charter), the 2 cohorts will then enroll independently in expansion and a further 3 
cohorts evaluating BNT151 in combination with SoC will be opened for enrollment: 
RCC (Cohort 3), NSCLC (Cohort 4) and TNBC (Cohort 5). Further cohorts may be 
opened based on sponsor’s decision.  
Each Part 2 cohort will consist of 2 sub-parts: 

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• 
Part 2A where the dose of BNT151 will be established for each combination using 
either a safety run-in or abbreviated dose finding based on predefined criteria 
described in Section 4.1.4 Adaptive trial design elements.  
• 
Part 2B where a predefined number of patients will be treated with the confirmed 
RP2D of BNT151 in combination with respective SoC. In case the same dosing 
regimen is used in Parts 2A and 2B (i.e., in case option of safety run-in is adopted), 
the patients enrolled in Part 2A are eligible for efficacy evaluation in Part 2B. In 
case a different dosing regimen is used for Part 2A compared to Part 2B (i.e., in 
case option of abbreviated dose finding is adopted), efficacy generated in Part 2A 
will be used as supporting data. 
In all parts, efficacy will be assessed by on-treatment imaging at Week 6 (+7 days), every 
6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) thereafter until disease 
progression is assessed by the investigator (unless the investigator elects to continue 
treatment [see below for conditions of continued treatment]), withdrawal of consent, trial 
termination by the sponsor, or death, whichever occurs first.  
Further information on efficacy assessment can be found in Section 8.1.1. 
Safety will be assessed on a regular basis by means of clinical and laboratory parameters, 
as defined in the schedule of activities (SoA, Section 1.3).  
PK of translated IL-2 variant and various markers, which may act as indicators of safety 
and activity of BNT151 monotherapy and in combination with SoC, will be evaluated, as 
defined in SoA. 
The overall trial design is shown in Figure 1. 
4.1.1 
MTD and RP2D definitions 
The MTD is defined as the highest tolerated dose. 
The RP2D will be determined based on integrated evaluation of safety, tolerability, clinical 
benefit, PK and PD data, for all dose levels tested. The RP2D will be determined 
according to the following guidelines:  
• 
The RP2D will not exceed the MTD. 
• 
Toxicities other than DLTs will be considered, including: treatment emergent 
adverse events (TEAEs) assessed as related to BNT151 treatment but not 
considered dose limiting, the nature and frequency of toxicities, and the emergence 
of any specific category of toxicities. 
• 
Evidence of clinical activity, as available. 
• 
Available PK and PD data. 
If the RP2D cannot be distinguished using the criteria above, cohort expansion for 
optimized RP2D determination may take place at up to 2 dose levels to obtain data for up 
to 6 additional patients per dose level. If serious related toxicities are observed in later 
cycles beyond Cycle 1, a reduction of the MTD and/or adjustment of RP2D may be 
considered. This determination will be made by the SRC. 

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4.1.2 
Dose escalation Part 1 - Monotherapy dose escalation 
The monotherapy dose escalation starts with an accelerated phase consisting of single-
patient cohorts followed by larger patient cohorts informed by a classical 3+3 design (i.e., 
accelerated titration design). The single˗patient cohorts will be expanded to 3+3-patient 
cohorts in case one of the following occurs: 
• 
Grade ≥2 related toxicity. 
• 
DLT. 
The SRC will review safety data and all available preliminary efficacy and PK/PD data and 
recommend to switch to 3+3. Once a single-patient cohort has been expanded, all future 
cohorts will follow the 3+3 design. 
In addition, in the single-patient cohort phase, the next cohort can only start once the DLT 
period for the previous dose level has been assessed and the next dose level is proposed 
by the SRC and endorsed by the sponsor. The DLT period is defined as one cycle (i.e., 
21 days). 
During the 3+3 phase, at every dose level to be tested, staggered enrollment will be 
employed as described below. In each dose level cohort, the 3 patients will be dosed 
successively with a safety monitoring interval of at least 48 hours between the IV 
administration of BNT151 in the first and the second patient, and between the second and 
the third patient. The 48 hour safety monitoring interval does not apply to patients enrolled 
into the Biomarker Cohort, as this cohort only opens dose levels that have already been 
deemed safe by the SRC. 
Hospitalization is required for the first 24 hours in Cycle 1 Day 1. For the assessments of 
each cohort, the DLTs will be collected for the first treatment cycle, i.e., a DLT evaluation 
period of 21 days. For hospitalization and DLT evaluation period during the adaptive trial 
design, please see Section 4.1.4. 
Dose escalation will follow a classical 3+3 design and continue until DLTs are observed in 
2/3 or 2/6 patients as described in the following dose escalation table (Table 6). 
 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 6 2  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
f a ct or of 5 0. B a s e d o n t h e n o n cli ni c al t o xi c ol o g y pr ofil e, w hi c h d o e s n ot s u g g e st a st e e p 
d o s e - or e x p o s ur e -r e s p o n s e c ur v e a n d s h o w e d n o s e v er e t o xi cit y fi n di n g s, a n i niti al 5-ti m e 
d o s e i n cr e m e nt i s pr o p o s e d. S u b s e q u e ntl y, st a n d ar d d o s e i n cr e m e nt i s pr o p o s e d st arti n g 
fr o m d o s e l e v el 2 i n li n e wit h t h e F D A G ui d a n c e f or I n d u str y “ S 9 N o n cli ni c al E v al u ati o n f or 
A nti c a n c er P h ar m a c e uti c al s”. 
 
 
A n y p ati e nt w h o e x p eri e n c e s a D L T aft er r e c ei vi n g B N T 1 5 1 s h o ul d b e c o u nt e d, r e g ar dl e s s 
of t h e a m o u nt of B N T 1 5 1 e x p o s ur e.  
Aft er c o m pl eti o n of t h e D L T p eri o d f or e a c h c o h ort, t h e S R C will r e vi e w t h e d at a fr o m t h e 
D L T p eri o d –  i n cl u di n g b ut n ot li mit e d t o all r el e v a nt s af et y, cli ni c al, P K a n d P D d at a –  t o 
pr o p o s e a d o s e l e v el f or t h e n e xt c o h ort of p ati e nt s . 
4. 1. 2. 1  
Bi o m ar k er C o h ort  
F or t h e Bi o m ar k er C o h ort at s el e ct e d U S sit e s o nl y: at e nr oll m e nt p ati e nt s m u st a gr e e t o 
h a v e o n e pr e -d o s e bi o p s y a n d l e si o n t h at i s d e e m e d a c c e s si bl e b y t h e i n v e sti g at or. If 
p o s si bl e, at l e a st o n e o n -tr e at m e nt bi o p s y ( pr ef err e d C 2 D 5-1 2) s h o ul d b e a c c e s si b l e fr o m 
s a m e t u m or l e si o n . P ati e nt s will b e s cr e e n e d wit hi n 3  w e e k s pri or t o t h e b e gi n ni n g of 
tr e at m e nt. P ati e nt s will b e tr e at e d wit h tr e at m e nt c y cl e s l a sti n g 2 1 d a y s u ntil pr o gr e s si o n, 
or tr e at m e nt di s c o nti n u ati o n of B N T 1 5 1 d u e t o ot h er f a ct or s. F oll o wi n g di s c o nti n u ati o n, 
a n d a s af et y f oll o w -u p p eri o d of 6 0  d a y s, p ati e nt s will b e f oll o w e d u p f or s ur vi v al e v er y 
1 2  w e e k s u ntil d e at h.  
4. 1. 3  
E x p a n si o n P art  2  - E x p a n si o n P h a s e  
T hi s p art of t h e C T P will b e u p d at e d b y a m e n d m e nt w h e n t h e pr ofil e of B N T 1 5 1 i s b ett er 
u n d er st o o d fr o m P art  1 . T h e d e ci si o n t o e x p a n d i s b a s e d o n t h e t ot alit y of d at a g e n er at e d 
i n P art  1 . All d e ci si o n s f or e x p a n si o n s h o ul d b e e n d or s e d b y t h e S R C. 
O n c e t h e m o n ot h er a p y R P 2 D i s e st a bli s h e d t h e tri al will pr o c e e d wit h t h e P art  2  
E x p a n si o n  P h a s e . T h e E x p a n si o n P h a s e  will b e c o n d u ct e d i n 5 c o h ort s a s f oll o w s:  
• 
C o h ort  1: S C C H N –  B N T 1 5 1 + p e m br oli z u m a b  
• 
C o h ort  2: H C C –  B N T 1 5 1 + p e m br oli z u m a b  
T h e f oll o wi n g c o h ort s will o nl y b e i niti at e d o n c e P art  2 A f or C o h ort s 1 a n d 2 i s c o m pl et e d:  
• 
C o h ort  3: R C C –  B N T 1 5 1 + p e m br oli z u m a b + a xiti ni b  
• 
C o h ort  4: N S C L C –  B N T 1 5 1 + p e m br oli z u m a b + c ar b o pl ati n + p e m etr e x e d  
• 
C o h ort  5: T N B C –  B N T 1 5 1 + at e z oli z u m a b + n a b -p a clit a x el  
T h e E x p a n si o n P h a s e m a y b e a m e n d e d b a s e d o n d at a g e n er at e d i n P art  1 . T h e 
E x p a n si o n  P h a s e will f oll o w eit h er Si m o n t w o -st a g e or K h a n o n e -st a g e d e si g n (K h a n et al. 
2 0 1 2 ) wit h d et ail s s p e cifi e d i n a s u b st a nti al a m e n d m e nt b a s e d o n P art  1  tri al r e s ult s. T h e 
p ur p o s e of t h e E x p a n si o n  P h a s e i s t o c o nfir m t h e d o s e a n d s c h e d ul e of B N T 1 5 1 i n 
c o m bi n ati o n wit h S o C. C o h ort s 3  t o 5 will o nl y st art aft er s uffi ci e nt d at a ar e g e n er at e d i n 
C o h ort s 1 a n d 2 si n c e B N T 1 5 1 i s c o m bi n e d wit h a nti -c a n c er t h er a pi e s ot h er t h a n 
C CI

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pembrolizumab. Further details on the Expansion Phase will be implemented by protocol 
amendment after completion of Part 1. 
4.1.4 
Adaptive trial design elements 
The following adaptive design elements define conditions under which changes to the trial 
design may be implemented based on the SRC recommendation. Further changes not 
specified here would be introduced via an amendment to this protocol. 
4.1.4.1 
Monotherapy dose escalation with pre-conditioning dose in 
Part 1 
In preclinical studies, it was shown that mice tolerated a higher dose of BNT151 after 
exposure to a lower dose in the previous cycle. This effect is most likely based on dose 
dependent stimulation of NK cells by the translated IL-2 variant. The IL-2 variant mediates 
a transient activation and expansion of NK cells, which release cytokines such as IFN-γ as 
part of their innate immune function. These cytokines in turn may mediate AEs, such as 
temporary weight loss and lethargy observed in mice. NK cell numbers normalize within 
14 days after BNT151 exposure. Re-challenges with BNT151, one to 3 weeks after the 
first treatment do not result in further NK cell stimulation or associated adverse effects 
such as weight loss in mice. NK cell expansion is BNT151 dose dependent and a low 
starting dose of BNT151 is better tolerated, yet is still capable of inducing refractory NK 
cells. An initial low dose can therefore increase the tolerability of a subsequent high-dose. 
To address the potential occurrence of a first dose effect observed in patients that was 
observed in mice, an adaptive design element is implemented in this trial. The sponsor 
hypothesizes that an initial lower lead-in dose that shows minimal NK-related activity could 
act as a pre-conditioning and may be a suitable measure in order to mitigate potential 
toxicity of subsequently increased BNT151 doses. 
The protocol may open a monotherapy dose escalation with pre-conditioning if there are 
indications for a first dose effect. For assessment of whether there is such an effect, not 
only AE profile data shall be taken in account, but also include PK, pharmcodynamics and 
other biomarker data, including exploratory biomarkers. SRC approval is required to 
initiate the pre-conditioning dose escalation. 
The pre-conditioning dose escalation will be conducted at the following potential dose 
levels as shown in Table 8 (the final dose levels will be determined based on the data 
generated). 
 

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4.1.4.3 
Further testing in a specific tumor type in the escalation stage 
Enrollment of up to 10 additional patients in the escalation stage may be allowed if efficacy 
is seen in a specific tumor type. 
4.1.4.4 
Lower increment during dose escalation 
If Grade 2 related AEs are observed at a given dose level, the increment to the next dose 
level may be reduced under SRC guidance, e.g., to 50% or lower of the planned 
increment. See also Section 4.1.2. 
4.1.4.5 
PK and PD sampling schedules 
The PK and PD sampling schedules will start using Table 2a and Table 2b (for Part 1: 
Monotherapy with and without pre-conditioning), and Table 4a and Table 4b (for the 
Biomarker Cohort), however additional time points up to a total of 3 during the first 
6 weeks may be added, or time points may be removed, based on the evolving PK and PD 
data. 
4.1.4.6 
Combination dose finding in Part 2 
Once the monotherapy RP2D is established (with or without pre-conditioning) based on 
safety, efficacy, PK and PD, the trial will proceed with the Part 2 Expansion Phase.  
4.1.4.6.1 
Safety run-in 
Safety run-in will be activated if no potential overlapping toxicities between BNT151 and 
SoC are anticipated based on the BNT151 monotherapy safety profile in Part 1. Guidance 
on assessment of overlapping toxicities is as follows: 
• 
No occurrence of life-threatening adverse reactions (ARs) in Part 1. 
• 
No occurrence of any related Grade ≥3 toxicities of BNT151, which are not 
amenable to standard clinical management overlapping with ARs known for SoC 
according to the ones listed in the USPI and SmPC. 
Six patients eligible for any expansion cohorts will be enrolled and dosed with a 
combination of BNT151 and SoC as described in Section 4.1.4.6.2. The SRC will review 
all available safety data. Further enrollment into the expansion cohorts can continue when 
the SRC declares the combination to be safe. In the safety run-in patients, the dose of 
BNT151 will be the RP2D-1 in combination with SoC at its approved doses. Further 
patients dosed after safety run-in may receive the BNT151 RP2D if it is deemed safe. 
In case pre-conditioning dose is identified in Part 1 (see Section 4.1.4.1), it will be applied 
for safety run-in with BNT151 with the same principle stated above. 
4.1.4.6.2 
Abbreviated dose escalation 
If overlapping toxicity is observed as described above in Section 4.1.4.6, an abbreviated 
dose escalation of BNT151 in combination with SoC will be performed. Patients eligible for 
the expansion cohorts with BNT151 and SoC will be enrolled and dosed as follows. 

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The trial will continue with classical 3+3 design as described in Part 1, including staggered 
enrollment, overnight stay, and DLT observation period. At least 2 dose levels of BNT151 
will be explored in combination with SoC given according to the Prescribing Information 
valid in a given country. The BNT151 dose will not exceed the monotherapy RP2D. The 
BNT151 starting dose will be one dose level below the monotherapy RP2D (i.e., RP2D-1). 
If safe, the BNT151 dose will be escalated to monotherapy RP2D. If the starting dose is 
declared too toxic according to the 3+3 design, dose levels with PK/PD activity below the 
starting dose can be explored in the combination.  
In case pre-conditioning dose is identified in Part 1 (see Section 4.1.4.1), it will be applied 
for the abbreviated dose escalation with BNT151 with the same principle stated above. 
 
 
Figure 2: 
Decision for safety run-in versus abbreviated dose escalation 
* Assessment of overlapping toxicities: 
• 
No occurrence of life-threatening adverse reactions in Part 1. 
• 
No occurrence of any related Grade ≥3 toxicities of BNT151, which are not amenable to standard clinical 
management overlapping with adverse reactions known for SoC according to the ones listed in the USPI and 
SmPC. 
 
DLT = dose limiting toxicity; MTD = maximum tolerated dose; RP2D = recommended Phase II dose; SmPC = Summary 
of Product Characteristics; SoC/SOC = standard of care; USPI = US Prescribing Information. 
4.1.5 
Planned number of patients 
In Part 1, the sample size will be up to 54 DLT-evaluable patients depending on the 
number of DLTs which may occur, with the possible enrollment of up to 10 additional 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 6 7  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
p ati e nt s if effi c a c y i s s e e n i n a s p e cifi c t u m or t y p e.  T h e Bi o m ar k er C o h ort  will e nr oll 
a p pr o xi m at el y  2 0 p ati e nt s.  
T h e o bj e cti v e f or t h e tri al P art  2 A a n d 2 B i s t o f urt h er i n v e sti g at e t h e s af et y pr ofil e a n d t o 
a s s e s s t h e effi c a c y of t h e I M P i n diff er e nt i n di c ati o n s i n c o m bi n ati o n wit h ot h er a p pr o v e d 
a nti -c a n c er a g e nt s. T h e d e si g n i n P art  2 A c a n eit h er b e a s af et y r u n -i n of 6 p ati e nt s  or a 
s h ort e s c al ati o n at 2 d o s e l e v el s a c c or di n g t o t h e 3 + 3  tri al d e si g n , t h er ef or e t h e s a m pl e 
si z e i n P art  2 A will r a n g e fr o m 6 t o 1 2  p ati e nt s  p er c o h ort. T h e s a m pl e si z e i n P art  2 B m a y 
b e b a s e d o n eit h er Si m o n t w o -st a g e d e si g n or o n e -st a g e d e si g n . T h e fi n al s a m pl e si z e 
c al c ul ati o n s will b e i ntr o d u c e d t hr o u g h pr ot o c ol a m e n d m e nt.  
4. 1. 6  
R e pl a c e m e nt of p ati e nt s  
P ati e nt s will b e r e pl a c e d i n t h e f oll o wi n g s c e n ari o s:  
• 
P ati e nt i s n ot e v al u a bl e f or D L T s ( o nl y a p pli e s t o  p ati e nt s  w h o d o n ot e x p eri e n c e a 
D L T).  
• 
P ati e nt w a s e nr oll e d i n t h e tri al b ut di d n ot r e c ei v e a d o s e of B N T 1 5 1.  
4. 2  
S ci e ntifi c r ati o n al e f or t h e tri al d e si g n  
T h e fir st p art ( P art  1 ) of t hi s tri al i s a FI H, o p e n-l a b el, d o s e e s c al ati o n tri al of B N T 1 5 1 
m o n ot h er a p y i n p ati e nt s wit h diff er e nt t y p e s of s oli d m ali g n a nt t u m or s i n or d er t o 
d et er mi n e t h e s af et y, P K a n d P D pr ofil e of B N T 1 5 1. T h e s e c o n d p art ( P art  2 A) ai m s t o 
d et er mi n e t h e s af et y pr ofil e of B N T 1 5 1 f urt h er i n c o m bi n ati o n wit h S o C ( P art  2 B) . Diff er e nt 
tr e at m e nt s c h e d ul e s m a y al s o b e e x pl or e d i n P art  2 A/ 2 B. P art  1 : M o n ot h er a p y d o s e 
e s c al ati o n  
I n or d er t o a d dr e s s t h e tri al o bj e cti v e s i n t hi s FI H tri al, a d o s e e s c al ati o n u si n g a n 
a c c el er at e d titr ati o n (i. e., si n gl e -p ati e nt c o h ort) f oll o w e d b y a 3 + 3 d e si g n w a s s el e ct e d. 
T h e fir st  d o s e l e v el s of B N T 1 5 1 ar e a s s u m e d t o i n d u c e n o or mi ni m al bi ol o gi c al eff e ct s 
i n h u m a n s a n d r efl e ct pr e c a uti o n s f or t h e p ati e nt’ s s af et y w hil e i ntr o d u ci n g a n o v el 
c o m p o u n d i n h u m a n s. I n c a s e of o c c urr e n c e of Gr a d e  ≥2 r el at e d t o xi citi e s, or D L T s 
o b s er v e d or S R C d e ci si o n w hi c h c a n al s o b e i nf or m e d b y all a v ail a bl e s af et y d a t a a n d 
s u p p orti v e P K/ P D d at a, t h e si n gl e -p ati e nt c o h ort s will b e e x p a n d e d t o 3 + 3 -p ati e nt c o h ort s. 
T h e cl a s si c al 3 + 3 d e si g n i s a p pr o pri at e f or a FI H d o s e e s c al ati o n tri al i n o n c ol o g y; 
h o w e v er, t hi s tri al will c o n si d er all d at a g e n er at e d t o d e ci d e o n t h e R P 2 D.  
T h e s af et y, P K, P D a n d cli ni c al effi c a c y d at a c o m bi n e d pr o vi d e b ot h m or e fl e xi bilit y a n d 
b ett er a c c ur a c y of t h e e sti m at e d R P 2 D w hil e s af e g u ar di n g t h e p ati e nt’ s s af et y. B N T 1 5 1 i s 
a n  L N P˗f or m ul at e d, si n gl e str a n d e d, 5′- c a p p e d R N A t h at i s tr a n sl at e d i nt o a h u m a n I L -2 
v ari a nt f u s e d t o h u m a n s er u m al b u mi n. It s m e c h a ni s m of a cti o n i s t o sti m ul at e t h e p ati e nt’ s 
I L-2 -s e n siti v e i m m u n e eff e ct or c ell s t o kill t u m or c ells. S el e ct e d P D bi o m ar k er s, w hi c h 
i nf or m a b o ut t h e i m m u n e a cti v ati o n st at u s, s u c h a s s ol u bl e i nt erl e u ki n -2 r e c e pt or  (s C D 2 5 ), 
a b s ol ut e l y m p h o c yt e c o u nt, c yt o ki n e s a n d c h e m o ki n e s, c a n p ot e nti all y b e u s e d t o g ui d e 
t h e d o s e e s c al ati o n i n P art  1  a n d if n e e d e d i n P art  2 A.  
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4.2.1 
Option of monotherapy dose escalation with pre-conditioning 
In preclinical studies, it was shown that mice better tolerated a higher dose of BNT151 
after exposure to a lower dose in the previous cycle. This effect was most likely based on 
stimulation of NK cells by the translated IL-2 variant. The IL-2 variant mediates a transient 
activation and expansion of NK cells, which release cytokines such as IFN-γ as part of 
their innate immune function. These cytokines in turn may mediate the IL-2 AEs, such as 
temporary weight loss and lethargy observed in mice. NK cell numbers normalize within 
14 days after BNT151 exposure. Therefore, their AE-mediating effect is self-limiting. 
Moreover, NK cells go into a transient refractory status. Re-challenges with BNT151, one 
to 3 weeks after the first treatment do not result in further NK cell stimulation or associated 
adverse effects such as weight loss in mice. In these mouse experiments NK cell 
expansion was BNT151 dose dependent and a low starting dose of BNT151 was better 
tolerated while it was still capable of inducing refractory NK cells, thereby increasing the 
tolerability of a subsequent high-dose.  
To address this, preconditioning has been implemented in this trial. The reason for the 
preconditioning dose is to increase tolerability of subsequent BNT151 doses. As the 
preconditioning dose is low, it is not expected that the full therapeutic potential of the drug 
in terms of expansion of tumor-specific effector T-cells will be achieved. To achieve a 
meaningful expansion of tumor-specific cells as early as possible, a second dose will be 
administered soon after the preconditioning dose. Preclinical studies suggest that the 
preconditioning effect will be present as early as one week after dosing, thus 
administration of the second dose 1 week after the preconditioning dose is planned. 
4.2.1.1 
Biomarker Cohort 
mRNA underlies an innovative and sophisticated drug platform to deliver a protein-based 
therapy but, ongoing data do potentially suggest an occurrence of interpatient variability 
especially in translation that can affect correct determination of effective dose, as well as 
establishing a confident safety profile of the product. Therefore, the implementation of the 
Biomarker Cohort to further elucidate the differences and understand the variabilities is 
justified. Dose levels that have been cleared by the SRC in the dose escalation will be 
investigated in the monotherapy Biomarker Cohort, in order to further investigate the mode 
of action of BNT151, to allow optimization of future combinations with other anti-cancer 
agents, and to assess the interpatient variability. 
4.2.2 
Part 2A: Combination dose finding 
The monotherapy RP2D of BNT151 will be re-evaluated in combination with SoC by a 
safety run-in in Part 2 or by performing an expedited combination dose escalation. The 
decision for one option over the other depends on the potential overlapping toxicity 
between BNT151 and SoC. 
The LNP-formulated RNA BNT151 codes for an IL-2 variant with prolonged half-life, 
increased capability to stimulate effector T cells and NK cells but abrogated activation of 
undesirable Treg cells. As such, potential toxicities of BNT151 may encompass but are not 
limited to those toxicities observed for approved recombinant IL-2 (aldesleukin) and 
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Recombinant IL-2 (aldesleukin) exhibits a very short half-life in the range of minutes and 
requires high and frequent dosing, which in turn potentiates its side effects. Frequent AEs 
comprise changes in blood counts (reduced thrombocytes, erythrocytes and neutrophils), 
chills, pruritus, nausea, vomiting, diarrhea, and hypotension (Assier et al. 2004, Baluna 
and Vitetta 1997, Lotze et al. 1986, Rosenberg et al. 1987). CLS is the main DLT. CLS 
usually occurs 3-4 days after IL-2 treatment and results in decreased microcirculatory 
perfusion and interstitial edema especially in lung and liver. 
NKTR-214 is an effector T-cell and NK cell biased human recombinant IL-2 that is 
attached to an average of 6 releasable polyethylene glycol (PEG) chains to alter both its 
receptor binding and PK. When fully PEGylated, NKTR-214 is a pro-drug that slowly 
releases the PEG chains in vivo to generate active cytokine species. Active NKTR-214 
cytokine selectively increases the proliferation, activation, and effector function of effector 
T cells and NK cells, and is thus similar to the BNT151 translated IL-2 variant. Frequent 
AEs of NKTR-214 comprise fatigue, chills, pruritus, hypotension and rash (Bentebibel et al. 
2019). 
BNT151 is believed to yield higher efficacy as compared to recombinant IL-2 while 
ameliorating peak dose mediated toxicities. Furthermore, due to its beneficial PK 
properties, BNT151 requires less frequent dosing. Compared to NKTR-214, BNT151 
translated IL-2 variant is not a pro-drug and does not require an additional processing step 
to be fully active. However, besides IL-2 mediated toxicities, potential toxicities of BNT151 
can also be induced by the LNP-formulated RNA drug product. 
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its 
interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the 
immune response, including the anti-tumor immune response. The safety profile of 
pembrolizumab has been documented from hundreds of clinical trials. Most commonly 
associated AEs are distinct immune-related AEs (irAEs).  
The sponsor acknowledges that since BNT151 and pembrolizumab are both 
immunotherapies but with different mechanisms of action, the toxicities may not overlap. In 
such a case, a combination dose finding with a safety run-in phase is justified. The 
sponsor, however, also acknowledges the potential overlapping toxicities with the 2 
compounds, thus a clear algorithm to trigger a typical combination dose escalation design 
is also outlined (see Section 4.1.4.6). 
4.2.3 
Part 2B: Expansion Phase 
The trial design in the expansion cohorts are either Simon two-stage design or Khan one-
stage design. 
The Simon two-stage design is often used for Phase II cancer clinical trials. A trial 
proceeds to the second stage unless the null hypothesis, that the true tumor response rate 
is below some specified value, is already accepted at the end of stage one. This limits 
exposing more patients to a compound without sufficient anti-tumor activity. 
The one-stage design per Khan et al. (2012) is used to examine several sample sizes for 
the same treatment effect and choose one that is the smallest. This would be especially 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 7 0  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
u s ef ul f or tri al s of n o v el a g e nt s ( w h er e littl e i s k n o w n a b o ut t h e tr e at m e nt) or f or r ar e 
di s or d er s, w h er e it i s a p pr o pri at e t o mi ni mi z e t h e s a m pl e si z e.  
F urt h er i nf or m ati o n a n d d et ail s o n P art  2 B will b e d o n e b y pr ot o c ol a m e n d m e nt.  
4. 3  
J u stifi c ati o n f or d o s e  
T h e pr o p o s e d st arti n g d o s e of B N T 1 5 1 i s i n a c c or d a n c e wit h t h e I C H S 9 r e c o m m e n d ati o n 
( 2 0 0 9) f or a nti-c a n c er bi o p h ar m a c e uti c al s wit h i m m u n e a g o ni sti c pr o p erti e s a n d 
i nt e gr at e s: 
• 
N o n cli ni c al d at a o n p h ar m a c ol o gi c al a cti vit y of t h e B N T 1 5 1 -tr a n sl at e d I L-2 -v ari a nt 
i n h u m a n a n d c y n o m ol g u s m a c a q u e p eri p h er al bl o o d m o n o n u cl e ar c ell s ( P B M C s) 
in  vitr o . 
• 
T h e l y m p h o pr olif er ati o n -b a s e d M A B E L d o s e i d e ntifi e d i n B N T 1 5 1 -e x p o s e d 
c y n o m ol g u s m a c a q u e s . 
• 
T h e I L -2 R a cti v ati o n -b a s e d M A B E L i d e ntifi e d i n a n a c c e s s or y in  vitr o  st u d y t o t h e 
n o n˗ G L P P K a n d t ol er a bilit y st u d y i n c y n o m ol g u s m a c a q u e s . 
• 
P r e vi o u s e x p eri e n c e o n i nt er s p e ci e s s c ali n g of L N P-tr a n sf e cti o n a n d R N A 
tr a n sl ati o n effi c a c y wit h li v er-t ar g et e d L N P-f or m ul at e d R N A. 
T h e p h ar m a c ol o gi c al d at a d e m o n str at e d t h at tr a n sl at e d h Al b -hI L 2 v ar e x hi bit s si mil ar 
p h ar m a c ol o gi c al a cti vit y i n h u m a n a n d c y n o m ol g u s m a c a q u e P B M C s. A c c or di n gl y, t h e 
c a p a bilit y of h Al b -hI L 2 v ar t o i n d u c e l y m p h o pr olif er ati o n i n c y n o m ol g u s m o n k e y s w a s 
a s s e s s e d  a s a P D m ar k er of i m m u n e sti m ul ati o n aft er I V B N T 1 5 1 a d mi ni str ati o n. 
L y m p h o c yt e c o u nt s a b o v e pr e -d o s e l e v el s w er e fir st d et e ct e d at a d o s e of 
 µ g/ k g  
B N T 1 5 1 wit h a tr e n d t o w ar d s m or e pr o n o u n c e d l y m p h o pr olif er ati o n i n a ni m al s tr e at e d wit h 
 µ g/ k g . D u e to t h e r at h er l ar g e d o s e i n cr e m e nt i n -b et w e e n t h e 
 µ g/ k g  
c o h ort s, 
 µ g/ k g  B N T 1 5 1  w a s d efi n e d a s a c o n s er v ati v e l y m p h o pr olif er ati o n -b a s e d 
M A B E L d o s e.  
 
Fi g ur e  3 : 
L y m p h o pr olif er ati o n -b a s e d M A B E L pr oj e cti o n  
D o s e -r e s p o n s e of t ot al l y m p h o c yt e c o u nt s a s P D m ar k er of i m m u n e sti m ul ati o n i n c y n o m ol g u s m a c a q u e s 
tr e at e d wit h 
 µ g/ k g  B N T 1 5 1. L y m p h o c yt e c o u nt s at pr e -d o s e (t e st d a y 1) a n d at 
T e st  d a y s 7 or 8 ( T D 7/ T D 8) ar e s h o w n. Gr e e n r e ct a n gl e i n di c at e s t h e d o s e r a n g e i n w hi c h M A B E L w a s 
r e a c h e d. 
M A B E L  =  mi ni m u m a nti ci p at e d bi ol o gi c al eff e ct l e v el; P D  =  p h ar m a c o d y n a mi c s.  
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• 
All patients have discontinued IMP treatment; and 
• 
All patients have completed safety follow-up assessment at Day 30/60 subsequent 
to last dose; 
and/or 
• 
The relevant authorities or 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 criteria 
Each potential patient must fulfill all of the inclusion criteria provided in Section 5.1.1 and 
Section 5.1.2 to be enrolled in the trial. 
5.1.1 
Disease-specific inclusion criteria 
For all Parts  
1. Histological documentation of the original primary tumor via a pathology report. 
2. Measurable disease per RECIST 1.1. 
For Part 1: 
3. Histologically confirmed solid tumor that is metastatic or of advanced unresectable 
stage and for whom there is no available standard therapy likely to confer clinical 
benefit, or patient who is not a candidate for such available therapy. If there is no 
contraindication, patients should have exhausted all SoC therapies before entering 
the trial, if possible.  
For Part 2 (Including 2A and 2B): 
Cohort 1: SCCHN 
4. Histologically confirmed, R/M SCCHN with disease progression on or after a 
platinum-based therapy. 
Cohort 2: HCC 
5. Histologically confirmed unresectable or metastatic HCC who have been previously 
treated with a first-line systemic treatment. 
Cohort 3: RCC 
6. Histologically confirmed RCC eligible for pembrolizumab in combination with 
axitinib, for the first-line treatment of patients with advanced RCC. 
Cohort 4: NSCLC 
7. Histologically or cytologically confirmed NSCLC eligible for pembrolizumab in 
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of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic 
tumor aberrations. 
Cohort 5: TNBC 
8. Histologically confirmed TNBC eligible for atezolizumab in combination with 
paclitaxel protein-bound for the treatment of unresectable locally advanced or 
metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating 
immune cells of any intensity covering ≥1% of the tumor area), as determined by an 
FDA approved test. 
5.1.2 
Other inclusion criteria 
For all Parts  
9. ≥18 years of age. 
10. Must sign an ICF indicating that he or she understands the purpose and procedures 
required for the trial and are willing to participate in the trial prior to any trial-related 
assessments or procedures.  
11. ECOG performance status of 0 to 1. 
12. Adequate coagulation function at screening as determined by: 
− 
INR or prothrombin time ≤1.5 × ULN; (unless on therapeutic anticoagulants 
with values within therapeutic window),  
− 
aPTT ≤1.5 × ULN (unless on therapeutic anticoagulants with values within 
therapeutic window). 
13. Adequate hematologic function at screening as determined by: 
− 
White blood cell count (WBC) ≥3 × 109/L 
− 
ANC ≥1.5 × 109/L (patient may not use G-CSF or GM-CSF in the 7 days prior 
to trial treatment to achieve these WBC and ANC levels) 
− 
Platelet count ≥100 × 109/L 
− 
Hgb ≥9.0 g/dL. 
14. Adequate hepatic function at screening as determined by: 
− 
TBili ≤1.5 mg/dL (or ≤2.0 mg/dL for patients with known Gilbert's syndrome or 
liver metastasis) 
− 
AST and ALT ≤2.5 × ULN; ≤3 × ULN for patients with liver metastasis. 
15. Adequate renal function at screening as determined by: 
Glomerular filtration rate (GFR) 45 mL/min/1.73 m² – 
According to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation, expressed as a single equation: 
 
GFR = 141 × min(Scr/κ,1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
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Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 
for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max 
indicates the maximum of Scr/κ or 1. 
− 
For creatinine assays using methods traceable to isotope dilution mass 
spectrometry (IDMS) assigned National Institute of Standards and Technology 
(NIST) certified reference materials (Levey et al. 2009). 
16. Able and willing to attend trial visits as required by the protocol.  
17. WOCBP must have a negative serum (β-hCG) test/value at screening. Patients 
who are postmenopausal or permanently sterilized (Section 10.4) can be 
considered as not having reproductive potential. 
18. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the entire trial, until 6 months after last BNT151 treatment. 
19. A man who is sexually active with a woman of childbearing potential and has not 
had a vasectomy must agree to use a barrier method of birth control, e.g., either 
condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository, and all men must also not donate sperm during 
the trial and for 6 months after receiving the last dose of BNT151 (refer 
Section 10.4 for information for further recommendations). 
20. WOCBP must agree to use highly effective contraception during the trial and for 
6 months after receiving the last dose of BNT151. Birth control methods are 
considered highly effective if they have a failure rate of less than 1% per year, when 
used consistently and correctly. Further guidance on contraceptive measures for 
female patients can be found in Section 10.4. 
For the Biomarker Cohort: 
21. At selected US sites only: at enrollment patients must agree to have one pre-dose 
biopsy and lesion that is deemed accessible by the investigator. If possible, at least 
one on-treatment biopsy should be accessible from same tumor lesion.  
5.2 
Exclusion criteria 
Any potential patient who meets any of the following criteria will be excluded from 
participating in the trial. 
Prior and concomitant therapy 
1. Use of any IMP or device within 28 days before administration of first dose of trial 
treatment. 
2. Has been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or 
tyrosine kinase inhibitors within 2 weeks or 5 half-lives (whichever is longer) of the 
start of trial treatment; immunotherapy/monoclonal antibodies within 3 weeks of the 
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nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the 
start of trial treatment. 
3. Ongoing participation in the active treatment phase of interventional clinical trial. 
4. Receives concurrent systemic (oral or IV) steroid therapy >10 mg prednisone daily 
or its equivalent for an underlying condition. 
5. Has had major surgery within the 4 weeks before the first dose of BNT151. 
6. Ongoing or active infection requiring IV treatment with anti-infective therapy that 
has been administered less than 2 weeks prior to the first dose of BNT151. 
7. Has ongoing side effects to any prior therapy or procedures for any medical 
condition not recovered to NCI CTCAE v5.0 Grade ≤1. 
Note: Peripheral neuropathy Grade ≤2 is allowed; alopecia of any Grade is allowed. 
Medical conditions 
8. Current evidence of new or growing brain or leptomeningeal metastases during 
screening. Patients with known brain metastases may be eligible if they:  
− 
had radiotherapy, surgery or stereotactic surgery for the brain metastases;  
− 
have no neurological symptoms (excluding Grade ≤2 neuropathy); 
− 
have stable brain metastasis on the CT or MRI scan within 4 weeks before 
signing the informed consent; and 
− 
are not undergoing acute corticosteroid therapy or steroid taper. 
Notes: Patients with central nervous system (CNS) symptoms should undergo a 
CT-scan or MRI of the brain to exclude new or progressive brain metastases. 
Spinal bone metastases are allowed, unless imminent fracture with cord 
compression is anticipated. 
9. Has a history of a cerebrovascular accident or transient ischemic attack less than 
6 months ago. 
10. Effusions (pleural, pericardial, or ascites) requiring drainage. 
11. History of autoimmune disease active or past including but not limited to 
inflammatory bowel disease, SLE, ankylosing spondylitis, scleroderma, or multiple 
sclerosis. Has any active immunologic disorder requiring immunosuppression with 
steroids or other immunosuppressive agents (e.g., azathioprine, cyclosporine A) 
with the exception of patients with isolated vitiligo, resolved childhood asthma or 
atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and patients with a 
history of Grave’s disease with stable thyroid function. Patients with controlled 
hyperthyroidism must be negative for thyroglobulin, thyroid peroxidase antibodies, 
and thyroid stimulating immunoglobulin prior to administration of trial treatment. 
12. Known history of seropositivity for HIV with CD4+ T˗cell (CD4+) counts 
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13. Known history/positive serology for hepatitis B requiring active antiviral therapy 
(unless immune due to vaccination or resolved natural infection or unless passive 
immunization due to immunoglobulin therapy). Patients with positive serology must 
have HBV viral load below the limit of quantification. 
14. Active HCV infection; patients who have completed curative antiviral treatment with 
HCV viral load below the limit of quantification are allowed. 
Note: Country-specific criteria for Germany: To confirm that a patient would be 
eligible, an active infection with HIV/hepatitis B or C should be ruled out by serum 
blood test at screening (see Section 12.2.1). 
15. Any contraindication to the combination therapies as per USPI or SmPC for patients 
receiving BNT151 in combination with other systemic anticancer agent(s). 
16. Another primary malignancy that has not been in remission for at least 2 years, with 
the exception of those with a negligible risk of metastasis or death (including but not 
limited to adequately treated carcinoma in situ of the cervix, basal or squamous cell 
skin cancer, localized prostate cancer, or ductal carcinoma in situ). 
Note: should be discussed with medical monitor (for contact information see 
Section 8.12) in case of uncertainties. 
Other comorbidities 
17. Abnormal ECGs that are clinically significant, such as Fridericia-corrected QT 
prolongation >480 ms. 
18. In the opinion of the treating investigator, has any concurrent conditions that could 
pose an undue medical hazard or interfere with the interpretation of the trial results; 
these conditions include, but are not limited to:  
− 
Ongoing or active infection requiring antibiotic/antiviral/antifungal therapy 
− 
Concurrent congestive heart failure (NYHA Functional Classification Class III or 
IV) 
− 
Concurrent unstable angina 
− 
Concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic 
atrial fibrillation) 
− 
Acute coronary syndrome within the previous 6 months 
− 
Pulmonary embolism within the previous 3 months 
− 
Significant pulmonary disease (shortness of breath at rest or on mild exertion) 
for example due to concurrent severe obstructive pulmonary disease. 
19. Cognitive, psychological or psychosocial impediment that would impair the ability of 
the patient to receive therapy according to the protocol or adversely affect the ability 
of the patient to comply with the informed consent process, protocol, or protocol-
required visits and procedures. 
20. Is pregnant or breastfeeding. 

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5.3 
Lifestyle considerations 
Not applicable. 
5.4 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical trial but 
are not subsequently entered in the trial. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Patients who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened. Patients who fail their first screening for trial eligibility may qualify for 
2 re˗screening opportunities (for a total of 3 screenings per patient) at the investigator’s 
discretion. Patients must re-sign the ICF prior to re-screening. Results of SoC tests or 
examinations performed prior to obtaining informed consent and within 28 days prior to the 
treatment may be used; such tests do not need to be repeated for screening or re-
screening. 
6 
TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatment(s), marketed product(s), or 
placebo intended to be administered to a trial patient according to the trial protocol. 
6.1 
Trial treatments administered 
In this trial the trial treatments are: For Part 1, BNT151 monotherapy (refer to Table 9) and 
for Part 2, BNT151 and one of the combination therapies proposed in Section 2.2.2.2.  
Potential treatment candidates will be described in an amendment to the protocol prior to 
the initialization of Parts 2A and 2B (Cohort 1 and 2). 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
B N T 1 5 1 -0 1  
P a g e 7 8  of 1 5 0  
V er si o n: 8. 0  
D at e: 1 3 D E C 2 0 2 3  
 
 
T a bl e  9 : 
Tri al tr e at m e nt s t o b e ad mi ni st er e d i n P art  1  
Tr e at m e nt n a m e  
B N T 1 5 1  
T y p e  
Bi ol o gi c  
D e si g n ati o n  
A d v a n c e T h er a p y ( F D A)/ A d v a n c e T h er a p y M e di ci n al Pr o d u ct 
( E M A) 
D o s e f or m ul ati o n  
A m p ul e  
U nit d o s e str e n gt h( s)  
I M P c o n c e ntr ati o n ( 
 m g/ m L). R ef er t o t h e P h ar m a c y M a n u al  f or 
f urt h er i nf or m ati o n 
D o s a g e l e v el( s)  
0. 4  µ g/ k g  R N A f or t h e fir st d o s e, i n cr e m e nt s u p t o 
 µ g/ k g  ar e 
d e s cri b e d i n m or e d et ail i n S e cti o n  4. 1. 2  t o 4. 1. 4  a n d T a bl e  7  
R o ut e of a d mi ni str ati o n  
I V b ol u s i nj e cti o n/I V i nf u si o n ( d e p e n di n g o n t h e a d mi ni st er e d 
v ol u m e)  
U s e  
E x p eri m e nt al  (I M P) 
S o ur ci n g  
Pr o vi d e d c e ntr all y b y t h e s p o n s or  
P a c k a gi n g a n d l a b eli n g  
I M P will b e pr o vi d e d i n a f ol di n g b o x. E a c h f ol di n g b o x a n d e a c h vi al 
will b e l a b el e d a s r e q uir e d p er c o u ntr y r e q uir e m e nt  
I M P =  i n v e sti g ati o n al m e di ci n al pr o d u ct; I V =  i ntr a v e n o u s; R N A =  ri b o n u cl ei c a ci d. 
 
I n P art 1, B N T 1 5 1 will b e a d mi ni st er e d I V o n D a y 1 of e a c h 3-w e e k tr e at m e nt c y cl e 
( 2 1 d a y s ; or 7 d a y s  f or t h e p r e-c o n diti o ni n g c y cl e ) aft er all r e q uir e d pr o c e d ur e s a n d 
a s s e s s m e nt s b ef or e a d mi ni str ati o n h a v e b e e n c o m pl et e d. O n c e eli gi bilit y i s c o nfir m e d, 
a d mi ni str ati o n of B N T 1 5 1 c a n b e d el a y e d f or u p t o 7  d a y s u nl e s s ot h er wi s e a p pr o v e d b y 
t h e s p o n s or m e di c al m o nit or. 
6. 2  
Pr e p ar ati o n/ h a n dli n g/ st or a g e/ a c c o u nt a bilit y  
T h e i n v e sti g at or or d e si g n e e m u st c o nfir m a p pr o pri at e t e m p er at ur e c o n diti o n s h a v e b e e n 
m ai nt ai n e d d uri n g tr a n sit f or all tri al i nt er v e nti o n r e c ei v e d a n d a n y di s cr e p a n ci e s ar e 
r e p ort e d a n d r e s ol v e d b ef or e u s e of t h e tri al i nt er v e nti o n. 
O nl y p ati e nt s e nr oll e d i n t h e tri al m a y r e c ei v e tri al tr e at m e nt a n d o nl y a ut h ori z e d sit e st aff 
m a y s u p pl y or a d mi ni st er tri al i nt er v e nti o n. All tri al i nt er v e nti o n m u st b e st or e d i n a s e c ur e, 
e n vir o n m e nt all y c o ntr oll e d, a n d m o nit or e d ( m a n u al or a ut o m at e d) a r e a i n a c c or d a n c e wit h 
t h e l a b el e d st or a g e c o n diti o n s wit h a c c e s s li mit e d t o t h e i n v e sti g at or a n d a ut h ori z e d sit e 
st aff.  
T h e i n v e sti g at or, sit e, or t h e h e a d of t h e sit e ( w h er e a p pli c a bl e) i s r e s p o n si bl e f or tri al 
tr e at m e nt a c c o u nt a bilit y, r e c o n cili ati o n, a n d r e c or d m ai nt e n a n c e (i. e., r e c ei pt, 
r e c o n cili ati o n, a n d fi n al di s p o siti o n r e c or d s). 
F urt h er g ui d a n c e a n d i nf or m ati o n f or t h e fi n al di s p o siti o n of u n u s e d tri al tr e at m e nt ar e 
pr o vi d e d i n t h e P h ar m a c y M a n u al  a n d/ or Cli ni c al Tri al S u p pl y M a n u al . 
6. 3  
M e a s ur e s t o mi ni mi z e bi a s: r a n d o mi z ati o n a n d bli n di n g  
T hi s i s a n o p e n -l a b el tri al. 
C CI
C CI

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6.4 
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 trial intervention and trial patient identification will be confirmed at the time of dosing by 
a member of the trial site staff other than the person administering the trial intervention. 
Fasting status at treatment will be recorded. 
6.4.1 
Concomitant medication and non-drug therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or procedure that the patient is receiving or undergoing at the 
time of signing the ICF, or receives or undergoes during the trial must be recorded along 
with, as applicable: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant 
or prior therapy. Contact information for the medical monitor can be found in Section 8.12. 
It is recommended that patients should abstain from taking nonprescription drugs 
(including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug 
is a potential enzyme inducer) or 5 half-lives (whichever is longer) if not medically 
necessary before the start of trial intervention until completion of the follow-up visit, unless, 
in the opinion of the investigator and sponsor, the medication will not interfere with the trial. 
Concomitant antiemetics, antidiarrheal agents, IV fluids, or electrolyte replacement based 
on clinical or laboratory assessments and blood transfusions while on-treatment based on 
individual institutional guidelines will be allowed. 
Palliative radiotherapy of, for example, painful bone metastases not defined as target 
lesions will be allowed. Radiotherapy should be documented in the eCRF including total 
dose, fractionation and location. 
The prohibited medications while on trial treatment are as follows: 
• 
Other anti-cancer therapy not included under trial treatment either as IMP or one of 
the combination therapies in a given part of the trial (e.g., Part 1, Part 2A and 
Part 2B) proposed in Section 2.2.2.2. 
• 
Other prohibited concomitant medications as listed in inclusion and exclusion 
criteria (Section 5.1 and Section 5.2). 
For further guidance on prohibited and restricted medications, please refer to the IB for 
BNT151, and USPI or SmPCs for other approved agents used in combination with 
BNT151. 

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6.4.2 
Premedication 
Pre- and post-medications with antipyretics (e.g., acetaminophen, nonsteroidal anti-
inflammatory drugs), antiemetics, proton-pump inhibitors and anxiolytics per institutional 
guidelines are allowed. If necessary, patients should be properly prehydrated before 
BNT151 treatment. Corticosteroid should not be used as a premedication for BNT151. 
Patients who have experienced prior administration related Grade 2 or Grade 3 reactions 
in the trial should be premedicated. Premedication to prevent injection/infusion-related 
reactions (IRR) in subsequent administrations may be administered at the investigator's 
discretion according to local guidelines but preferably includes an antihistamine (e.g., 
diphenhydramine 50 mg orally twice daily [per os] or equivalent antihistamine), 
acetaminophen/paracetamol (e.g., acetaminophen 500-1000 mg per os or equivalent), and 
if considered necessary, patients should receive corticosteroids at a suggested maximum 
dose of 100 mg prednisone or equivalent. 
All premedication must be reported on the concomitant medication page in the eCRF. 
Further details on the administration of BNT151 in Cohort 3, 4 and 5 of Part 2 will be 
implemented by protocol amendment. 
6.4.3 
Rescue medication  
There is no rescue medication for BNT151. For mitigation plans for particular AEs, refer to 
Section 6.5.4. 
6.5 
Dose modifications 
6.5.1 
Dose limiting toxicity 
In general, a DLT for a drug or other treatment is defined as an AE that prevents an 
increase of the dose level of that treatment (for details on reporting see SRC Charter). 
For the purpose of dose escalation, the DLT monitoring period will be 21 days. The 
occurrence of any of the toxicities outlined in this section will be considered a DLT, 
excluding toxicities clearly related to disease progression or intercurrent illness.  
SAEs, non-serious Grade ≥3 AEs and clinically significant abnormal laboratory values 
Grade ≥3 will be collected and assessed for DLTs (for each dose level during the first 
cycle). NCI CTCAE v5.0 will be used to grade the intensity of AEs. 
Other clinically significant toxicities, including a single event or multiple occurrences of the 
same event, may be considered as DLTs. 
AEs occurring after treatment Cycle 1 may be considered DLTs upon discussion between 
the investigator(s) and the sponsor(s) medical monitor (for contact information see 
Section 8.12). 
Any other toxicity assessed as related to BNT151 treatment, and which in the opinion of 
the trial investigator(s) and the sponsor’s medical monitor constitutes a DLT. 

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Dose escalation: 
Patients experiencing a DLT (an AE fulfilling the DLT criteria within the DLT period of 
21 days) should discontinue trial drug immediately and indefinitely.  
6.5.2 
DLTs for Part 1 and Part 2A (dose escalation) 
During the first treatment cycle of both Part 1 and Part 2A (dose escalation) (during 
second treatment cycle if pre-conditioning dose is applied), a DLT is considered as any 
toxicity of Grade 3 and which does not resolve to Grade 1 or lower within a week despite 
the use of medical intervention, or that is of Grade 4 or Grade 5 (i.e., death), but with 
exceptions as follows: 
• 
The following events occurring during the DLT period are also considered a DLT: 
− 
Hypotension of Grade 3 that persists for >4 hours and requires hospitalization.  
− 
Any other toxicity that is greater than baseline grade, is clinically significant 
and/or unacceptable, and is judged to be a DLT by the investigator and the 
sponsor. 
• 
The following events occurring during the DLT period ARE NOT considered a DLT: 
− 
Grade ≤3 nausea or vomiting controllable with antiemetics within 72 h. 
− 
Hypotension (systolic pressure <90 mm Hg) of Grade <3 that is of limited 
duration (less than 72 h) or can be managed with hydration measures. 
− 
Hypotension that requires a precautionary admission for observation after 
Grade 3 hypotension that persists for ≤4 h. 
− 
Grade 3 amylase and lipase elevations that are not accompanied by clinical 
signs/symptoms of pancreatitis. 
− 
Liver transaminase elevation lower than 8 × ULN or TBili lower than 3 × ULN. 
− 
Grade 3 endocrinopathy that is managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the patient is asymptomatic.  
− 
Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes) that resolves 
to Grade ≤1 within 3 weeks.  
− 
Concurrent vitiligo or alopecia of any AE grade. 
6.5.3 
Dose modification guidance/rules 
6.5.3.1 
DLTs 
Patients who experience a DLT during the DLT observation period of any dose 
escalation/safety run-in period should permanently discontinue trial treatment.  

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6.5.3.2 
Dose modifications after the DLT Observation Period has ended 
for patients in escalation/safety run-ins and for all patients in 
expansion cohorts 
Patients who experience Grade 4 clinical AEs and clinically significant Grade 4 lab AEs 
attributed to BNT151 should permanently discontinue trial treatment. Should an individual 
patient show overwhelming evidence of clinical benefit at this time, continuation of trial 
treatment at a substantially reduced dose upon recovery may be discussed with the 
medical monitor. 
Grade 3 clinical AEs and Grade 3 lab AEs attributed to BNT151 that are clinically 
significant should be handled as shown in Figure 5. 
 
 
Figure 5: 
Handling of Grade 3 BNT151-related AEs outside of DLT periods 
*Dose delay: Next dose of BNT151 can maximally be delayed 21 days unless approved otherwise by the sponsor 
medical monitor. 
# No delay for recovery from Grade ≥2 allowed 
## Unless Grade at baseline was Grade ≥2 and AE has resolved to baseline grade 
Note: Grade 4 treatment-related AEs will always lead to BNT151 discontinuation. 
AE = adverse event; G = grade; DL = dose level; DLT = dose limiting toxicity. 
 
First occurrence of Grade 3 AE: 
• 
As a first measure, administration of BNT151 needs to be withheld. 
• 
Investigator must contact sponsor for thorough discussion in order to decide 
whether the patient should be withdrawn from BNT151 treatment or next dosing 
should be delayed. 
• 
Administration of BNT151 can be delayed for up to 21 days (i.e., one cycle) unless 
otherwise approved by the sponsor medical monitor (for contact information see 
Section 8.12). If the intensity resolves to Grade ≤1 or baseline within this period, re-
treatment may be considered under the following: 
− 
Sponsor and investigator will discuss any safety concerns in order to decide 
whether the next dose of BNT151 should be administered at same dose level 

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or one dose level lower (DL-1). Intermediate dose levels defined in the protocol 
may also be considered. The sponsor may also consult the SRC. 
Second occurrence of an identical AE Grade 3 after re-exposure to BNT151: 
• 
As a first measure, administration of BNT151 needs to be withheld. 
• 
If re-treatment leads to an identical AE with same intensity, the next administration 
of BNT151 can be delayed for up to 21 days unless otherwise approved by the 
sponsor medical monitor (for contact information see Section 8.12). If the intensity 
of the AE resolves to Grade ≤1 or baseline within this period, re-treatment may be 
considered under the following conditions: 
− 
The next dose of BNT151 should be administered at one dose level lower 
(DL-1 or DL-2) than the dose level causing the recurrence of the AE. 
Intermediate dose levels defined in the protocol may be considered. 
Third occurrence of an identical AE Grade ≥2 after re-exposure to BNT151: 
• 
As a first measure, administration of BNT151 needs to be withheld. 
• 
If re-treatment at a lower dose leads to a third identical AE with intensity Grade ≥2, 
the patient must permanently discontinue trial treatment. No dose delay is allowed. 
However, if the AE is Grade ≤1 or baseline, re-treatment may be considered under 
the following condition: 
− 
Next dose of BNT151 should be administered at same reduced dose level 
(DL-1 or DL-2). 
Please note: 
• 
Re-escalation of BNT151 dose is not allowed for patients who have previously 
been dose reduced. 
• 
BNT151 must be permanently discontinued if the patient experiences a Grade 3 
AE that fails to resolve to Grade ≤1 within 21 days after the planned dosing date 
unless otherwise approved by the sponsor medical monitor (for contact information 
see Section 8.12). 
• 
BNT151 must be permanently discontinued if more than 2 dose reductions are 
required. 
• 
BNT151 must be permanently discontinued in case of a dose delay of more than 
21 days due to toxicity possibly related to BNT151 unless otherwise approved by 
the sponsor medical monitor (for contact information see Section 8.12). 
• 
The investigators are encouraged to contact the sponsor in case of any safety 
concern that needs thorough discussion and evaluation. 
• 
If the causal relationship of AE cannot be attributed to either BNT151 or SoC, 
BNT151 should be discontinued; SoC should be dose modified as per the USPI or 
SmPC. 

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6.5.4 
Mitigation plans for specific AEs 
6.5.4.1 
Injection/Infusion-related reactions (IRRs) 
IRR is a general risk to be considered for any new compound administered IV irrelevant of 
its mechanism of action. An IRR is typically of immediate onset after the compound’s 
administration. The risk of IRR cannot be excluded due to the given limited experience 
with BNT151. 
The following treatment guidelines are provided below for patients who experience an IRR 
associated with administration of BNT151 treatment: 
• 
Grade 1: If a Grade 1 IRR occurs, the administration does not need to be 
interrupted and can be continued at the investigator’s discretion at half the 
injection/infusion rate under close medical supervision. 
• 
Grade 2 or 3: If a Grade 2 or Grade 3 IRR occurs, the administration should be 
interrupted and appropriate medical management instituted. The administration 
may be re-started at the investigator’s discretion at half the administration rate 
under close medical supervision if symptoms have resolved to Grade ≤1 within an 
hour. 
− 
Patients who have experienced prior administration related Grade 2 or Grade 3 
reactions in the trial should be premedicated. Premedication to prevent IRR in 
subsequent administrations may be administered at the investigator's discretion 
according to local guidelines but preferably includes an antihistamine 
(e.g., diphenhydramine 50 mg orally twice daily [per os] or equivalent 
antihistamine), acetaminophen/paracetamol (e.g., acetaminophen 500-
1000 mg per os or equivalent), and if considered necessary, patients should 
receive corticosteroids at a suggested maximum dose of 100 mg prednisone or 
equivalent. 
− 
If the patient has a second Grade 3 IRR despite premedication, the 
administration should be stopped and the patient should be withdrawn from 
treatment. 
• 
Grade 4: If anaphylaxis or a Grade 4 IRR occurs, administration of BNT151 should 
be discontinued immediately and permanently, and appropriate medical therapy 
should be administered. 
Please note: 
• 
At all times during BNT151 administration, immediate emergency treatment of an 
anaphylactic reaction according to institutional standards must be assured. In order 
to treat possible anaphylactic reactions, for instance, dexamethasone 10 mg and 
epinephrine in a 1:1000 dilution or equivalents should always be available along 
with equipment for assisted ventilation. 
• 
All premedication must be reported on the concomitant medication page in the 
eCRF. 

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6.5.5 
Safety stopping criteria 
Across all patients in Both Part 1 and Part 2A, the following rules apply: 
The trial will be paused for: 
• 
Any death possibly related to BNT151 
• 
Two Grade 4 AEs that are considered possibly, probably, or definitely related to 
BNT151 
If a suspected DLT occurs, an SRC meeting will be held as rapidly as possible. In the 
meantime, dosing of the ongoing patients in that cohort will continue unless there is reason 
to suspect there is an unacceptable safety risk-based on the nature and/or severity of the 
observed DLT.  
The SRC will decide whether and when the trial can be restarted after approval of a 
substantial amendment by the regulatory authorities and ethics committee (EC); or, with 
the sponsor’s concurrence, whether the trial should be stopped. 
In individual patients, treatment with BNT151 should be discontinued due to safety 
concerns under the following conditions: 
• 
If the patient experiences an AE fulfilling the DLT criteria during the DLT 
observation period during any dose escalation or safety run-in part of the trial. 
• 
If the patient experiences a BNT151-related Grade 4 clinical AE or Grade 4 
clinically significant lab AE (after the DLT period has ended in the dose 
escalation/safety run-in parts of the trial or for any patient in the expansion 
cohorts). 
• 
If the patient experiences a BNT151-related Grade 3 clinical AE or Grade 3 
clinically significant lab AE that fails to resolve to Grade ≤1 within 21 days after the 
planned dosing date (after the DLT period has ended in the dose escalation/safety 
run-in parts of the trial or for any patient in the expansion cohorts). 
• 
Any dose delay of more than 21 days due to toxicity possibly related to BNT151. 
• 
If more than two dose reductions are required. 
• 
In case of cytokine release syndrome (CRS) Grade 4, the patient should be 
discontinued from treatment. 
• 
Second occurrence of an IRR of Grade ≥3 despite premedication prior to second 
administration. 
• 
First occurrence of anaphylaxis or Grade 4 IRR. 
Please note: 
• 
Patients should, whenever possible, irrespective of the reason for discontinuation, 
be examined as soon as possible. 
• 
Should an individual patient show overwhelming evidence of clinical benefit at the 
time of treatment-limiting AEs as defined above, continuation of trial treatment at a 
substantially reduced dose upon recovery may be discussed with the medical 

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monitor and must be approved by the medical monitor (for contact information see 
Section 8.12). 
6.6 
Treatment after the end of the trial - New anti-cancer treatment 
New anti-cancer treatment according to SoC can be started after discontinuation from the 
trial treatment. 
7 
DISCONTINUATION OF TRIAL TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of trial treatment 
Patients will receive BNT151 treatment until one of the predefined discontinuation of 
treatment criteria has been met: 
• 
Radiographic disease progression per RECIST 1.1 (Section 12) 
• 
Death 
• 
Unacceptable AEs requiring BNT151 discontinuation (refer to safety stopping 
criteria Section 6.5.5) 
• 
Investigator believes that it is in the best interest of the patient to stop BNT151 
treatment 
• 
Withdrawal of consent 
• 
Pregnancy 
• 
Lost to follow-up 
• 
Trial termination by the sponsor 
If BNT151 treatment is permanently discontinued for other reasons than radiographic 
disease progression, every effort should be made to continue tumor assessments. 
Patients should, whenever possible, irrespective of the reason for discontinuation, be 
examined as soon as possible and the treatment discontinuation visit should be performed 
(Section 1.3). 
7.1.1 
Temporary discontinuation 
See Section 6.5.5.  
7.1.2 
Rechallenge (if applicable) 
Not applicable. 
7.2 
Patient discontinuation/withdrawal from the trial 
Patients will be withdrawn from the trial (dose escalation or expansion) for the following 
reasons: 
• 
A patient may withdraw from the trial at any time at his or her own request, 

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• 
At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons, 
• 
Lost to follow-up,  
• 
Patient died, 
• 
Trial closure. 
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the trial, he or she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site trial records. 
The sponsor will make any effort to ensure patients are followed up for completion of 
safety assessment in the trial. See Section 1.3 for data to be collected at the time of trial 
discontinuation and follow-up and for any further evaluations that need to be completed. 
When a patient withdraws consent, the reason for withdrawal is to be documented in the 
eCRF and in the source document. Trial drug assigned to the withdrawn patient may not 
be assigned to another patient.  
7.2.1 
Safety follow-up evaluations 
Patients discontinuing from treatment for any reason will have safety follow-up visits 
30 days (+5 days) and 60 days (±7 days) after the patient receives the last dose of 
BNT151. If the patient initiates new anti-cancer treatment within 60 days of the last dose of 
trial treatment, the safety follow-up visit should be performed prior to starting new anti-
cancer treatment. Once new anti˗cancer treatment is initiated, the patient will move into 
Survival follow-up. 
7.3 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for trial visits without 
stating an intention to withdraw consent, the investigator should show “due diligence” by 
contacting the patient, family or family physician as agreed in the ICF and by documenting 
in the source documents steps taken to contact the patient, e.g., dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due 
diligence has been completed (where possible, three telephone calls and, if necessary, a 
certified letter to the patient’s last known mailing address or local equivalent methods). 
Patients lost to follow-up should be recorded as such on the appropriate disposition eCRF. 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
Trial procedures and their timing are summarized in the SoAs for dose escalation 
(Section 1.3) and Part 2 (the SoA for this phase will be based on a substantial amendment 
based on the experiences from Part 1) of the trial. Protocol waivers or exemptions are not 
allowed. 

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Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue trial 
treatment. 
Adherence to the trial design requirements, including those specified in the SoA, is 
essential and required for trial conduct. 
All screening evaluations must be completed and reviewed to confirm that 
potential patients meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol specified criteria and were performed 
within the time frame defined in the SoA. 
8.1 
Efficacy assessments 
8.1.1 
Anti-tumor activity assessment – CT/MRI imaging  
Anti-tumor activity will be evaluated according to RECIST 1.1 (Eisenhauer et al. 2009) (see 
Section 12). Efficacy will be assessed by on-treatment imaging at Week 6 (+7 days), every 
6 weeks (±7 days) for 48 weeks, and every 12 weeks (±7 days) thereafter until disease 
progression is assessed by the investigator (unless the investigator elects to continue 
treatment [see below]), withdrawal of consent, trial termination by the sponsor, or death, 
whichever occurs first. The RECIST 1.1 criteria will be used for secondary endpoint 
response evaluation including PFS (Eisenhauer et al. 2009). All images obtained must be 
submitted to the central imaging vendor.  
In all parts of the trial, treatment should be discontinued in all patients who exhibit 
evidence of progressive disease by RECIST 1.1. However, to better accommodate 
standard clinical practice which is guided by the fact that these patients have, in general, 
limited treatment options and such options have limited efficacy and significant 
toxicity, patients may be considered for treatment beyond progression at the discretion of 
the investigator and after appropriate discussion with the patient and obtaining informed 
consent, only if all of the following criteria are met: 
• 
Absence of clinical symptoms or signs indicating clinically significant disease 
progression 
• 
No decline in performance status 
• 
Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites [e.g., CNS metastasis, respiratory failure due to tumor compression, spinal 
cord compression] requiring urgent alternative medical intervention 
• 
No significant, unacceptable or irreversible toxicities related to trial treatment 
• 
Patients must provide written consent to acknowledge deferring alternative 
treatment options including other clinical trials in favor of continuing trial treatment 
at the time of initial progression. 

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Patients who continue treatment beyond radiographic disease progression per 
RECIST 1.1 should be closely monitored clinically and with a follow-up scan in 6 weeks or 
sooner if symptomatic deterioration occurs. Treatment should be discontinued if clinical 
deterioration due to disease progression occurs at any time, or if persistent disease growth 
is confirmed in a follow-up scan. In addition, patients should be discontinued for 
unacceptable toxicity or for any other signs or symptoms of deterioration attributed to 
disease progression as determined by the investigator after an integrated assessment of 
radiographic data and clinical status. 
Patients who discontinue treatment for reasons other than radiographic disease 
progression (e.g., toxicity) will continue scheduled tumor assessments at the same 
frequency as would have been followed if the patient had remained on trial treatment.  
8.1.2 
Survival follow-up 
Survival follow-up starts 12 weeks after all other trial visits have been completed. Survival 
follow-up may be performed as telephone, e-mail, or clinic visit. Planned time points for 
Survival follow-up are provided in Section 1.3. Survival follow-up will continue until the 
patient dies, or the sponsor, whichever occurs earlier, closes the study. 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in Section 1.3. 
8.2.1 
Physical examinations including height and body weight 
Physical examinations will be performed (by inspection, palpation, and auscultation) by a 
physician at the trial site according to the SoA for Part 1 (Section 1.3) and Part 2 of the trial 
(table to follow with protocol amendment). 
A complete physical examination will be performed at screening, up to 21 days prior to first 
administration of IMP. The complete physical examination includes evaluation of the head, 
eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems. Abnormalities 
(clinical significant findings) observed at screening will be recorded on the general Medical 
History/Concomitant Diseases page of the eCRF, if started before signing the ICF. New or 
worsened clinically significant abnormalities detected after signing the ICF have to be 
recorded on the AE page of the eCRF. 
A limited, symptom-directed physical examination will be performed at the other times 
noted in the SoA and as clinically indicated at other time points. New or worsened clinically 
significant abnormalities will be recorded on the AE page of the eCRF. 
Height and weight will be assessed at screening. Weight will be assessed at additional 
time points as indicated in the SoA. Assessment of weight should be repeated at any time 
if there are apparent weight changes. 
8.2.2 
Vital signs 
Vital signs will be assessed by the appropriate trial personnel at the time points listed in 
the SoA for Part 1 (Section 1.3) and Part 2 of the trial (table to follow with protocol 

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amendment). The same methods for measuring vital signs such as body temperature 
should be used for one patient throughout the trial. 
During dose escalation, body temperature, heart rate, respiratory rate, and blood pressure 
will be assessed as summarized in Table 10 on BNT151 administration days. On days 
when BNT151 is not administered, vital signs only need to be obtained once, at any time 
during the visit. 
Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• 
Blood pressure and heart rate measurements should be preceded by at least 5 min 
of rest for the patient in a quiet setting without distractions (e.g., television, cell 
phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 1 blood pressure measurement (if the blood pressure measurement is 
abnormal, 2 further measurements must be done at intervals of 1 minute and the 
average of the three measurement must be recorded on the eCRF). 
 
Table 10: 
Vital signs during Part 1 (administration days) 
Pre-administration  
BNT151 pre-administration (up to 30 min before administration) 
During administration: 
If the IMP is given as an infusion, vital signs will be measured every 15 min during the infusion until infusion 
is completed (±5 min) 
If the IMP is given as a bolus, vital signs will be measured 15 min after the injection (±5 min) 
Post-administration: 
30 min after end of administration (±5 min)  
60 min after end of administration (±10 min)  
120 min after end of administration (±15 min)  
IMP = investigational medicinal product. 
 
8.2.3 
Electrocardiograms (ECGs) 
12-lead ECG will be obtained as outlined in Section 1.3 using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT 
(QTc) intervals. For the assessment the patients will be in the supine position, lying still 
and quietly for at least 10 minutes until the assessment has been done. 
In general, increases in QT/QTc to >500 ms or of >60 ms over baseline are commonly 
used as thresholds for potentially discontinuing trial treatment; consultation with a 
cardiologist should be considered for any such increases to determine whether they are 
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8.2.7 
Pregnancy testing 
In this trial, patients are considered to have reproductive potential, unless they are 
postmenopausal or permanently sterile. Details and definitions are provided in 
Section 10.4. See Section 1.3 for the time points when pregnancy tests should be 
performed for WOCBP. A serum pregnancy test is performed at screening. Thereafter, 
urine pregnancy test is sufficient unless indicated otherwise. A serum pregnancy test is 
warranted to confirm a positive urine pregnancy test. Refer to Section 10.4.3 for details of 
reporting pregnancies. 
8.3 
Adverse events (AEs) and serious adverse events (SAEs) 
Definitions of AEs and SAEs can be found in Section 10.3. 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 AE and SAE information 
All AEs and SAEs will be collected from signing of the ICF until the Safety Follow-up Visit 2 
at the time points specified in the SoA (Section 1.3). 
All SAEs (initial and follow-up reports) will be recorded and reported to the sponsor or 
designee within 24 hours after becoming aware of the event, as indicated in 
Section 10.3.1.12. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the trial 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial treatment or trial participation, the investigator must promptly 
notify the sponsor. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and 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 SAEs and DLTs (as defined in Section 10.3 and 6.5.1) 
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).  
The investigator is obliged 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 

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include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
If a patient dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any post mortem findings including 
histopathology. 
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 hours 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 the Safety Follow-up 2 Visit 
(Section 1.3), the investigator must confirm the unavailability of a final status. 
Further information on follow-up procedures is provided in Section 10.3. 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
trial treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (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 suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
For the IMPs, the sponsor or delegate will take care of the reporting of SUSAR Reports to 
the regulatory authority, the IEC and the other investigators as required by national law 
and applicable guidelines. 
An investigator who receives a safety report describing a SAE or other specific safety 
information (e.g., summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Regulatory reporting requirements for SAEs in Part 2 of the trial will be added by 
amendment. 
8.3.5 
Pregnancy 
Any female participant who becomes pregnant while participating in the trial will 
discontinue the IMP. Details of all pregnancies in female patients and, if indicated, female 
partners of male patients will be collected (procedures described in Section 10.4). 

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If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (details defined in 
Section 10.4). 
8.3.6 
Death events 
Any death that occurs within the observation period (please note details below) will be 
reported as an SAE (please note details below). Exemptions to the SAE definition as 
defined in Section 10.3.1.5 do also apply for fatal cases. 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 1 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, “unexplained death” should 
be documented as event term. 
In addition to reporting as SAE, the death page of the eCRF needs to be completed. 
Deaths clearly related to the progression of the disease will not be documented as AEs, 
nor reported as SAEs. These deaths must be collected on the death page of the eCRF. 
8.3.7 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs 
The progression of underlying disease (e.g., new metastases) during trial participation is 
not considered as an AE. 
Because disease progression is common for patients with cancer, it will not be reported 
according to the standard process for expedited reporting of an SAE even though the 
event may meet the definition of a SAE. These events will be recorded on the 
corresponding eCRF page in the patient’s eCRF. 
NOTE: Symptoms resulting from the progression and clearly stated as related to the PD 
and fatal cases clearly related to the progression will not be documented as AEs nor 
reported as SAEs. However, specific symptoms at time of progression that are considered 
that may be caused by other reason, and fatal cases where other reason rather than the 
PD may not be discarded, will have to be documented as AEs and reported as SAEs if 
applicable.  
8.3.8 
Adverse events of special interest 
Not applicable. 
8.4 
Treatment of overdose 
For this trial, an overdose is defined as a patient receiving a dose of BNT151 15% in 
excess of the intended dose specified in this protocol. For guidance on overdose for 
approved agents in combination with BNT151, refer to the relevant SmPC and USPI. 

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In the event of an overdose, the investigator should: 
• 
Contact the medical monitor (for contact information see Section 8.12) 
immediately. 
• 
Closely monitor the patient for any AE/SAE and laboratory abnormalities until 
BNT151 can no longer be detected systemically (at least 21 days). 
• 
Document the quantity of the excess dose in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor (for contact information see Section 8.12) based on 
the clinical evaluation of the patient. 
8.5 
Pharmacokinetics 
Blood samples for (including but not limited to) maximum concentration (Cmax), time to Cmax 
(Tmax), area under the curve (AUC0-τ), and half-life (t1/2) analyses of BNT151 translated IL-2 
variant will be collected according to the SoA (Section 1.3). 
All samples will be analyzed centrally. For details, please see the Laboratory Manual. 
Lipid PK samples will be drawn to enable potential further exploratory PK assessments. 
Refer to Table 4a and Table 4b (related to the Biomarker Cohort). Samples may be stored 
for up to 15 years (or according to local regulations) following the patient’s last visit in the 
trial at a facility selected by the sponsor to enable analysis for lipid PK. 
8.6 
Exploratory pharmacodynamics 
Details described in Section 8.8.2. 
8.7 
Genetics 
Genetic as well as non-genetic analyses may be part of the biomarker investigations in this 
trial. Blood and tissue samples will only be used for genetic analysis if the patients have 
provided informed consent for this genetic analysis (see Section 10.1.3). 
The genetic analyses comprise analysis of biomarker variants thought to play a role in the 
mechanism of action of BNT151. 
All data generated using the samples, will be handled in accordance with applicable laws 
and regulations; this includes requirements applicable for data protection, for sample 
shipment, and a potential withdrawal of consent. 
Samples will be analyzed according to the Laboratory Manual. 
8.8 
Biomarkers 
See the SoA in Section 1.3 (for the dose esclatation Table 2a and Table 2b, for the 
Biomarker Cohort Table 4a and Table 4b) for planned time points of sample collection. 
Sample handling and storage – details on the collection, processing, shipment and storage 
of samples will be provided in separate documents (e.g., Laboratory Manual). Samples 

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may be stored for a maximum of 15 years (or according to local regulations) following the 
end of the trial at a facility selected by the sponsor to enable further analyses. 
Reporting – Some of the results of biomarker investigations may be reported separately 
(e.g., in a biomarker report). 
Biomarker and related CRF data (e.g. clinical outcome) will be monitored regularly during 
the trial. 
8.8.1 
Tumor tissue 
Tumor tissue collected at baseline or on-treatment or archival FFPE tumor blocks will be 
analyzed for biomarkers confirming and/or elucidating the mode of action, and to explore 
potential predictive factors as well as identify possible future combination therapies.  
If feasible, all patients should provide a fresh biopsy (core needle biopsies preferred, 
aspirates are not acceptable) performed at screening or before the first dose and an on-
treatment biopsy from the same lesion within the first two cycles, preferably in the time 
window C2D5-12 (see Table 2a and Table 2b, Table 4a and Table 4b). For patients 
enrolled in the Dose Escalation Cohort all biopsies are optional, for patients in the 
Biomarker Cohort the screening biopsy is required and the on-treatment biopsy is required 
if feasible. An additional biopsy upon treatment discontinuation in the trial is also requested 
if feasible. For each biopsy the trial site should provide a formalin-fixed paraffin embedded 
(FFPE) block (see Laboratory Manual) and only at selected US sites fresh tumor tissue 
cores for isolation of tumor infiltrating lymphocytes (TILs) (see the Laboratory Manual for 
instructions). In case the site and the patients are willing to provide biopsies on-treatment 
but cannot provide fresh biopsy during screening, archived material is allowed to be used 
as a screening sample (not allowed for the Biomarker Cohort). 
8.8.2 
Pharmacodynamic biomarkers 
Pharmacodynamic biomarkers will be evaluated in samples collected before and during 
treatment in order to determine the impact of BNT151 in monotherapy or in combination 
therapy on these biomarkers. 
Blood samples for PD biomarkers, which might act as anti-tumor, and safety indicators of 
activity of BNT151 monotherapy and in combination with SoC, will be collected as defined 
in detail in the SoA (Section 1.3). Relevant details on sample collection and handling will 
be documented in the Laboratory Manual. 
Pharmacodynamic biomarkers in blood may include, but will not be limited to: absolute 
lymphocyte count, immune cell populations, e.g., T cells, regulatory T cells (Tregs), B cells 
and NK cells, as well as sCD25, and cytokines/chemokines as assessed by Flow 
cytometry and ELISA. The list of planned assessments may be subject to change 
dependent on the results obtained.  
All samples will be analyzed centrally. For details, please see the Laboratory Manual. 

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8.8.3 
Screening for predictive biomarkers 
For consenting patients, candidate biomarkers in archived or fresh baseline tumor tissue 
will be evaluated for correlation with response to treatment to identify possible predictive 
biomarkers. 
Predictive biomarkers may include but are not limited to presence of specific immune cell 
types and their respective abundance within the tumor immune microenvironment as may 
be assessed by immunohistofluorescence, immunohistochemistry, flow cytometry, and/or 
gene expression analysis (e.g., RNAseq) of archival or freshly obtained baseline FFPE 
biopsies. Predictive biomarker screening may also include specific tumor characteristics 
such as tumor mutational burden or tumor signatures assessed by Next Generation 
Sequencing (Whole Exome Sequencing and RNAseq) from the tumor tissue and cell pellet 
of the peripheral blood. 
For withdrawal of consent from the use of biomarker samples refer to Section 10.1.3.1. 
8.8.4 
Additional biomarkers 
In addition to the biomarkers described above, for consenting patients, further biomarkers 
related to, e.g., the mode of action or the safety of the trial intervention and similar drugs 
may be investigated by using longitudinal blood samples or serial biopsies. These 
biomarkers in serial biopsies may be specific immune cell types or specific tumor 
signatures as assessed by immunohistofluorescence, immunohistochemistry, flow 
cytometry, and/or gene expression analysis (e.g., RNAseq). The same applies to further 
biomarkers deemed relevant to cancer and associated health problems. These 
investigations may include e.g., diagnostic, safety, PD, monitoring, or potentially predictive 
biomarkers. For withdrawal of consent from the use of biomarker samples refer to 
Section 10.1.3.1. 
8.9 
Supplementary biomarker assessments 
Blood sampling for immunophenotyping of peripheral immune cells will be (only) 
mandatory for consenting patients in the Biomarker Cohort as well as for trial sites where 
logistically manageable. For all other sites, the sampling is optional. The blood samples 
will be collected according to Table 2a and Table 2b (with and without pre-conditioning), 
Table 4a and Table 4b (for Biomarker Cohort with and without pre-conditioning). For 
withdrawal of consent from the use of biomarker samples refer to Section 10.1.3.1. 
8.10 
Immunogenicity assessments 
Antibodies to PEG lipid and BNT151 translated IL-2 variant will be evaluated in serum 
samples, which will be collected from all patients according to Table 2a and Table 2b (with 
and without pre-conditioning), Table 4a and Table 4b (for Biomarker Cohort with and 
without pre-conditioning). These samples will be tested by the sponsor or sponsor's 
designee. An extra sample will be taken for retesting or retrospective testing if required. 
Blood samples for immunogenicity analysis will be collected and handled as outlined in the 
Laboratory Manual. They will be analyzed centrally and batch-wise. 

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The detection and characterization of antibodies to PEG lipid and BNT151 translated IL-2 
variant will be analyzed by or under the supervision of the sponsor. Samples may be 
stored for a maximum of 15 years (or according to local regulations) following the last 
patient’s last visit for the trial at a facility selected by the sponsor to enable further analysis 
of immune responses to PEG lipid and BNT151 translated IL-2 variant. 
8.11 
Blood collection 
Blood samples will be collected from all subjects for immunogenicity, PD and PK analysis. 
Additional blood will be collected for immunophenotyping for patients enrolled on the 
Biomarker cohort only. Additionally, for this cohort, the cell pellet, a byproduct from plasma 
preparation, will be collected once and used for genetic analysis. The total blood sampling 
volume for individual patients in this trial is up to approximately 770 mL for patients on the 
regular Dose Escalation Cohorts and 988 mL for patients in the Biomarker Cohort, within 
the first 6 months of the trial. 
8.12 
Medical monitor contact information 
The site(s) may contact the medical monitor directly during normal German business hours 
(09:00am to 05:00pm central European time) via telephone or e-mail 
(
) for routine issues.  
After normal business hours there will be a 24/7 Protocol Coverage for urgent protocol-
related medical questions (see Section 8.13). 
8.13 
24/7 coverage for urgent protocol-related medical questions 
In a trial-related health emergency, when the assigned medical monitor for the trial cannot 
be reached, for discussion of urgent protocol Medical-related questions an on-call 
physician can be reached 24 hours per day, 7 days per week via Syneos 24/7 Call-Center:  
• 
Telephone: 
 (chargeable US telephone number allowing a global 
reach from both landlines and mobile phones) 
• 
 
On the above internet page, a list of country-specific toll-free access codes are provided. 
Call the direct access code, then enter: 
 (without the leading 0 from the 
direct access code). 
It should be noted that not all countries globally have access to toll-free numbers. 
Countries without toll-free numbers need to dial the chargeable number as indicated 
above. Furthermore, there may be restrictions when dialing toll-free numbers from a 
mobile phone. 
8.14 
Collection of demographic and other baseline characteristics 
8.14.1 
Demographic data 
At screening, the demographic data and baseline characteristics will be recorded for all 
trial patients. 

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8.14.2 
Medical history 
Medical history information will be recorded for at the times given in the SoA (Section 1.3). 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical hypotheses 
The primary objectives of this trial Part 1 are to assess the safety profile and to identify the 
MTD and/or RP2D. The Biomarker Cohort examines the exploratory markers for the 
mechanism of action in the tumor and periphery. Hence, no statistical hypothesis is under 
test for trial Part 1. For trial Part 2A and 2B hypothesis testing for each expansion cohort 
may be introduced through protocol amendment. 
9.2 
Sample size determination 
The sample size for Part 1 of the trial is driven by accelerated titration design of single-
patient cohorts with a switch to the 3+3 trial design. In Part 1, the sample size will be up to 
54 DLT-evaluable patients depending on the number of DLTs which may occur, with the 
possible enrollment of up to 10 additional patients if efficacy is seen in a specific tumor 
type.  
In addition, approximately 20 patients will be enrolled in the Biomarker Cohort with paired 
biopsies. This sample size is based on the proportion of patients who have achieved at 
least 50% increase from baseline in lymphocytes (total lymphocytes, CD4+, CD8+, Tregs, 
and NK cells) upon treatment with BNT151. Twenty patients are estimated to have >80% 
chance to rule out a proportion of 10% if the true proportion is 40% at a 2-sided 
significance level of 0.05. 
The objective for the trial Part 2A and 2B is to further investigate the safety profile and to 
assess the efficacy of the IMP in different indications in combination with other approved 
anti-cancer agents. The design in Part 2A can either be a safety run-in of 6 patients or a 
short escalation at 2 dose levels according to the 3+3 trial design, therefore the sample 
size in Part 2A will range from 6 to 12 patients per cohort. The sample size in Part 2B may 
be based on either Simon two-stage design or one-stage design. The final sample size 
calculations will be introduced through protocol amendment. 
9.3 
Analysis sets 
Analysis sets are defined in Table 12. 

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Time-to-event-endpoints will be analyzed using Kaplan-Meier methodology by cohort and 
censored in accordance with the FDA Guidance: “Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics” and the EMA guidance “Guideline on the evaluation of 
anti˗cancer medicinal products in man”. Censoring rules will be defined in the SAP.  
The median survival time (including 95% confidence limits according to Brookmeyer and 
Crowley (1982) and the first and third quartile will be presented for each cohort. Survival 
rates (including two-sided 95% confidence interval based on Greenwood's formula) as well 
as the number and percentage of patients with events, censored and under risk will be 
displayed for selected time points (e.g., at 3, 6, 12 months). 
The time-to-event analysis will be illustrated using Kaplan-Meier plots. 
Baseline is defined as last available value prior to first dose of IMP. 
Data up to and including the clinical cut-off date for the statistical analysis will be taken into 
account for the statistical analysis. 
9.4.2 
Primary endpoints 
Primary endpoints include the occurrence of DLTs within a patient during the DLT 
evaluation period to identify the MTD and/or RP2D, and the occurrence of TEAE as well as 
the occurrence of dose reduction and discontinuation of IMP due to TEAE to assess the 
safety and tolerability of the IMP. The analysis of these endpoints is described in 
Section 9.4.5. 
9.4.3 
Secondary endpoints 
Secondary endpoints include evaluation of anti-tumor activity in terms of ORR, disease 
control rate (DCR), and DOR. 
Objective response rate (ORR) 
ORR is defined as the proportion of patients in whom a CR or partial response (PR) is 
observed as best overall response. Patients not meeting the criteria for CR or PR, 
including those without any post˗baseline tumor assessments, will be considered as non-
responders.  
ORR will be summarized with absolute and relative frequencies along with two-sided 95% 
Clopper-Pearson confidence intervals by cohort using the treated set. Statistical 
hypotheses for expansion cohorts may be introduced by protocol amendment prior to the 
start of Expansion Phase. For Part 2, a sensitivity analysis will be performed using the 
efficacy evaluable set. 
Disease control rate (DCR) 
DCR is defined as the proportion of patients in whom a CR or PR or stable disease (SD) 
(SD assessed at least 6 weeks 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-
baseline 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 cohort. 

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Duration of response (DOR)  
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 has been confirmed will be analyzed for DOR.  
DOR will be analyzed using Kaplan-Meier methodology by cohort. 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. 
9.4.4 
Exploratory endpoints 
Exploratory endpoints include analysis of PK parameters (including but not to be limited to 
AUC, Cmax, Tmax, and t1/2), and changes of peripheral (cytokines or other soluble proteins 
or cell types) and intratumoral biomarkers (immune cells, or tumor signatures) that might 
act as PD, anti-tumor, and safety indicators. 
The analysis of these exploratory endpoints including PFS and OS will be described in the 
SAP. 
9.4.5 
Safety analyses 
All safety analyses will be made on the safety set. 
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. 
A TEAE is defined as any AE with an onset date on or after the first administration of IMP 
(if the AE was absent before the first administration of IMP) or worsened after the first 
administration of IMP (if the AE was present before the first administration of IMP). AEs 
with an onset date more than 60 days after the last administration of IMP will be 
considered as treatment emergent only if assessed as related to IMP by the investigator. 
TEAEs will be summarized overall and by cohort.  
The number and percentage of patients reporting at least one AE will be summarized by 
PT nested within SOC for each of the following AE types:  
• 
Any AE  
• 
Related AE  
• 
Grade ≥3 AE  
• 
Related Grade ≥3 AE  
• 
Any SAE  
• 
Related SAE  
• 
SAE leading to death  
• 
AE leading to dose reduction  

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• 
AE leading to permanent discontinuation of treatment  
• 
DLT  
Moreover, the number and percentage of patients with any AE will be summarized by 
worst NCI CTCAE Grade by PT nested within SOC.  
DLTs will be presented in terms of listings presenting the reported term and MedDRA® PT 
and SOC, its time of onset, duration, and outcome, relationship, NCI CTCAE grade, and 
seriousness including dose exposure data. 
9.4.6 
Other analyses 
Other analyses will be described in the SAP. 
9.5 
Interim analyses 
No formal interim analysis is planned. However, data will be reviewed after each cohort. 
The main analysis of the trial will be performed based on all available data from a clinical 
data cut-off that will occur when all patients have been followed up for at least 6 months of 
treatment or discontinued before.  
A final analysis will be performed when the last patient has discontinued from the trial. 
9.6 
Data Monitoring Committee 
A DMC is not planned. An SRC is planned, for details see Section 10.1.5. 
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, Good clinical practice (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, will be 
submitted to the relevant regulatory authorities as required by applicable regulations. If 
required, approval for conducting the trial will be obtained from regulatory authorities in 
accordance with relevant regulatory requirements.  

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The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
hazard to trial patients. 
The investigator will be responsible for the following: 
• 
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 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 deemed 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 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 medical record must include a statement that written informed consent was obtained 
using an ICF before the patient was enrolled in the trial and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
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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 re-screened (see Section 5.4) must sign and date a new ICF.  
A separate Biomarker Cohort ICF will also include genetics that will need to be signed and 
dated by consenting patients. 
10.1.3.1 
Withdrawal from the use of biomarker samples 
The patient may withdraw their consent for future use of research samples at any time. To 
initiate the sample destruction process, the investigator must notify the sponsor of 
withdrawal of consent for the research samples and to request sample destruction. The 
sponsor will then initiate the process for sample destruction. If requested, the investigator 
will receive written confirmation from the sponsor that the samples have been destroyed. If 
the patient withdraws consent for research samples, the sponsor may retain and continue 
to use any data from samples already analyzed before such a withdrawal of consent. 
Samples will be destroyed after they are no longer needed for the clinical trial (up to five 
years following reporting of trial results), or as per local standards, whichever comes first. 
Samples for future exploratory research will be shipped to the sponsor and will be stored 
for up to 15 years (or according to local regulations) following the patient’s last visit.  
10.1.4 
Data protection 
All data collected and processing during this trial will be performed in accordance with the 
applicable data protection requirements. 
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 
Committees structure – SRC 
An SRC, composed of the investigators and the sponsor’s representatives will assess the 
cumulative safety data (e.g., SAEs, AEs, laboratory data and DLTs where applicable) 
collected during the trial to help ensure patient’s safety.  

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The SRC will make recommendations for the adaptive trial design as well as for the 
recommended dose for pre-conditioning if needed and for Parts 2A and 2B and will 
recommend whether to activate the Expansion Phase (Part 2). 
Meetings with the SRC will take place at the time points outlined in the SRC Charter. 
If a toxic dose is reached, the medical monitor will e-mail the investigators and site staff to 
inform them that recruitment has been suspended pending review by the SRC. If the 
e-mail is not acknowledged, the site will be telephoned until contact with the appropriate 
site staff is made. Investigators and site staff who do not attend SRC meetings will be 
provided with an e-mail update of all SRC decisions within 24 hours of each meeting. 
10.1.6 
Dissemination of clinical trial data 
All information concerning the product as well as any information such as clinical 
indications for the IMP, its formula, methods of manufacture and other scientific data 
relating to it, that have been provided by the sponsor or designee, and are unpublished, 
are confidential, and must remain the sole property of the sponsor. The investigator will 
agree to use the information only for the purposes of carrying out this trial and for no other 
purpose unless prior written permission from the sponsor is obtained. The sponsor has full 
ownership of the eCRFs completed as part of the trial. 
10.1.7 
Data quality assurance 
Pseudonymized patient data obtained during the trial as a result of the trial procedures, as 
well as relevant data from the medical history of the patient, findings as they occur, and 
other relevant data must be reported to the sponsor by the investigator. Data must be 
reported in the eCRF or other media approved by the sponsor. 
Different eCRF accounts are available for investigator site staff and other users (e.g., 
clinical research associates [CRAs], data managers, etc.). Roles and rights of the site 
personnel responsible for entering the clinical data into the eCRF or approving them will be 
defined in advance and documented on the delegation form. All data must be entered in 
English. 
The site team and other users will be trained on the eCRF. Completion of the training to be 
performed by each individual is to be documented appropriately and only afterwards the 
individual account valid for the trial-specific database is received. eCRF completion 
guidelines should be provided to the investigator sites. 
During the trial, all data will be reported in pseudonymized form and will be identified by 
the assigned patient identification code. The investigator site will keep a patient 
identification code list, which is only available to the investigator site staff. The eCRFs 
must be completed, and electronically approved, by the investigator or sub-investigator in 
a timely manner after the patient visits. Corrections and clarification requested by the CRA, 
the Data Manager or other qualified people should be resolved/answered in an adequate 
time period. This will be audit˗trailed by the eCRF system, meaning that the name of the 
person who entered/updated data, and date/time are captured. The investigator must keep 
the eCRFs in good order and up˗to˗date so that they always reflect the latest observations 
on the patients enrolled in the trial. 

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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 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Clinical Monitoring Plan. 
The sponsor assumes accountability for actions delegated to other patients (e.g., Contract 
Research Organizations). 
Trial monitors will perform ongoing source data verification (SDV) to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of patients are being protected; and that 
the trial is being conducted in accordance with the currently approved protocol and any 
other trial agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must 
be archived by the investigator and the sponsor for a duration in accordance with the 
national law, but not less than 15 years after trial completion unless local regulations or 
institutional policies require a longer retention period. The content of the clinical trial 
master file must be archived for at least 25 years after the end of the clinical trial. 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 
The CRA will compare source data (original or certified copy) documents to data entered 
in the eCRF. For this trial, 100% SDV will be performed. 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. 
Source documents are original documents, data and records (e.g., hospital records, 
laboratory notes, evaluation checklist, pharmacy dispense records, drug accountability 
logs per patient, and recorded data from automated instruments, CT and MRI results, and 
discharge letters). 
10.1.9 
Trial and site start and closure 
The trial start date is the date on which the clinical trial will be open for recruitment of 
patients. The first act of recruitment is considered as the trial start date. 

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The sponsor 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 CRO(s) used in the trial of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 
10.1.10 
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 before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• 
Authorship will be determined by mutual agreement and in line with BioNTech’s 
publication policy, which follows the International Committee of Medical Journal 
Editors authorship requirements. 
The sponsor or designee will prepare a final report on the trial. The investigator’s right to 
publish or present any information on the trial, and publication procedures to be followed, 
will be defined in the investigator site agreement. 
10.1.11 
Protocol preparation and approval 
This protocol has been prepared, reviewed and approved, including wet ink sign-off by the 
sponsor’s responsible person, in accordance with the sponsor’s standard operating 
procedures (SOP). Documentation of this process is filed in the trial master file (TMF). 

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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. However, specific symptoms at time of progression that are considered that may 
be caused by other reason, and fatal cases where other reason rather than the PD may 
not be discarded will 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. 
Disease-Related Events and/or Disease-Related Outcomes not Qualifying as AEs or SAEs 
are further specified in Section 8.3.7. 
10.3.1.3 
Treatment emergent adverse events (TEAE) 
A TEAE is defined as any AE with an onset date on or after the first administration of IMP 
(if the AE was absent before the first administration of IMP) or worsened after the first 
administration of IMP (if the AE was present before the first administration of IMP). AEs 
with an onset date more than 60 days after the last administration of IMP will be 
considered as treatment emergent only if assessed as related to IMP by the investigator. 
10.3.1.4 
Suspected adverse reaction (suspected AR) 
All untoward and unintended responses to an IMP related to any dose administered. 
• 
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. 
10.3.1.5 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
Is life-threatening 

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− 
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. 
• 
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. 
10.3.1.6 
Suspected unexpected serious adverse reaction (SUSAR) 
All suspected ARs related to an IMP (the tested drugs and comparators) that occur in this 
trial, and that are both unexpected and serious are “suspected unexpected serious 
adverse reaction,” or SUSAR. SUSARs are subject to expedited reporting. 

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10.3.1.7 
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 10.3.1.8 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 immediately (i.e., no more than 
24 hours after learning of the event; see Section 10.3.1.12 for reporting instructions). 
10.3.1.8 
Recording and follow-up of AEs and/or SAEs 
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 (from signing of ICF until 60 days 
after the patient receives the last dose of BNT151). 
• 
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 performed during the visit. The 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 
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 CTCAE v5.0 
− 
Seriousness 
− 
Outcome 
− 
Causal relationship of the AE to the trial treatment 
− 
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 

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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 CTCAE v5.0 should be classified according to the 
investigator’s discretion as close as possible to 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: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. An event that is easily tolerated by the patient, 
causing minimal discomfort and not interfering with everyday activities. 
• 
Grade 2 - Moderate: Minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).  
• 
Grade 3 - Severe: Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting of self-care ADL. An AE that is assessed as severe should not be confused 
with a SAE. Severe is a category utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. 
• 
Grade 4 - Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 - Death related to AE. 
With regards the intensity of an AE the following needs to be documented 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 
CTCAE 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 drug (IMPs) by the investigator can be: 

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• 
Dose not changed (= continuation of IMP administration according to the trial 
protocol) 
• 
Dose reduced (= reduction of the trial treatment dosage *) 
• 
Trial treatment withdrawn temporarily (= interruption and resumption), i.e.: 
− 
Delayed administration of IMP within one vaccination cycle 
− 
Delayed start of the next vaccination cycle 
− 
Cancellation of administration at a given visit 
− 
Interruption of IMP administration during a given visit  
• 
Trial treatment permanently withdrawn (= discontinuation) 
• 
Unknown (e.g., in case the patient is lost to follow-up) 
• 
Not applicable (e.g., in case treatment with IMP has not yet started or event starts 
after last IMP administration) 
*Note: If an increase of trial treatment dosage is intended according to the trial protocol 
and the dosage is kept in comparison to last administration of trial treatment, it needs to be 
documented as “Dose reduced.” 
Other action(s) that may be taken by the investigator include: 
• 
None 
• 
Initiation of a concomitant drug therapy for the treatment of the AE 
• 
Termination of a concomitant drug therapy (please specify; e.g., if this might be the 
cause of the AE) 
• 
Change of the dose of a concomitant medication 
• 
Initiation/termination of a non-drug therapy 
• 
Other (please specify) 
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) 

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* 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. 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 to a trial treatment will be made by the 
investigator after having evaluated all accessible data and, if necessary, he/she will re-
evaluate the case as new information becomes available.  
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 
IMPs itself should be documented as suspected ARs but not events caused by the 
procedure of trial treatment administration. 
How the investigator should assess the relationship between anti-cancer agents used in 
combination with BNT151 and each occurrence of each AE/SAE will be specified by 
amendment. 
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 AEs can occur on the site of injection of the trial treatment e.g., 

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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 Adverse 
Event 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. 
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. 
10.3.1.9 
SAE 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 10.3.1.5). 
In the present trial, some events are excluded from the SAE definition given in 
Section 10.3.1.5. The following events do not need to be reported as SAEs: 
• 
AEs and SAEs occurring later than 60 days after the last dose of trial treatment 
must only be reported by the investigator to the sponsor if a relationship to trial 
drug 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 drug administration 
or insertion of access device for trial drug administration) will not be considered as 
reportable SAE. 
• 
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. 
− 
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. 

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• 
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 are considered that may be caused by other reason, and fatal 
cases where other reason rather than the PD may not be discarded will have to be 
documented as AEs and reported as SAEs if applicable.  
• 
Routine treatment or monitoring of the underlying disease not associated with any 
deterioration in the patient’s condition. 
10.3.1.10 
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 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: 
For definition and treatment of overdose, please refer to Section 8.4. 
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 the eCRF and reported as SAE if applicable.  

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10.3.1.11 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a patient dies during participation in the trial or during a recognized follow-up 
period, the investigator will provide the sponsor (contacts given in 
Section 10.3.1.12) 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 contacts given in 
Section 10.3.1.12 within 24 hours of receipt of the information. 
10.3.1.12 
Reporting of SAEs 
All SAEs which occur in a patient during the observation period (defined in 
Section 10.3.1.5), whether considered to be associated with trial medication or not, must 
be reported by the investigator to the sponsor within 24 hours following knowledge of 
the event.  
All SAEs occurring after the end of the period of observation only have to be reported to 
the sponsor if the investigator suspects a relationship to trial medication or procedure. 
SAE reporting to 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 

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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 
Investigator’s site file (ISF). 
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. 
10.4 
Contraceptive guidance and collection of pregnancy 
information 
Definition of reproductive potential and measures of contraception for BNT151 are detailed 
below. Further guidance for other trial treatment agents should be according to the 
authorized product information (for approved concomitant medications). 
10.4.1 
Female patients 
In this trial, patients are considered to have reproductive potential, UNLESS they are 
post-menopausal or permanently sterile:  
• 
A postmenopausal state is defined as no menses, in patients >45 years of age, for 
12 months without an alternative medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in patients not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
• 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. 
All female patients must agree not to donate eggs (ova, oocytes) for the purpose of 
assisted reproduction during the trial and for 6 months after receiving the last dose of 
BNT151. 
Female patients of reproductive potential must agree to use adequate contraception during 
and for 6 months after the last BNT151 administration. Adequate contraception is defined 
as highly effective methods of contraception (Table 14). Birth control methods are 
considered highly effective if they have a failure rate of less than 1% per year, when used 
consistently and correctly. 
 

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Table 14: 
Highly effective methods of contraception 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation 1 (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 device 2 
• 
Intrauterine hormone-releasing system 2 
• 
Bilateral tubal occlusion 2 
• 
Vasectomized partner 2, 3 
• 
Sexual abstinence 4 
1 
Hormonal contraception may be susceptible to interaction with BNT151, which may reduce the efficacy of the 
contraception method. Therefore, hormonal contraception method alone is not considered as a highly effective 
method of contraception. Hormonal contraception should be combined with a barrier method or/and an 
intrauterine device to be a highly effective method of contraception. 
2 
Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 
Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
woman of child-bearing potential (trial patient) and that the vasectomized partner has received medical assessment 
of the surgical success. 
4 
In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the trial treatments. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient. 
Table adapted from ‘Recommendations related to contraception and pregnancy testing in clinical trials. Advisory non-
binding guidance represented at the Clinical Trial Facilitation Group (CTFG)-meeting in Rome 2014’ (CTFG 2014). 
 
10.4.2 
Male patients 
1. Recommendations for male patients with pregnant partner: 
Male contraception (condom) is recommended in order to avoid exposure of an 
existing embryo/fetus. Contraception should be continued for 6 months after receiving 
the last dose of BNT151. 
2. Recommendations for male patients with non-pregnant WOCBP partner: 
The male patient should use condom during treatment and for 6 months after receiving 
the last dose of BNT151. For a non-pregnant WOCBP partner, contraception 
recommendations should also be considered. 
All men must also not donate sperm during the trial and for 6 months after receiving the 
last dose of BNT151. 
10.4.3 
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 
treatment and until 90 days after the last dose for pregnant patients (or until 28 days after 
the last dosing of the male patient for pregnant female partners). 

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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 learning of a patient’s 
pregnancy/partner’s pregnancy. The completed form needs to be sent to the sponsor 
using either the Safety Report Fax number: 
 or the e-mail 
address:
 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 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 
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 IMP. 
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 treatment 
by the investigator will be reported to the sponsor. 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 
See Section 8.7. 
10.6 
Liver safety: Suggested actions and follow-up assessments 
Potential cases of drug induced liver injury (DILI) 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations 
in transaminases) are termed “tolerators”, while those who show transient liver injury, but 
adapt are termed “adaptors”. In some cases, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. Patients 
who experience a transaminase elevation above 3 × ULN should be monitored more 
frequently to determine if they are an “adaptor” or are “susceptible.” 
LFTs are not required as a routine safety monitoring procedure for all participants in this 
trial. However, should an investigator deem it necessary to assess LFTs because a 
participant present with clinical signs/symptoms, such LFT results should be managed and 
followed as described below. 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (i.e., AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential 

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DILI. Therefore, abnormal elevations in either AST or ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
patient’s individual baseline values and underlying conditions. Patients who present with 
the following laboratory abnormalities should be evaluated further as potential DILI (Hy’s 
law) cases to definitively determine the etiology of the abnormal laboratory values: 
Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST or ALT values >3 × ULN AND a TBili value >2 × ULN with 
no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not available. 
For patients with baseline AST or ALT or TBili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline: 
Preexisting AST or ALT baseline values above the normal range: AST or ALT values >2 
times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller). 
Preexisting values of TBili above the normal range: TBili level increased from baseline 
value by an amount of at least 1 × ULN or if the value reaches >3 × ULN (whichever is 
smaller). 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether 
it represents a potential Hy’s law case should be reviewed with the sponsor.  
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 h from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin (PT)/INR, total bile 
acids, and alkaline phosphatase. Consideration should also be given to drawing a 
separate tube of clotted blood and an anticoagulated tube of blood for further testing, as 
needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a co-formulated 
product in prescription or over the counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of 
contact with a jaundiced person, surgery, blood transfusion, history of liver or allergic 
disease, and potential occupational exposure to chemicals, should be collected. Further 
testing for acute hepatitis A, B, C, D, and E infection and liver imaging (e.g., biliary tract) 
and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT 
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no other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s 
law) cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 
10.7 
Investigators and trial administrative structure 
10.7.1 
Investigators and trial site personnel 
There must be an investigator at each trial site.  
Note: Country-specific criteria for Germany: There must be an investigator and deputy to 
the 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 
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 CROs must be maintained according to GCP and applicable 
regulatory requirements. This includes documentation of any delegation of responsibilities 
to CROs. 

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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. For information regarding country-specific 
requirements, refer to Appendix 2: Country-specific information. 
10.9 
Other standard abbreviations and definitions 
For trial-specific abbreviations, see the list of trial-specific abbreviations. 
For definitions related to safety, see Section 10.3. 
 
Abbreviation 
Explanation 
AE 
Adverse Event 
CRA 
Clinical research associate 
CRO 
Clinical research organization 
CTP 
Clinical trial protocol 
GCP 
Good Clinical Practice 
h 
Hour(s) 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization (of technical requirements for registration 
of pharmaceuticals for human use) 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
ISF 
Investigator’s site file 
MedDRA® 
Medical Dictionary for Regulatory Activities 
min 
Minute(s) 
ms 
Millisecond 
PT 
Preferred Term 
SAE 
Serious adverse event 
SoA 
Schedule of activities 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reaction 

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appropriate. Additional reviews by the qualified team (e.g., medical review, SAE 
reconciliation, etc.) may also lead to queries. All discrepancies and queries need to be 
resolved prior to database lock. 
Data Coding 
In order to code medical conditions, AEs and non-drug therapies, the MedDRA® will be 
used throughout the trial.  
In order to code medications, the World Health Organization Drug Dictionary (WHO-DD) 
will be used with product group/level codes assigned according to the anatomical, 
therapeutic and chemical classification system. 
At least before database lock, MedDRA® and WHO-DD will be updated to the most recent 
version and coding will be re-checked, reviewed, and approved by the sponsor 
representative. 
Database Lock 
Prerequisite for database lock is that all required data are entered in the eCRF, queries 
are addressed and closed appropriately, all terms are coded, all external data is 
imported/reconciled, pages are verified/re-verified, and upon resolution of all issues, 
principal investigator signoff/approval of eCRF pages is obtained. 
10.11.3 
Investigator’s Site File (ISF) and the Trial Master File (TMF) 
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/investigational site’s policy, but at least until informed by the sponsor that 
the trial-related records are no longer required. 
11 
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12 
APPENDICES 
12.1 
Appendix 1: Response evaluation criteria in solid tumors 
version 1.1 (RECIST 1.1) 
Evaluation of target lesions 
Complete response 
• 
Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm (the sum may not be 
“0” if there are target nodes). 
Partial response 
• 
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive disease 
• 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on trial (this includes the baseline sum if that is the 
smallest on trial). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression.) 
Stable disease 
• 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum of diameters while on 
trial. 
Evaluation of non-target lesions 
Complete response 
• 
Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-complete response/non-progressive disease 
• 
Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
Progressive disease 
• 
Unequivocal progression of existing non-target lesions will be defined as the 
overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy (see Section 7.1). In the absence of 
measurable disease, change in non-measurable disease comparable in magnitude 
to the increase that would be required to declare progressive disease for 

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measurable disease. Examples include an increase in a pleural effusion from 
‘trace’ to ‘large,’ an increase in lymphangitic disease from localized to widespread. 
Appearance of new lesions 
The appearance of new lesions is considered progressive disease according to 
RECIST 1.1. Considering the unique response kinetics that have been observed with 
immunotherapy, new lesions may not represent true disease progression. In the absence 
of rapid clinical deterioration, patients may continue to receive IMP therapy if investigators 
consider that patients continue to benefit from treatment. 
Evaluation of overall response 
For the overall response based on RECIST 1.1, confirmation of CR and PR is required by 
a repeat, consecutive assessment no less than 4 weeks from the date of first 
documentation. A confirmatory scan will also be required after an initial assessment of 
progressive disease for the purpose of managing treatment. If a patient discontinues the 
trial due to progressive disease and begins another treatment, a confirmatory scan is not 
required. If the next protocol-scheduled scan is due within 2 weeks after the confirmatory 
scan was obtained, the protocol-scheduled scan does not need to be done. Treatment of 
patients may continue between the initial assessment of progressive disease and 
confirmation of progressive disease (which is not required by RECIST 1.1). These patients 
may continue to receive trial therapy beyond confirmed progressive disease if investigators 
consider that patients continue to receive benefit from treatment. In the absence of clinical 
deterioration, such modifications to the RECIST may discourage the early discontinuation 
of treatment and provide a more complete evaluation of trial therapy anti-tumor activity 
than would be seen with conventional response criteria. 
Table 15 provides overall responses for all possible combinations of tumor responses in 
target and non-target lesions with or without the appearance of new lesions. 
 

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individual patient’s situation. In any given situation, all measures must be taken by the trial 
physicians to ensure the optimal clinical management is delivered to the patients based on 
the diagnosis. 
For assessment, reporting and analysis of CRS in connection with this trial, all events will 
be graded according to NCI CTCAE v5.0 as shown in Table 16. 
 
Table 16: 
CRS grading per NCI CTCAE v5.0 
CRS is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused 
by the release of cytokines. 
CRS = cytokine release syndrome; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; FiO2 = fraction of inspired oxygen. 
 
For treatment recommendations for the management of CRS, the following guidelines are 
adapted based on the American Society for Transplantation and Cellular Therapy (ASTCT) 
Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated 
with Immune Effector Cells. The CRS consensus grading of ASTCT (previously known as 
American Society for Bone Marrow Transplant) is given in Table 17 (Lee et al. 2019). 
 
Table 17: 
American Society for Transplantation and Cellular Therapy CRS consensus grading 
CRS parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever 1 
Temperature 
≥38°C 
Temperature 
≥38°C 
Temperature 
≥38°C 
Temperature 
≥38°C 
with 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring 
vasopressor with 
or without 
vasopressin 
Requiring 
vasopressors 
(excluding 
vasopressin) 
and/or 2 
Hypoxia 
None 
Requiring 
lowflow- nasal 
cannula 3 or blow-
by 
Requiring high-
flow nasal cannula, 
facemask, 
nonrebreather 
mask, or Venturi 
mask 
Requiring positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
1 
Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
Grading 
system 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
NCI CTCAE 
version 5.0 
Fever, with or 
without 
constitutional 
symptoms 
Hypotension 
responding to 
fluids. Hypoxia 
responding to 
<40% FiO2 
Hypotension 
managed with 
one pressor. 
Hypoxia 
requiring ≥40% 
FiO2 
Life-threatening 
consequences; 
urgent 
intervention 
needed 
Death 

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2 
CRS grade is determined by the more severe event: Hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring low-
flow nasal cannula is classified as Grade 3 CRS. 
3 
Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low-flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release 
syndrome. 
 
Organ toxicities associated with CRS may be graded according to NCI CTCAE v5.0 but 
they do not influence CRS grading. 
For the management of CRS, the following guidelines should apply (Table 18):  
 
Table 18: 
Guidelines for management of cytokine release syndrome 
ASTCT CRS Grade 
Management 
Grade 1 
• 
Antipyretics and IV hydration 
• 
Diagnostic work-up to rule out infection 
• 
Consider growth factors and antibiotics if neutropenic 
Grade 2 
• 
Supportive care as in Grade 1 
• 
IV fluid boluses and/or supplemental oxygen 
• 
Tocilizumab +/- dexamethasone or its equivalent of methylprednisolone 
Grade 3 
• 
Supportive care as in Grade 1 
• 
Consider monitoring in ICU 
• 
Vasopressor support and/or supplemental oxygen 
• 
Tocilizumab + dexamethasone 10-20 mg IV q6h or its equivalent of 
methylprednisolone 
Grade 4 
• 
Supportive care as in Grade 1 
• 
Monitoring in ICU 
• 
Vasopressor support and/or supplemental oxygen via positive pressure 
ventilation 
• 
Tocilizumab + methylprednisolone 1000 mg/d 
ASTCT = American Society for Transplantation and Cellular Therapy (previously known as: ASBMT, American Society 
for Bone Marrow Transplant); CRS = cytokine release syndrome; ICU = intensive care unit; IV = intravenous; q6h = every 
6 hours. 
Source: Neelapu 2019. 
 
12.4 
Appendix 4: Risk-benefit assessment of COVID-19 vaccination 
in BNT151-01 trial 
BNT151 is a single stranded, pharmacologically optimized, 5′-capped messenger RNA 
coding for an IL-2/serum albumin fusion construct. IL-2 is a key cytokine in T-cell 
homeostasis and pivotal for the differentiation, proliferation, survival and effector functions 
of T cells (Bamford et al. 1994, Blattman et al. 2003, Gillis and Smith 1977, Kamimura and 
Bevan 2007). BNT151 may also stimulate other cells of the immune system (e.g., NK 
cells). Clinically, due to its mechanism of action, chills, fever, malaise and all other flu-like 

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symptoms may be the first and most commonly seen adverse reactions in patients treated 
with BNT151. 
At this time, there are three COVID-19 vaccines authorized and recommended in the 
United States: The Pfizer-BioNTech, Moderna, and Johnson & Johnson/Janssen vaccines. 
These vaccines are described on the US centers for disease control and prevention 
(CDC)’s vaccine page. In the EU, the same vaccines are authorized and recommended 
with the addition of the COVID-19 vaccine by AstraZeneca. The Pfizer-BioNTech and 
Moderna vaccines are mRNA vaccines, whereas both Johnson & Johnson/Janssen and 
AstraZeneca are viral vector vaccines. None of the vaccines are a live virus vaccine 
mentioned by the protocol as per exclusion criterion 2 (i.e., received any live vaccine within 
4 weeks of the start of trial treatment). 
The COVID-19 pandemic is an ongoing pandemic with different stages and impacts at any 
one time across the whole world. The governments of the countries involved in this trial 
have started a nationwide vaccination program including vaccination for oncology patients. 
All prominent regulatory, government and professional bodies have recommended for 
COVID-19 vaccination even in oncology patients under active treatment. As to this date, 
there is no clear or specific guidance for patients enrolled in interventional oncology clinical 
trials and should be taken as per case-by-case basis. 
Recently results of short-term safety of the Pfizer-BioNTech mRNA COVID-19 vaccine in 
oncology patients treated with immune checkpoint inhibitors were published (Waissengrin 
et al. 2021). Considering the high mortality due to COVID-19 in patients with cancer who 
are being treated, data supports current guidelines and call for vaccination of patients 
being treated with immune checkpoint inhibitors, especially during pandemic surges. 
The interaction of BNT151 with all the vaccines approved in the US and EU are not known. 
It is unlikely that there will be any data of IL-2 in combination with any of the COVID-19 
vaccines. However, the sponsor assesses the risk of significant side effects of BNT151 in 
combination with COVID-19 vaccine to be low. National Comprehensive Cancer Network 
(NCCN) and American Society of Clinical Oncology (ASCO) recommend for the COVID-19 
vaccine to be administered on the same day as oncology therapy, including 
immunotherapy. However, since BNT151 is still under development in Phase 1 trial without 
comprehensive clinical data, the protocol would recommend at least a few days of interval 
between COVID-19 vaccine and administration of BNT151 as a precaution. The COVID-19 
vaccine Comirnaty results in high antigen expression for around 72 h which then 
decreases to low levels after approximately one week (EMA assessment report 2020). If 
administered within the timeframe of high COVID-19 antigen expression, BNT151 is 
anticipated to strongly boost COVID-19 vaccine induced T-cell responses. On one hand 
this can result in an improved efficacy of the vaccine but on the other hand could also lead 
to an increased reactogenicity as well as to reduced expansion of tumor antigen specific 
T cells due to T-cell competition. For this reason, we would recommend at least a 7-day 
interval between BNT151 treatment and COVID-19 vaccination. 
However, a longer interval may be necessary during the DLT observation period, because 
the dose of BNT151 has not yet been declared safe as per the trial design. The oncologist 
should always assess the situation on an individual basis and discuss with the sponsor. 
Considering the high morbidity and mortality from COVID-19 in patients with cancer, the 

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benefits of vaccination are likely to far outweigh the risks of vaccine-related AEs in patients 
enrolled in clinical trials (Desai et al. 2021). 
12.5 
Appendix 5: COVID-19 vaccination in BNT151-01 trial during 
the pandemic 
BioNTech as the sponsor of the BNT151-01 trial recommends that patients and their 
physicians discuss on an individual basis the risks and benefits of COVID-19 vaccination 
in the context of the BioNTech oncology trials, considering also guidelines from the FDA, 
EMA, CDC, ASCO, European Society for Medical Oncology (ESMO) and local agencies. 
Taking this into account, COVID-19 vaccination may be performed with the following 
recommendations:  
• 
Patients with prior COVID-19 vaccination may be allowed to enter the trial with a 
wash-out period of at least 7 days since the last COVID-19 vaccine dose. 
• 
For patients already enrolled in the clinical trial and still receiving trial treatment, 
COVID-19 vaccination may be allowed if at least 7 days between individual dose of 
COVID19 vaccine and trial treatment dose are ensured. 
• 
COVID-19 vaccination during DLT evaluation period in the dose escalation parts of 
the trial should be avoided to prevent any confounding effect of the vaccination on 
the DLT evaluation. However, as the data in dose escalation are accumulating, the 
decision to vaccinate should be made by the treating oncologist, and any decision 
should be discussed with the sponsor’s Medical Monitor. 
• 
Administration of COVID-19 vaccine during participation in BNT151-01 trial should 
be documented as a concomitant medication. 
• 
Previous administration of COVID-19 vaccine should be documented on the prior 
and concomitant medication form. Past confirmed infection of COVID-19 by 
reverse transcription polymerase chain reaction (RT-PCR) before enrolment in the 
BNT151-01 trial should be documented in the medical history.