Clinical trial NCT04683939
Conditions: Solid Tumor Gastric Cancer Gastroesophageal Junction Adenocarcinoma Esophageal Adenocarcinoma Pancreatic Cancer Biliary Tract Cancer Cholangiocarcinoma Metastatic Cancer
Keywords: CLDN18.2-positive solid tumors Gastric cancer Gastric adenocarcinoma Gastroesophageal junction adenocarcinoma Esophageal adenocarcinoma Esophageal cancer Pancreatic cancer Pancreatic ductal adenocarcinoma Biliary tract cancers Cholangiocarcinoma Mucinous ovarian cancers Metastatic Treatment Therapy Targeted immunotherapy Metastatic cancer Ribomab CLDN18.2-positive tumors Biomarker Precision medicine Precision oncology Solid tumors mRNA
Sponsor: BioNTech SE
Start date: 2022-01-18; Completion date: 2023-07-24
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study was planned as an open-label, multi-site, Phase I/IIa dose escalation, safety, and pharmacokinetic (PK) trial of BNT141 followed by expansion cohorts in patients with Claudin 18.2 (CLDN18.2)-positive tumors.

The sponsor decided to stop the development of BNT141 on 24 July 2023 and the study was terminated early.

Detailed description:
The study design consisted of three parts:

* Part 1A was a dose escalation of BNT141 as monotherapy in patients with advanced unresectable or metastatic CLDN18.2-positive solid tumors for which there was no available standard therapy considered to confer clinical benefit, or the patient was not a candidate for such available therapy. The dose of BNT141 was planned to be escalated until the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BNT141 as monotherapy was defined. However, due to the early study termination, the dose of BNT141 was not fully escalated as planned per protocol (i.e., only four doses were tested, i.e., 0.15 mg/kg, 0.30 mg/kg, 0.45 mg/kg, and 0.60 mg/kg). Once the MTD was reached, up to 10 additional patients with CLDN18.2 expressing pancreatic and biliary tract cancers were planned to be enrolled at the MTD level to obtain additional data on safety, PK and pharmacodynamics (PD). Eligible tumor types were gastric cancer, gastroesophageal junction (GEJ) and esophageal adenocarcinoma, pancreatic, biliary tract (cholangiocarcinoma and gallbladder cancer), and mucinous ovarian cancers. Additionally, patients with specific tumors (including colorectal cancer, non-small-cell lung cancer, gastric subtype of endocervical adenocarcinoma) where there is scientific evidence that the CLDN18.2 could be elevated could be tested for CLDN18.2 expression.
* Part 1B was planned to be a dose escalation of BNT141 in combination with nab-paclitaxel and gemcitabine in patients with locally advanced unresectable or metastatic CLDN18.2-positive pancreatic adenocarcinoma or cholangiocarcinoma who were eligible for treatment with nab-paclitaxel and gemcitabine. Part 1B intended to define the MTD and/or RP2D of the combination. Once the MTD was reached, up to 10 additional patients with CLDN18.2-expressing pancreatic adenocarcinoma or cholangiocarcinoma were planned to be enrolled at the MTD level to obtain additional data on safety, PK and PD. The MTD of BNT141 in combination with nab-paclitaxel and gemcitabine in Part 1B was planned to not exceed the monotherapy BNT141 MTD determined in Part 1A.
* Part 2 (Expansion) was planned to consist of two predefined expansion cohorts in patients with CLDN18.2-positive solid tumors eligible for treatment with nab-paclitaxel and gemcitabine.

Part 1B and Part 2 did not proceed and no participant was enrolled in Part 1B and Part 2.

Arms: arm 1: Administration once every three weeks (Q3W) arm 2: BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle. arm 3: BNT141 in combination with nab-paclitaxel and gemcitabine
Interventions: intervention 1: BNT141 intervention 2: Nab-paclitaxel intervention 3: Gemcitabine
Intervention descriptions: intervention 1: Intravenous (IV) intervention 2: IV intervention 3: IV

Protocol documents:
Prot_002.pdf: 
 
 
 
Page 1 of 122 
 
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 proprietors. 
CLINICAL TRIAL PROTOCOL 
BNT141-01 
 
Version: 
4.0 
Date: 
13 JUN 2022 
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 BNT141 as a 
monotherapy and in combination with other anti-cancer agents in 
patients with CLDN18.2-positive solid tumors 
Brief title: 
Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy 
trial of BNT141 in patients with unresectable or metastatic CLDN18.2-
positive gastric, pancreatic, ovarian and biliary tract tumors 
Trial phase: 
I/IIa 
Indication: 
CLDN18.2-positive solid tumors 
Product: 
BNT141 
Trial sites: 
Approximately 20 sites in Europe and North America. Additional sites 
may be included during the trial. For details, see the Trial Master File. 
Sponsor’s responsible 
persons: 
Leticia de Mattos Arruda, MD, PhD, Senior Director, Clinical 
Development 
Sponsor: 
BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany 
Clinical Research 
Organization: 
Syneos Health UK Ltd., Farnborough Business Park, 1 Pinehurst Road, 
Farnborough, Hampshire, GU14 7BF, UK 
Regulatory identifiers: 
IND number 27153 
Clinicaltrials.gov identifier NCT04683939 
EudraCT number: 2022-001843-25 
Medical Monitor: 
The sponsor’s Medical Monitor name and contact information will be 
provided separately. 
 
Document history 
Date 
Version number 
Valid for  
First approved version* 
14 DEC 2020 
1.0 
All countries 
Second approved version* 
03 MAR 2021 
2.0 
All countries 
Third approved version* 
06 AUG 2021 
3.0 
All countries 
Fourth approved version* 
13 JUN 2022 
4.0 
All countries 
* Sponsor approved 
 






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gastroesophageal junction (GEJ) and esophageal adenocarcinoma, pancreatic, 
biliary tract (cholangiocarcinoma and gallbladder cancer), and mucinous ovarian 
cancers. Additionally, patients with specific tumors (including colorectal cancer, 
non-small-cell lung cancer, gastric subtype of endocervical adenocarcinoma) where 
there is scientific evidence that the CLDN18.2 could be elevated can be tested for 
CLDN18.2 expression. 
• Part 1B is a dose escalation of BNT141 in combination with nab-paclitaxel and 
gemcitabine in patients with advanced unresectable or metastatic CLDN18.2-
positive pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for 
treatment with nab-paclitaxel and gemcitabine. Part 1B intends to define the MTD 
and/or RP2D of the combination.  
• Part 2 (Expansion) consists of the following pre-defined expansion cohorts: 
− 
CLDN18.2-positive 
 
 eligible for treatment with nab-paclitaxel and gemcitabine.  
− 
CLDN18.2-positive 
 
eligible for treatment with nab-paclitaxel and gemcitabine.  
Part 2 will be further defined via an amendment after careful evaluation of all available 
safety, PK and PD, and efficacy data generated in Parts 1A and 1B by the Safety Review 
Committee (SRC). 
Trial duration 
The trial is considered completed when all patients have had at least 12 months survival 
follow up or are lost to follow up or have withdrawn consent or have died or the sponsor 
discontinues the trial. However, the maximum trial duration is 3 years after the last 
subject’s first treatment in the trial. 
Population 
A maximum of approximately 48 DLT-evaluable patients will be enrolled to trial treatment 
in each of the trial Parts 1A and 1B, depending on the DLTs which may occur. Non-DLT-
evaluable patients will be replaced. Once the MTD is reached, up to 10 additional patients 
with CLDN18.2 expressing pancreatic and biliary tract cancers will be enrolled at the MTD 
level in Part 1A and up to 10 additional patients with CLDN18.2 expressing pancreatic 
adenocarcinoma and cholangiocarcinoma in Part 1B, to obtain additional data on safety, 
PK and PD. The sample size and design in Part 2 will be further determined after careful 
evaluation of all available safety, PK and PD, and efficacy data generated in Parts 1A and 
1B by the SRC and will be further defined via an amendment. 
Key inclusion criteria 
Patients who meet the following inclusion criteria will be eligible for trial entry: 
For all parts: 
• 
Metastatic or unresectable solid tumor. 
• 
Histological or cytological documentation of a solid tumor via a pathology report.  
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BNT141-01 
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• 
CLDN18.2-positive tumor sample defined as moderate-to-strong CLDN18.2 protein 
expression defined as intermediate (2+) to strong (3+) staining intensity in ≥ 50% of 
tumor cells as assessed by central testing using a CLIA-validated 
immunohistochemistry assay in formalin-fixed, paraffin-embedded (FFPE) 
neoplastic tissues. New biopsies and archival bio-samples are allowed. Bone 
biopsies are not allowed. Cytology specimens (including fine needle aspirates) will 
not be accepted for CLDN18.2 examination. If archival tissue samples from several 
points of time are available, the most recent one is preferred. Patients with a lower 
expression level or with CLDN18.2-negative cancers are not eligible. 
Trial part-specific inclusion criteria: 
• 
For Part 1A: Patients with solid tumors, for which there is no available standard 
therapy likely to confer clinical benefit, or the patient is not a candidate for such 
available therapy. Patients must have received all available standard therapies and 
failed at least first-line SOC therapy prior to enrolment. Measurable or evaluable 
disease per RECIST 1.1. Eligible tumor types are gastric cancer, gastroesophageal 
junction (GEJ) and esophageal adenocarcinoma, pancreatic, biliary tract 
(cholangiocarcinoma and gallbladder cancer), and mucinous ovarian cancers. 
Additionally, patients with specific tumors (including colorectal cancer, non-small-
cell lung cancer, gastric subtype of endocervical adenocarcinoma) where there is 
scientific evidence that the CLDN18.2 could be elevated can be tested for 
CLDN18.2 expression. 
• 
For Part 1B: Patients with advanced pancreatic adenocarcinoma or 
cholangiocarcinoma who are eligible for treatment with nab-paclitaxel and 
gemcitabine. Measurable or evaluable disease per RECIST 1.1. 
• 
For Part 2 (Expansion): 
− 
Cohort 1 – 
eligible 
for treatment with nab-paclitaxel and gemcitabine. Measurable disease per 
RECIST 1.1. 
− 
Cohort 2 –
 eligible for treatment 
with nab-paclitaxel and gemcitabine. Measurable disease per RECIST 1.1. 
Key exclusion criteria 
Patients who meet at least one of the following exclusion criteria will not be eligible for trial 
entry: 
• 
Receiving: radiotherapy, chemotherapy, or molecularly-targeted agents within 
3 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 
(excluding BNT141); nitrosoureas, antibody-drug conjugates, or radioactive 
isotopes within 6 weeks of the start of trial treatment. Palliative radiotherapy will be 
allowed. 
• 
Receives concurrent systemic (oral or intravenous [IV]) steroid therapy 
> 10 mg prednisone daily or its equivalent for an underlying condition. 
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Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 6  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
R e pl a c e m e nt t h er a p y ( e. g., t h yr o xi n e, i n s uli n, or p h y si ol o gi c c orti c o st er oi d 
r e pl a c e m e nt t h er a p y f or a dr e n al or pit uit ar y i n s uffi ci e n c y) i s n ot c o n si d er e d a f or m 
of s y st e mi c tr e at m e nt a n d i s p er mitt e d.  
• 
M aj or s ur g er y wit hi n  4  w e e k s b ef or e t h e fir st d o s e of B N T 1 4 1.  
• 
Pri or tr e at m e nt wit h a C L D N 1 8. 2 t ar g eti n g m A b  ot h er t h a n B N T 1 4 1 . 
• 
O n g oi n g or a cti v e i nf e cti o n r e q uiri n g I V tr e at m e nt wit h a nti-i nf e cti v e t h er a p y t h at 
h a s b e e n a d mi ni st er e d l e s s t h a n 2  w e e k s pri or t o t h e fir st d o s e of B N T 1 4 1.  
• 
Si d e eff e ct s of a n y pri or t h er a p y or pr o c e d ur e s f or a n y m e di c al c o n diti o n n ot 
r e c o v er e d t o N ati o n al C a n c er I n stit ute C o m m o n T er mi n ol o g y Crit eri a f or A E s ( N CI -
C T C A E) v. 5 Gr a d e  ≤ 1 , wit h t h e e x c e pti o n of an or e xi a, f ati g u e, h y p ert h yr oi di s m, 
h y p ot h yr oi di s m, a n d p eri p h er al n e ur o p at h y , w hi c h m u st h a v e r e c o v er e d t o 
≤ G r a d e 2. Al o p e ci a of a n y gr a d e i s all o w e d.   
• 
C urr e nt e vi d e n c e of n e w or gr o wi n g br ai n or l e pt o m e ni n g e al m et a st a s e s d uri n g 
s cr e e ni n g. P ati e nt s wit h k n o w n br ai n or l e pt o m e ni n g e al m et a st a s e s m a y b e eli gi bl e 
if t h e y h a v e:  
− R a di ot h er a p y, s ur g er y or st er e ot a cti c s ur g er y f or t h e br ai n or l e pt o m e ni n g e al 
m et a st a s e s.  
− N o n e ur ol o gi c al s y m pt o m s ( e x cl u di n g Gr a d e  ≤ 2 n e ur o p at h y).  
− St a bl e br ai n or l e pt o m e ni n g e al di s e a s e o n t h e c o m p ut er t o m o gr a p h y ( C T) or 
m a g n et r e s o n a n c e i m a gi n g ( M RI) s c a n wit hi n 4  w e e k s b ef or e si g ni n g t h e 
i nf or m e d c o n s e nt f or m (I C F). 
− N ot u n d er g oi n g a c ut e c orti c o st er oi d t h er a p y or st er oi d t a p er.  
Tri al tr e at m e nt s :  
P art  1 A: E a c h tr e at m e nt c y cl e at P art  1 A h a s a d ur ati o n of 3  w e e k s ( 2 1  d ).  
B N T 1 4 1 will b e a d mi ni st er e d I V o n c e e v er y t hr e e  w e e k s ( Q 3 W) at ei g ht m ai n d o s e l e v el s: 
0. 1 5, 0. 3, 0. 6
m g/ k g.   
P art  1 B: E a c h tr e at m e nt c y cl e i n P art  1 B h a s a d ur ati o n of 4  w e e k s ( 2 8  d ). 
B N T 1 4 1 will b e a d mi ni st er e d I V 
 of t h e fir st 2 8 -d a y c y cl e a n d Q 3 W 
t h er e aft er. T h e B N T 1 4 1 st arti n g d o s e l e v el will b e d et er mi n e d i n t h e P art  1 A  m o n ot h er a p y  
d o s e e s c al ati o n  a n d will b e s u b s e q u e ntl y e s c al at e d t o t h e M T D .  
N a b -p a clit a x el will b e a d mi ni st er e d I V o n 
 of e a c h 2 8 -d a y c y cl e at a d o s e 
of 
.  
G e m cit a bi n e will b e a d mi ni st er e d I V o n 
 of e a c h 2 8 -d a y c y cl e at a d o s e of 
. 
St ati sti c s : F or P art s  1 A a n d 1 B, t h e M T D a s m o n ot h er a p y  a n d i n c o m bi n ati o n wit h n a b -
p a clit a x el/ g e m cit a bi n e r e s p e cti v el y will b e d et er mi n e d u si n g a 3 + 3 d e si g n.  
C CI
C CI
C CI
C CI
C CI
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The Part 2 expansion cohort will be conducted in 
 types. The sample size and 
design in Part 2 will be further determined based on careful evaluation of all available 
safety, PK and PD, and efficacy data generated in Parts 1A and 1B and will be further 
defined via an amendment. 
Adverse events will be presented using summary statistics. 
Individual curves of plasma concentration for RiboMab
 will be presented for all patients. 
PK parameters will be calculated based on non-compartmental methods and will be 
calculated separately. 
RECIST 1.1 will be used to define response. Summaries of objective response and 
disease control will be presented by dose cohort/indication and total.  
The PFS, OS, and DOR will be summarized using survival analysis methods. 
SRC: The SRC will review safety, clinical, and available PK and PD data on an ongoing 
basis. At a minimum the data will be reviewed at each dose level after all patients enrolled 
in this dose level have completed the DLT period. A comprehensive review of all available 
safety, PK and PD, and efficacy data will occur prior to starting Part 2 (Expansion). 
Formal statistical analysis will occur at the end of the trial. 
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Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 8  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
1. 2  
S c h e m a ( gr a p hi c al r e pr e s e nt ati o n of t h e tri al)  
Fi g ur e  1 : 
Tri al d e si g n  
P ar t 1 A  i s a d o s e e s c al ati o n of B N T 1 4 1 a s m o n ot h er a p y i n p ati e nt s wit h a d v a n c e d u nr e s e ct a bl e or m et a st ati c C L D N 1 8. 2-p o siti v e s oli d t u m or s  f or w hi c h t h er e i s n o a v ail a bl e 
st a n d ar d t h er a p y li k el y t o c o nf er cli ni c al b e n efit, or t h e p ati e nt i s n ot a c a n di d at e f or  s u c h a v ail a bl e t h er a p y.  Eli gi bl e t u m or t y p e s ar e g a stri c c a n c er, g a str o e s o p h a g e al j u n cti o n 
( G E J) a n d e s o p h a g e al a d e n o c ar ci n o m a, p a n cr e ati c, bili ar y tr a ct ( c h ol a n gi o c ar ci n o m a a n d g all bl a d d er c a n c er), a n d m u ci n o u s o v ar i a n c a n c er s. A d diti o n all y, p ati e nt s with s p e cifi c 
t u m or s (i n cl u di n g c ol or e ct al c a n c er, n o n -s m all -c ell l u n g c a n c er, g a stri c s u bt y p e of e n d o c er vi c al a d e n o c ar ci n o m a) w h er e t h er e i s s ci e ntifi c e vi d e n c e t h at t h e C L D N 1 8. 2 c o ul d b e 
el e v at e d c a n b e t e st e d f or C L D N 1 8. 2 e x pr e s si o n.  
 
 
C CI
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Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 9  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
 
 
 
  
 C L D N 1 8. 2  =  C l a u di n 1 8. 2; C L D N 1 8. 2 p o s  =  C l a u din 1 8. 2 p o siti v e; 
 D L  =  d o s e l e v el; D L T  =  d o s e -
li miti n g t o xi cit y; G E J  =  g a str o e s o p h a g e al j u n cti o n ; m o n o T x  =  m o n ot h er a p y tr e at m e nt;  M T D  =  m a xi m u m t ol er at e d d o s e;  N  =  n u m b er of p ati e nt s;  P D  =  p h ar m a c o d y n a mi c s; 
P D A C  =  p a n cr e ati c a d e n o c ar ci n o m a; P K  =  p h ar m a c o ki n eti c s; pt s  =  p ati e nt s; R P 2 D  =  r e c o m m e n d e d P h a s e II d o s e; S O C  =  st a n d ar d of c ar e ; T x  =  tr e at m e nt. 
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1.3 
Schedule of activities 
The schedule of activities (SoA) and procedures for Part 1A (BNT141 monotherapy dose 
escalation) is shown in Table 1, with the schedule of central laboratory assessments (PK, 
PD, immunogenicity, and lipids) shown in Table 2, and local laboratory assessments in 
Table 3. 
The SoA and procedures for Part 1B (BNT141 dose escalation in combination with nab-
paclitaxel and gemcitabine) is shown in Table 4, with the schedule of central laboratory 
assessments (PK, PD, immunogenicity and lipids) shown in Table 5, and local laboratory 
assessments in Table 6. 
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 R&D. On the days of tumor imaging, blood sampling can be before or after 
imaging assessments. 
For Part 1A, 1 cycle is defined as 21 d and the DLT evaluation period is also 21 d.  
For Part 1B, 1 cycle is defined as 28 d, with the DLT evaluation period lasting 28 d. 
Details regarding the expansion cohorts in Part 2 will be further determined after careful 
evaluation of all available safety, PK and PD, and efficacy data generated in Parts 1A and 
1B by the SRC and will be submitted by a major amendment to this protocol. 
Investigators must make every effort to adhere to the given visit schedule and to perform 
all assessments within the given time window for each visit as specified in the SoA in 
Table 1 and Table 4. This is especially true for the extensive PK assessments according to 
the SoA (Table 2 and Table 5). 
Please refer to Section 7.1 and Section 7.3 for treatment discontinuation and lost to follow-
up criteria. Please note, however, that lost to follow-ups should be avoided by all means 
and every effort should be taken by the trial site to follow-up on the whereabouts of the 
patients and their survival status. 
 




Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 1 2  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
1  
If ≥ 5 0 % m o d er at e -t o-str o n g C L D N 1 8. 2 pr ot ei n e x pr e s si o n i s d et e ct e d, p ati e nt c a n e nt er t h e s cr e e ni n g p h a s e. F or s cr e e ni n g, all l a b or at or y a s s e s s m e nt s m u st b e p erf or m e d ≤ 7  d pri or t h e pl a n n e d 
tr e at m e nt st art wit h B N T 1 4 1. R e s ult s of S O C t e st or e x a mi n ati o n s p erfor m e d pri or t o o bt ai ni n g i nf or m e d c o n s e nt a n d wit hi n 2 1  d pri or t o C y cl e  1 D a y  1 m a y b e u s e d, s u c h t e st s d o n ot n e e d t o b e 
r e p e at e d f or s cr e e ni n g. 
2  
If t h e p ati e nt h a s t o g o off tr e at m e nt p er tr e at m e nt wit h dr a w al crit eri a, t h e E n d of Tr e at m e nt Vi sit s h o ul d b e p erf or m e d a s s o o n a s p o s si bl e aft er p er m a n e nt di s c o nti n u ati o n crit eri a b ut n ot l at er t h a n 
3 0  d aft er l a st d o s e (i n t hi s l att er c a s e, d u e t o t h e E n d of Tr e at m e nt Vi sit  o c c urri n g cl o s e t o S af et y F U 1, S af et y F U 1 c a n b e s ki p p e d). T h e vi sit at w hi c h a n i m a g i n g s h o w s di s e a s e pr o gr e s si o n 
r e s ulti n g i n tr e at m e nt di s c o nti n u ati o n m a y b e u s e d a s t h e E n d of Tr e at m e nt Vi sit, at w hi c h ti m e all a s s e s s m e nt a s s o ci at e d wit h t h e E n d of Tr e at m e nt Vi sit s h o ul d b e p erf or m e d.  
3  
U n s c h e d ul e d vi sit s c a n b e p erf or m e d at a n y ti m e p oi nt w h e n cli ni c all y i n di c at e d a n d c a n i n cl u d e a s s e s s m e nt s a s i n di c at e d.  
4  
B ot h f r e s h a n d ar c hi v al bi o p si e s will b e a c c e pt e d.  
5  
A d diti o n al t u m or ti s s u e ( 1 0  µ m t hi c k t u m or c url s) s h o ul d b e s e nt fr o m all p ati e nt s r e c ei vi n g st u d y dr u g t o t h e c e ntr al l a b or at or y f or f urt h er e x pl or at or y r e s e ar c h o n C L D N 1 8 -A R H G A P 6/ 2 6 f u si o n . 
6  
O n -tr e at m e nt bi o p s y s h o ul d b e p erf or m e d i n p ati e nt s w h er e f e a si bl e/ wit h o ut a ri s k of c o m pli c ati o n s f or t h e p ati e nt. Pr ef err e d o n C y cl e 2 D a y 8 (±  1  d), b ut c a n b e p erf or m e d at a n y ti m e d ur i n g t h e 
st u d y tr e at m e nt.  
7  
M e di c al hi st or y i n cl u d e s c a n c er hi st or y (i n cl u di n g b ut n ot li mit e d t o, pri or c a n c er t h er a pi e s a n d pr o c e d ur e s a n d t u m or c h ar a c t eri sti c s s u c h a s m ut ati o n st at u s, c a n c er r el at e d s o m ati c g e n o mi c 
alt er ati o n s a n d g er mli n e st at u s , ot h er cli ni c all y r el e v a nt di s e a se s, s ur g eri e s, u s e of al c o h ol a n d/ or dr u g s a b u s e a n d, r e pr o d u cti v e st at u s).  
8  
H ei g ht will o nl y b e m e a s ur e d at s cr e e ni n g. T h e b o d y w ei g ht m e a s ur e m e nt t a k e n at t h e vi sit pri or t o d o si n g s h o ul d b e u s e d f or I M P pr e p ar ati o n. 
9  
F ull p h y si c al e x a mi n ati o n s s h o ul d b e p erf or m e d d uri n g s cr e e ni n g, t h er e aft er a s y m pt o m ori e nt at e d li mit e d p h y si c al e x a mi n ati o n s h o ul d b e p erf or m e d.  
1 0  I n cl u d e s t e m p er at ur e, bl o o d pr e s s ur e ( s y st oli c a n d di a st oli c), h e art r at e, o x y g e n s at ur ati o n a n d r e s pir at or y r at e. 
1 1  A 1 2 -l e a d E C G will b e p erf or m e d i n tri pli c at e. Si n gl e E C G r e c or di n g s m a y b e o bt ai n e d at a n u n s c h e d ul e d ti m e p oi nt a s cli ni c all y i n di c at e d.  
1 2  T h e s a m e i m a gi n g m et h o d ( C T/ M RI) m u st b e u s e d f or a p ati e nt t hr o u g h o ut t h e tri al at s cr e e ni n g, at W e e k  6 ( ±  7  d), t h e n e v er y 6  w e e k s ( ±  7  d) f or 2 4 w e e k s, a n d e v er y 1 2 w e e k s ( ± 7  d) t h er e aft er 
u ntil di s e a s e pr o gr e s si o n. T u m or a s s e s s m e nt s will n ot b e p erf or m e d at t h e b e gi n ni n g of t h e tri al if l a st t u m or a s s e s s m e nt w a s  wit hi n  4  w e e k s b ef or e C 1 D 1 a n d t h e s e i m a g e s c a n b e u s e d. I m a gi n g 
will b e a s s e s s e d b y a n e x p eri e n c e d r a di ol o gi st at sit e u si n g R E CI S T  1. 1 crit eri a a n d s e nt t o a n e xt er n al s er vi c e pr o vi d er f or st or a g e. M o nit ori n g of t h e li v er a n d t h e s pl e e n si z e will b e p erf or m e d a s 
d e s cri b e d i n t h e I m a gi n g M a n u al.  
1 3  A E s/ S A E s will b e r e p ort e d fr o m t h e st art of st u d y dr u g tr e at m e nt u ntil S af et y F U 2. D uri n g pr e -s cr e e ni n g n o A E s/ S A E s will b e r e p ort e d, wit h t h e e x c e pti o n of A E s/ S A E s r el at e d t o t h e pr o c e d ur e of 
c oll e cti o n of a fr e s h bi o p s y.  
1 4  Pri or m e di c ati o n s ar e a n y m e di c ati o n s a n d n o n -dr u g t h er a pi e s ( s e e S e cti o n  6. 5 ) u s e d b y t h e p ati e nt wit hi n 2 1 d pri or t o i niti ati o n of tri al tr e at m e nt a n d d uri n g s cr e e ni n g. C o n c o mit a nt m e di c ati o n s ar e 
a n y m e di c ati o n ( e. g., pr e s cri pti o n dr u g s, o v er -t h e-c o u nt er dr u g s, v a c ci n e s, h er b al or h o m e o p at hi c r e m e di e s, n utriti o n al s u p pl e m e nt s) u s e d b y a p ati e nt i n a d diti o n t o pr ot o c ol -m a n d at e d tr e at m e nt 
(i n cl u di n g pr o p h yl a cti c tr e at m e nt aft er B N T 1 4 1 a d mi ni str ati o n a n d m e di c ati o n s a s a r e s ult of a n a d v er s e e v e nt). Pri or/ C o n c o mit a nt m e di c ati o n s a n d n o n -dr u g t h er a pi e s i n cl u d e all pr e vi o u s a n d o n -
tri al C O VI D-1 9 v a c ci n ati o n s.  
1 5  B N T 1 4 1 will b e a d mi ni st er e d 
. 
1 6  N e w a nti -c a n c er tr e at m e nt s w ill b e c oll e ct e d fr o m tr e at m e nt di s c o nti n u ati o n u ntil d e at h ( u nl e s s t h e p ati e nt wit h dr a w s c o n s e nt or t h e s p o n s or t er mi n at e s th e tri al).  
1 7  I nf or m ati o n o n s ur vi v al F U, n e w a nti-c a n c er t h er a p y a n d c a n c er -r el at e d pr o c e d ur e s will b e c oll e ct e d f or all p ati e nt s vi a t el e p h o n e c all s, p ati e nt m e di c al r e c or d s, a n d/ or cli ni c vi sit s a p pr o xi m at el y 
e v er y 1 2  w e e k s u ntil d e at h ( u nl e s s t h e p ati e nt wit h dr a w s c o n s e nt or t h e s p o n s or t er mi n at e s t h e tri al). If t h e p ati e nt wit h dr a w s fr o m t ri al, t h e tri al st aff m a y u s e a p u bli c i nf or m ati o n s o ur c e ( e. g., 
c o u nt y r e c or d s) t o o bt ai n i nf or m ati o n a b o ut s ur vi v al st at u s o nl y.   
1 8  L o c al l a b or at or y a s s e s s m e nt s c a n t a k e pl a c e o n e d a y pri or t o p ati e nt vi sit a p art fr o m C y cl e  2 D a y  1. T h e s cr e e ni n g s a m pl e s m u st b e o bt ai n e d wit hi n 7  d of C y cl e 1 D a y  1 . All D a y 1 s a m pl e s m u st b e 
t a k e n b ef or e st u d y dr u g a d mi ni str ati o n. A d diti o n al s af et y l a b or at or y a s s e s s m e nt s c a n b e p erf or m e d at a n y ti m e p oi nt w h e n cli ni c all y i n di c at e d a n d c a n i n cl u d e a s s e s s m e nt s a s i n di c at e d. L o c al 
l a b or at or y a s s e s s m e nt s ar e d et aile d i n T a bl e  3 .  
1 9  C e ntr al l a b or at or y a s s e s s m e nt s ar e gi v e n i n T a bl e  2 . 
A E  =  a d v er s e e v e nt; A R H G A P  =  R h o G T P a s e A cti v ati n g Pr ot ei n 6; C L D N  =  Cl a u di n; C O VI D  =  c or o n a vir u s di s e a s e; C T  =  c o m p ut er t o m o gr a p h y; d  =  d a y; E C G  =  el e ctr o c ar di o gr a m; E C O G  =  E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p; E O T  =  e n d of tr e at m e nt; F U  =  f oll o w-u p; I C F  =  i nf or m e d c o n s e nt f or m; IM P  =  in v e sti g ati o n al m e di ci n al pr o d u ct ; M RI  =  m a g n eti c r e s o n a n c e i m a gi n g; R E CI S T  =  R e s p o n s e 
E v al u ati o n Crit eri a S oli d T u m or s; S A E  =  s eri o u s A E; S O C  =  st a n d ar d of c ar e.  
 
 
C CI








Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 1 6  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
1  
Tri al vi sit s will b e p erf or m e d w e e kl y f or C y cl e s 1, 2 a n d 4 ( D a y s  1, 8, 1 5, 2 2). Aft er t h e fir st 4 c y cl e s, tri al vi sit s will b e p erf or m e d at t h e d a y s w h er e B N T 1 4 1 a n d/ or n a b -p a clit a x el a n d g e m cit a bi n e 
ar e a d mi ni st er e d. Tr e at m e nt will c o nti n u e u ntil di s e a s e pr o gr e s si o n a n d u ntil pr ot o c ol -d efi n e d tr e at m e nt di s c o nti n u ati o n crit eri a ar e m et.  
2  
If ≥5 0 % m o d er at e -t o-str o n g C L D N 1 8. 2 pr ot ei n e x pr e s si o n i s d et e ct e d, p ati e nt c a n e nt er t h e s cr e e ni n g p h a s e. F or s cr e e ni n g, all l a b or at or y a s s e s s m e nt s m u st b e p erf or m e d ≤ 7  d pri or t h e pl a n n e d 
tr e at m e nt st art wit h B N T 1 4 1. R e s ult s of S O C t e st or e x a mi n ati o n s p erf or m e d pri or t o o bt ai ni n g i nf or m e d c o n s e nt a n d wit hi n 2 1 d pri or t o C y cl e  1 D a y  1 m a y b e u s e d, s u c h t e st s d o n ot n e e d t o b e 
r e p e at e d f or s cr e e ni n g. 
3  
If t h e p ati e nt h a s t o g o off tr e at m e nt p er tr e at m e nt wit h dr a w al crit eri a, t h e E n d of Tr e at m e nt Vi sit s h o ul d b e p erf or m e d a s so o n a s p o s si bl e aft er p er m a n e n t di s c o nti n u ati o n crit eri a b ut n ot l at er t h a n 
3 0  d aft er l a st d o s e (i n t hi s l att er c a s e, d u e t o t h e E n d of Tr e at m e nt Vi sit  o c c urri n g cl o s e t o S af et y F U 1, S af et y F U 1 c a n b e s ki p p e d). T h e vi sit at w hi c h a n i m a gi n g s h o w s di s e a s e pr o gr e s si o n 
r e s ulti n g i n tr e atm e nt di s c o nti n u ati o n m a y b e u s e d a s t h e E n d of Tr e at m e nt Vi sit, at w hi c h ti m e all a s s e s s m e nt a s s o ci at e d wit h t h e E n d of Tr e at m e nt Vi sit s h o ul d b e p erf or m e d.  
4  
U n s c h e d ul e d vi sit s c a n b e p erf or m e d at a n y ti m e p oi nt w h e n cli ni c all y i n di c at e d a n d c a n i n cl u d e a s s e s s m e nt s a s i n di c at e d.  
5  
Fr e s h a n d ar c hi v al bi o p si e s will b e a c c e pt e d . 
6  
A d diti o n al t u m or ti s s u e ( 1 0  µ m t hi c k t u m or c url s) s h o ul d b e s e nt fr o m all p ati e nt s r e c ei vi n g st u d y dr u g t o t h e c e ntr al l a b or at or y f or f urt h er e x pl or at or y r e s e ar c h o n C L D N 1 8 -A R H G A P 6/ 2 6 f u si o n . 
7  
O n -tr e at m e nt bi o p s y s h o ul d b e p erf or m e d i n p ati e nt s w h er e f e a si bl e/ wit h o ut a ri s k of c o m plic ati o n s f or t h e p ati e nt. Pr ef err e d o n C y cl e  2 D a y  8 ( ±  1 d), b ut c a n b e p erf or m e d at a n y ti m e d uri n g t h e 
st u d y tr e at m e nt.  
8  
M e di c al hi st or y i n cl u d e s c a n c er hi st or y (i n cl u di n g b ut n ot li mit e d t o, pri or c a n c er t h er a pi e s a n d pr o c e d ur e s a n d t u m or c h ar a c t eri stic s s u c h a s m ut ati o n st at u s, c a n c er r el at e d s o m ati c g e n o mi c 
alt er ati o n s a n d g er mli n e st at u s , ot h er cli ni c all y r el e v a nt di s e a s e s, s ur g eri e s, u s e of al c o h ol a n d/ or dr u g s a b u s e a n d, r e pr o d u cti v e st at u s). 
9  
H ei g ht will o nl y b e m e a s ur e d at s cr e e ni n g. T h e b o d y w e i g ht m e a s ur e m e nt t a k e n at t h e vi sit pri or t o d o si n g s h o ul d b e u s e d f or I M P pr e p ar ati o n. 
1 0  F ull p h y si c al e x a mi n ati o n s s h o ul d b e p erf or m e d d uri n g s cr e e ni n g, t h er e aft er a s y m pt o m ori e nt at e d li mit e d p h y si c al e x a mi n ati o n  s h o ul d b e p erf or m e d.  
1 1  I n cl u d e s t e m p erat ur e, bl o o d pr e s s ur e ( s y st oli c a n d di a st oli c) , h e art r at e, o x y g e n s at ur ati o n a n d r e s pir at or y r at e.  
1 2  A 1 2 -l e a d E C G will b e p erf or m e d i n tri pli c at e. Si n gl e E C G r e c or di n g s m a y b e o bt ai n e d at a n u n s c h e d ul e d ti m e p oi nt a s cli ni c all y i ndi c at e d.  
1 3  T h e s a m e i m a gi n g m et h o d ( C T/ M RI) m u st b e u s e d f or a p ati e nt t hr o u g h o ut t h e tri al at s cr e e ni n g, at W e e k  8 ( ±  7  d), t h e n e v er y 8  w e e k s ( ±  7  d) f or 2 4  w e e k s, a n d e v er y 1 2  w e e k s ( ± 7  d) t h er e aft er 
u ntil di s e a s e pr o gr e s si o n. M o nit ori n g of t h e li v er a n d t h e s pl e e n s i z e will b e p erf or m e d a s d e s cri b e d i n t h e I m a gi n g M a n u al. 
1 4  A E s/ S A E s will b e r e p ort e d fr o m t h e st art of st u d y dr u g tr e at m e nt u ntil S af et y F U 2. D uri n g pr e -s cr e e ni n g n o A E s/ S A E s will b e r e p ort e d, wit h t h e e x c e pti o n of A E s/ S A E s r el at e d t o t h e pr o c e d ur e of 
c o ll e cti o n of a fr e s h bi o p s y. 
1 5  Pri or m e di c ati o n s ar e a n y m e di c ati o n s a n d n o n -dr u g t h er a pi e s ( s e e S e cti o n  6. 5 ) u s e d b y t h e p ati e nt wit hi n 2 1 d pri or t o i niti ati o n of tri al tr e at m e nt a n d d uri n g s cr e e ni n g. C o n c o mit a nt m e di c ati o n s ar e 
a n y m e di c ati o n ( e. g., pr e s cri pti o n dr u g s, o v er -t h e-c o u nt er dr u g s, v a c ci n e s, h er b al or h o m e o p at hi c r e m e di e s, n utriti o n al s u p pl e m e nt s) u s e d b y a p ati e nt i n a d diti o n t o pr ot o c ol -m a n d at e d tr e at m e nt 
(i n cl u di n g pr o p h yl a cti c tr e at m e nt aft er B N T 1 4 1 a d mi ni str ati o n a n d m e di c ati o n s a s a r e s ult of a n a d v er s e e v e nt). Pri or/ C o n c o mi t a nt m e di c ati o n s a n d n o n-dr u g t h er a pi e s i n cl u d e all pr e vi o u s a n d o n -
tri al C O VI D-1 9 v a c ci n ati o n s.  
1 6  B N T 1 4 1 will  b e a d mi ni st er e d 
. 
1 7  N a b -p a clit a x el a n d g e m cit a bi n e will b e gi v e n p er S m P C aft er a d mi ni str ati o n of B N T 1 4 1 
 
1 8  N e w a nti -c a n c er tr e at m e nt s will b e c oll e ct e d fr o m tr e at m e nt di s c o nti n u ati o n u ntil d e at h ( u nl e s s t h e p ati e nt wit h dr a w s c o n s e nt, or t h e s p o n s or t er mi n at e s t h e tri al).   
1 9  I nf or m ati o n o n s ur vi v al F U, n e w a nti-c a n c er t h er a p y a n d c a n c er -r el at e d pr o c e d ur e s will b e c oll e ct e d f or all p ati e nt s vi a t el e p h o n e c all s, p ati e nt m e di c al r e c or d s, a n d/ or cli ni c vi sit s a p pr o xi m a t el y 
e v er y 1 2  w e e k s u ntil d e at h ( u nl e s s t h e p ati e nt wit h dr a w s c o n s e nt or t h e s p o n s or t er mi n at e s t h e tri al). If t h e p ati e nt wit h dr a w s fr o m t ri al, t h e tri al st aff m a y u s e a p u bli c i nf or m ati o n s o ur c e ( e. g., 
c o u nt y r e c or d s) t o o bt ai n i nf or m ati o n a b o ut s ur vi v al  st at u s o nl y.  
2 0  L o c al l a b or at or y a s s e s s m e nt s c a n t a k e pl a c e o n e d a y pri or t o p ati e nt vi sit a p art fr o m C y cl e  2 D a y  1. T h e s cr e e ni n g s a m pl e s m u st b e o bt ai n e d wit hi n 7  d of C y cl e 1 D a y  1 . All D a y 1 s a m ple s m u st b e 
t a k e n b ef or e st u d y dr u g a d mi ni str ati o n. A d diti o n al s af et y l a b or at or y a s s e s s m e nt s c a n b e p erf or m e d at a n y ti m e p oi nt w h e n cli ni c all y i n di c at e d a n d c a n i n cl u d e a s s e s s m e nt s a s i n di c at e d. L o c al 
l a b or at or y a s s e s s m e nt s ar e d et ail e d i n T a bl e  6 . 
2 1  C e ntr al l a b or at or y a s s e s s m e nt s ar e gi v e n i n  T a bl e  5 . 
2 2  C y cl e s  1 t o 3 o nl y.  
A E  =  a d v er s e e v e nt; A R H G A P  =  R h o G T P a s e A cti v ati n g Pr ot ei n 6; C L D N  =  Cl a u di n; C O VI D  =  c or o n a vir u s di s e a s e; C T  =  c o m p ut er t o m o gr a p h y; C 1 D 1  =  C y cl e 1 D a y 1; d  =  d a y; 
E C G  =  el e ctr o c ar di o gr a m; E C O G  =  E a st er n C o o p er ati v e O n c ol o g y Gr o u p; F U  =  f oll o w-u p; I C F  =  i nf or m e d c o n s e nt f or m; I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; M RI  =  m a g n eti c r e s o n a n c e i m a gi n g; 
S A E  =  s eri o u s A E; S m P C  =  s u m m ar y of pr o d u ct c h ar a ct eri sti c s; S O C  =  st a n d ar d of c ar e.  
 
C CI
C CI






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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY 
2 
1.1 
Trial synopsis 
2 
1.2 
Schema (graphical representation of the trial) 
8 
1.3 
Schedule of activities 
10 
TABLE OF CONTENTS 
19 
LIST OF TABLES 
23 
LIST OF FIGURES 
24 
TRIAL-SPECIFIC ABBREVIATIONS 
25 
2 
INTRODUCTION 
26 
2.1 
Trial rationale 
26 
2.2 
Background 
27 
2.2.1 
 
27 
2.2.2 
The target CLDN18.2 
30 
2.2.3 
Overview of the diseases 
33 
2.2.4 
Introduction to the investigational treatment 
35 
2.3 
Benefit/risk assessment 
37 
2.3.1 
Risk assessment of BNT141 as monotherapy (Part 1A) 
37 
2.3.2 
Risk assessment of BNT141 in combination with nab-paclitaxel and 
gemcitabine (Part 1B and Part 2) 
38 
2.3.3 
Benefit assessment 
39 
2.3.4 
Overall benefit/risk conclusion 
39 
3 
OBJECTIVES AND ENDPOINTS 
39 
4 
TRIAL DESIGN 
41 
4.1 
Overall design 
41 
4.1.1 
MTD, MAD and RP2D definitions 
43 
4.1.2 
Pre-screening 
44 
4.1.3 
Screening 
44 
4.1.4 
Dose escalation part 
44 
4.1.5 
Expansion part 
47 
4.1.6 
Safety follow-up period 
48 
4.1.7 
Survival follow-up 
48 
4.1.8 
Adaptive trial design elements 
48 
4.1.9 
Planned number of patients 
48 
4.2 
Scientific rationale for the trial design 
49 
4.2.1 
Trial design rationale for Part 1A: Monotherapy dose escalation 
49 
4.2.2 
Trial design rationale for bifurcated design 
50 
CCI


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4.2.3 
Trial design rationale for Part 2: Expansion Phase 
50 
4.3 
Justification for dose 
50 
4.4 
End of trial definition 
51 
5 
TRIAL POPULATION 
51 
5.1 
Inclusion criteria 
51 
5.1.1 
Disease-specific inclusion criteria 
51 
5.1.2 
Other inclusion criteria 
52 
5.2 
Exclusion criteria 
53 
5.3 
Lifestyle considerations 
55 
5.3.1 
Meals and dietary restrictions 
55 
5.3.2 
Caffeine, alcohol, and tobacco 
55 
5.3.3 
Activity restrictions 
56 
5.4 
Screen failures 
56 
6 
TRIAL TREATMENTS 
56 
6.1 
Trial treatments administered 
56 
6.1.1 
Investigational medicinal product 
56 
6.1.2 
Non-investigational medicinal product 
58 
6.2 
Preparation/handling/storage/accountability 
58 
6.3 
Measures to minimize bias: randomization and blinding 
58 
6.4 
Trial treatment compliance 
58 
6.5 
Concomitant therapy 
59 
6.5.1 
Permitted concomitant medications and therapies 
59 
6.5.2 
Prohibited concomitant therapy 
60 
6.5.3 
Premedication 
60 
6.6 
Dose modifications and safety management guidelines 
61 
6.6.1 
Dose-limiting toxicity 
61 
6.6.2 
Dose modification guidance/rules 
63 
6.6.3 
Mitigation plans for specific AEs 
66 
6.6.4 
Safety stopping criteria 
69 
6.7 
Treatment after the end of the trial 
70 
7 
DISCONTINUATION OF TRIAL TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
71 
7.1 
Discontinuation of trial treatment 
71 
7.1.1 
Temporary discontinuation 
71 
7.2 
Patient discontinuation/withdrawal from the trial 
71 
7.3 
Lost to follow-up 
72 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
72 
8.1 
Safety assessments 
73 


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8.1.1 
Physical examinations 
73 
8.1.2 
Vital signs 
73 
8.1.3 
Electrocardiograms 
74 
8.1.4 
Clinical safety laboratory assessments 
74 
8.2 
Adverse events and serious adverse events 
75 
8.2.1 
Time period and frequency for collecting AE and SAE information 
75 
8.2.2 
Method of detecting AEs and SAEs 
75 
8.2.3 
Follow-up of AEs and SAEs 
76 
8.2.4 
Regulatory reporting requirements for SAEs 
76 
8.2.5 
Pregnancy 
77 
8.2.6 
Cardiovascular and death events 
77 
8.2.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs 
or SAEs 
77 
8.2.8 
Adverse events of special interest 
78 
8.3 
Treatment of overdose 
78 
8.4 
Pharmacokinetics 
78 
8.5 
Efficacy assessments 
79 
8.5.1 
Computer tomography/magnetic resonance imaging scans 
79 
8.5.2 
Tumor marker CA 19-9 
79 
8.5.3 
Eastern Cooperative Oncology Group Performance Status 
80 
8.5.4 
New anti-cancer treatments and survival follow-up 
80 
8.6 
Pharmacodynamics 
80 
8.7 
Genetics 
80 
8.8 
Biomarkers 
80 
8.8.1 
Tumor biomarkers 
81 
8.9 
Immunogenicity assessments 
81 
8.10 
Blood lipids 
82 
9 
STATISTICAL CONSIDERATIONS 
82 
9.1 
Statistical hypotheses 
82 
9.2 
Sample size determination 
82 
9.3 
Analysis sets 
82 
9.4 
Statistical analyses 
83 
9.4.1 
General considerations 
83 
9.4.2 
Primary endpoints 
84 
9.4.3 
Secondary endpoints 
84 
9.4.4 
Tertiary/exploratory endpoints 
85 
9.4.5 
Safety analyses 
85 
9.4.6 
Other analyses 
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9.5 
Interim analyses 
87 
9.6 
Safety Review Committee 
88 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
 
 
88 
10.1 
Regulatory, ethical, and trial oversight considerations 
88 
10.1.1 
Regulatory and ethical considerations 
88 
10.1.2 
Financial disclosure 
89 
10.1.3 
Informed consent process 
89 
10.1.4 
Pre-screening ICF data protection 
89 
10.1.5 
Committees structure – SRC 
90 
10.1.6 
Dissemination of clinical trial data 
90 
10.1.7 
Data quality assurance 
90 
10.1.8 
Source documents 
91 
10.1.9 
Trial and site start and closure 
91 
10.1.10 
Publication policy 
92 
10.2 
Clinical laboratory tests 
92 
10.3 
Adverse events: Definitions and procedures for recording, evaluating, follow-up, 
and reporting 
92 
10.3.1 
Definition of an AE 
92 
10.4 
Contraceptive guidance and collection of pregnancy information 
102 
10.4.1 
Definitions 
102 
10.4.2 
Contraception guidance 
103 
10.4.3 
Collection of pregnancy information 
104 
10.5 
Liver safety: Suggested actions and follow-up assessments 
105 
10.6 
Investigators and trial administrative structure 
105 
10.6.1 
Investigators and trial site personnel 
105 
10.6.2 
Trial site personnel assigned trial-related duties 
105 
10.6.3 
Contract research organizations 
105 
10.6.4 
The sponsor and sponsor’s personnel 
106 
10.7 
Country-specific requirements 
106 
10.8 
Other standard abbreviations and definitions 
106 
10.9 
Protocol amendments 
108 
10.9.1 
Protocol amendment 01 
108 
10.9.2 
Protocol amendment 02 
110 
10.9.3 
Protocol amendment 03 
114 
10.10 
Data collection and management 
115 
10.10.1 
Case report forms 
115 
10.10.2 
Patient reported outcomes 
115 


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10.10.3 
Data management 
115 
11 
REFERENCES 
116 
Appendix 1: 
Recommendation for COVID-19 vaccination during trial participation 
120 
Appendix 2: 
Risk-benefit assessment of COVID-19 vaccination in BNT141-01 trial 121 
Appendix 3: 
Recommendation for COVID-19 infection in BNT141-01 trial 
122 
 
LIST OF TABLES 
Table 1: 
Schedule of activities and procedures: Part 1A – BNT141 monotherapy dose 
escalation 
11 
Table 2: 
Schedule of central laboratory assessments (PK, PD, immunogenicity and lipids) 
for Part 1A – BNT141 monotherapy dose escalation 
13 
Table 3: Local laboratory assessments: Part 1A – BNT141 monotherapy dose escalation
 
 
14 
Table 4: 
Schedule of activities: Part 1B – Combination dose escalation 
15 
Table 5: 
Schedule of central laboratory assessments (PK, PD, immunogenicity and lipids) 
for Part 1B – Combination dose escalation 
17 
Table 6: Local laboratory assessments: Part 1B – Combination dose escalation 
18 
Table 7: 
Dose escalations 
45 
Table 8: 
BNT141 dose increments 
45 
Table 9: 
Days of administration of BNT141 and nab-paclitaxel and gemcitabine in Part 1B
 
 
57 
Table 10: Criteria for liver enzyme elevations 
62 
Table 11: Recommended dosage modifications for gemcitabine for myelosuppression 65 
Table 12: Dose level reductions of nab-paclitaxel in combination with gemcitabine 
65 
Table 13:  Recommended dose modifications of nab-paclitaxel in combination with 
gemcitabine for neutropenia and thrombocytopenia 
65 
Table 14: Recommended dose modifications of nab-paclitaxel in combination with 
gemcitabine for other adverse drug reactions 
66 
Table 15: Treatment guidelines for patients who experience an IRR 
67 
Table 16: American Society for Transplantation and Cellular Therapy CRS consensus 
grading 
68 
Table 17: Guidelines for management of CRS 
69 
Table 18: Eastern Cooperative Oncology Group Performance Status grading 
80 
Table 19: Analysis set definitions 
82 
 


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LIST OF FIGURES 
Figure 1: Trial design 
8 
 
 
 
 
Figure 3: Immunohistochemistry of normal human tissues with CLDN18.2 antibodies 
31 
Figure 4: Immunohistochemistry of gastric tumor tissues with CLDN18.2 antibodies 
32 
Figure 5: Expression of CLDN18.2 in matched sets of primary PDAC tumors and 
metastases 
33 
 
 
 
Figure 7: Handling of Grade 3 AEs outside of DLT periods 
63 
 
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2 
INTRODUCTION 
2.1 
Trial rationale 
Outcomes of SOC therapies remain poor for patients with relapsed or refractory advanced 
solid tumors, including but not limited to pancreatic, biliary tract and gastric cancers. 
Treatment options include further palliative chemotherapy, best supportive care and 
investigational treatments without proven benefit. Therapy in this population is not curative, 
with an expected OS of a few months. Immunotherapy with monoclonal antibodies (mAbs) 
has provided treatment options in at least some cancers with high unmet medical need. 
However, the prognosis of several tumor types, including pancreatic and biliary tract 
tumors, remains dismal. Safe and effective targeted therapies are needed.  
Recent research has identified isoform 2 of the tight junction molecule Claudin-18 
(CLDN18.2) as a promising anti-cancer target suitable for therapeutic antibody 
development (Sahin et al. 2008). CLDN18.2 is expressed in various high medical need 
cancers, e.g., gastric, gastroesophageal, colorectal, pancreatic, biliary tract and in the 
mucinous subtype of ovarian cancer, while expression in healthy tissues is restricted to the 
gastric epithelia. To date, no therapy targeting CLDN18.2 has been approved for any 
cancer indication.  
BioNTech’s first development candidate of the RiboMab platform, BNT141, is a 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
 
 
 
 
 
 
 
 
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The BNT141-01 trial requires expression of intermediate or high CLDN18.2 levels 
enriching the trial populations for patients with a higher probability of benefit from BNT141 
and excluding patients not expressing this specific tumor target.  
2.2 
Background 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
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2.2.1.1 
Scientific rationale 
BNT141 encodes the 
 antibody RiboMab
 targeting CLDN18.2, which is a highly 
selective tumor-associated tight junction surface protein expressed in various cancers of 
high medical need, such as gastric, gastroesophageal, colorectal, pancreatic, biliary tract 
and mucinous ovarian cancer. The planned first-in-human (FIH), dose escalation trial will 
evaluate safety and preliminary efficacy of BNT141 as monotherapy and in combination 
with chemotherapy agents in patients with CLDN18.2-positive solid tumors. Eligibility for 
this trial requires expression of intermediate or high CLDN18.2 levels enriching the trial 
populations for patients with a higher probability of benefit from BNT141 and excluding 
patients not expressing the tumor target. 
To date, no therapy targeting CLDN18.2 has been approved for any cancer indication. 
BNT141 is a novel RNA 
where it encodes 
in vivo the protein RiboMab
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2.2 
The target CLDN18.2 
The target CLDN18.2 was selected based on the following key criteria: 
• 
Limited expression in healthy tissues (only expressed in differentiated cells of the 
gastric epithelia). 
• 
Luminal expression in gastric epithelia and thus inaccessible for immune effectors. 
• 
Expression in a substantial fraction of primary and metastatic lesions in solid 
tumors. 
• 
Exposition of CLDN18.2 epitopes on tumor cells due to malignant transformation 
and perturbations in cell polarity.  
• 
Tumor biological role, as blockade of CLDN18.2 associates with anti-tumor activity 
in preclinical studies. 
2.2.2.1 
CLDN18.2 expression in healthy tissue 
CLDN18.2 is a highly selective gastric lineage antigen (Sahin et al. 2008). Its expression is 
restricted to short-lived differentiated cells of gastric epithelia in the pit and base regions of 
gastric glands (Figure 3B). The stem cell zone, from which differentiated epithelial cells of 
the gastric glands are continuously replenished, is CLDN18.2-negative. No other normal 
cell type of the human body expresses CLDN18.2 at transcript level or at protein level 
(Figure 3A). 


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Figure 3: 
Immunohistochemistry of normal human tissues with CLDN18.2 antibodies 
(A) Sections prepared from normal human tissues were stained with anti-claudin-18/n-term antibody (1:300), which is 
specific for CLDN18.2, and anti-claudin-18/mid (1:50) antibody detecting CLDN18.1 and CLDN18.2 (Zymed). The anti-
claudin-18/mid antibody labels lung due to cross-reactivity with variant CLDN18.1. (B) Epithelia from the antral gastric 
region were stained with the anti-claudin-18/n-term antibody (top left). Close-ups show CLDN18.2 protein expression at 
the tip and the base of glands, but not in the neck region. (C) Double staining of gastric tissue sections with Ki67 (dark 
purple) and anti-claudin-18/mid antibodies (brown).  
CLDN = Claudin; CNS = central nervous system. 
Source: Sahin et al. 2008. 
 


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2.2.2.2 
CLDN18.2 expression in cancer 
CLDN18.2 is expressed in various human cancers including gastric, gastroesophageal, 
biliary tract and pancreatic cancers (Karanjawala et al. 2008; Shinozaki et al. 2011) 
(Figure 4, Figure 5), as well as precancerous lesions (Wöll et al. 2014; Tanaka et al. 
2011). Tumor-associated expression of CLDN18.2 has also been detected in ovarian 
(Sahin et al. 2008) and lung cancers (Micke et al. 2014). Expression has also been seen in 
colorectal cancer based on sponsor’s investigations. 
Sahin et al. (2008) showed that 77% of primary gastric adenocarcinomas are CLDN18.2-
positive. About half of gastric adenocarcinomas display intermediate (2+) to strong (3+) 
CLDN18.2 expression by immunohistochemical analysis in at least 60% of tumor cells. 
CLDN18.2 expression is more frequent in diffuse than in intestinal gastric cancers. The 
CLDN18.2 protein is also frequently detected in lymph node metastases of gastric cancer 
and in distant ovarian metastases (so-called Krukenberg tumors). Moreover, 50% of 
esophageal adenocarcinomas display significant expression of CLDN18.2. 
 
 
Figure 4: 
Immunohistochemistry of gastric tumor tissues with CLDN18.2 antibodies 
(A) Tissue sections obtained from gastric tumors expressing CLDN18.2. Overview (i) and close-up (ii) of a primary lesion 
and a lymph node metastasis (iii) obtained from the same patient. Gastric cancer specimen from a second patient (iv). 
Overview (v) and close-up (vi) from a gastric cancer metastasis in the ovary obtained from a third patient. (B) Overviews 
and close-ups of an adenocarcinoma of the esophagus (i, ii) and of a mucinous ovarian cancer (iii, iv), respectively. All 
cases shown in (A) and (B) had been scored as 3+ staining in 90% to 95% of cells. 
CLDN18.2 = Claudin 18.2. 
Source: Sahin et al. 2008. 
 
In pancreatic cancers, CLDN18.2 is expressed with a prevalence of 60 to 90% 
(Karanjawala et al. 2008; Wöll et al. 2014). Almost 60% of patients with pancreatic ductal 
adenocarcinoma (PDAC), the most common form of pancreatic cancer, express 
membrane-bound CLDN18.2 and in 20% of patients with pancreatic neuroendocrine 
A 
B 


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neoplasms, CLDN18.2 is ectopically activated. CLDN18.2 is expressed in primary and 
metastatic PDAC lesions (Wöll et al. 2014) (Figure 5). CLDN18.2 is also known to be 
expressed in patients with biliary tract cancer (6.3%) (Hong et al. 2020). In addition, it has 
been shown that CLDN18 is frequently expressed in various kinds of biliary neoplasms, 
including precancerous lesions and gallbladder cancer (Espinoza et al. 2019; Shinozaki et 
al. 2011). 
 
 
 
Figure 5: 
Expression of CLDN18.2 in matched sets of primary PDAC tumors and metastases 
Representative sections of the (i) PDAC (ii) liver metastasis and the corresponding intra-individual (iii) lymph node 
metastasis in a single patient (100x magnification).  
CLDN18.2 = Claudin 18.2; PDAC = pancreatic ductal adenocarcinoma. 
Source: Wöll et al. 2014. 
 
Downregulation of CLDN18.2 by small interfering RNA results in inhibition of proliferation 
of gastric cancer cells (Niimi et al. 2001), indicating its involvement in the proliferation of 
CLDN18.2-positive tumor cells. Independent antibody-based anti-CLDN18.2 approaches 
have also shown effective induction of tumor cell death in vitro as well as in animal models 
of gastric and/or pancreatic cancer (Zhu et al. 2019), further consolidating this strategy as 
a suitable therapeutic approach for CLDN18.2-positive tumors. Interestingly, gemcitabine, 
a first-line chemotherapeutic drug used in the treatment of pancreatic cancer, has been 
associated with upregulation of CLDN18.2 expression on the surface of cancer cells 
(Türeci et al. 2018). This represents an opportunity for synergy between chemotherapy 
and anti-CLDN18.2 targeting for increased efficacy. 
For this trial, patients will only be eligible if they have tumors displaying moderate-to-strong 
CLDN18.2 protein staining intensity in tumor cells using a validated immunohistochemistry 
assay. 
2.2.3 
Overview of the diseases 
2.2.3.1 
Solid tumors 
Cancer is the second leading cause of death globally and in 2018 was predicted to be 
responsible for an estimated 9.6 million deaths (Bray et al. 2018). In general, once a solid 
tumor has metastasized, with a few exceptions such as germ cell and some carcinoid 
tumors, 5-year survival rarely exceeds 25%. Incidence of CLDN18.2-positive tumors is 
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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 (United States) Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) have approved 
several checkpoint inhibitors for the treatment of patients with multiple cancer types, 
mainly solid tumors. These approvals have dramatically changed the landscape of cancer 
treatment. However, this revolution in cancer care has not benefited patients suffering from 
cancers such as advanced/metastatic pancreatic adenocarcinoma and biliary tract cancers 
that have not been shown to respond to existing immunotherapies. 
The poor prognosis of these cancer types highlights the need for additional treatment 
approaches. One such approach is that of targeted therapies, an ever-evolving field with 
promising modalities including RNA-encoded antibodies such as BNT141. Identifying a 
specific tumor-associated antigen for an oncology target that has limited normal tissue 
expression is critical. CLDN18.2 represents a potentially attractive tumor-associated 
antigen because it fulfills this criterion. The capability for RiboMab
 to induce ADCC and 
CDC could augment the cytotoxic effect of chemotherapy, potentially translating into 
improved outcomes. To date, no therapy targeting CLDN18.2 has been approved for any 
cancer indication. 
2.2.3.2 
PDAC 
The most common type of pancreatic cancer is exocrine pancreatic cancer, of which 90% 
are PDACs (ACS 2020a, Kleeff et al. 2016). Although there have been advances in 
treatments, clinical outcomes of patients with PDAC remain poor, with the 5-year OS rate 
being reported as 8% (Siegel et al. 2018, Luberice et al. 2017). This prognosis is due to 
diagnosis at an advanced stage, as well as limited response to available treatments which 
include chemotherapy, surgery and radiotherapy. Only a small proportion (10 to 20%) of 
patients present with resectable PDAC, where surgical resection followed by adjuvant 
chemotherapy is the only curative option. The majority of patients (80 to 90%) present with 
locally advanced, unresectable disease or distance metastases, and are treated up-front 
with systemic chemotherapy (Gillen et al. 2010; Werner et al. 2013). Chemotherapy 
regimens include nucleoside analogs, such as gemcitabine and capecitabine, or the 
pyrimidine analog 5-fluorouracil (5-FU) as single agents or in combination with other 
treatments such as radiotherapy. Some regimens, such as FOLFIRINOX (a combination of 
oxaliplatin, irinotecan, 5-FU, and leucovorin) have improved OS in patients with early stage 
pancreatic cancer, but have limited efficacy in the advanced setting (Orth et al. 2019, 
Conroy et al. 2011). The SOC for patients with locally advanced or metastatic disease and 
a good performance status (PS) is systemic therapy. The National Comprehensive Cancer 
Network (NCCN) recommends nab-paclitaxel and gemcitabine in patients with an Eastern 
Cooperative Oncology Group (ECOG) PS of 1 to 2, and FOLFIRINOX/modified 
FOLFIRINOX (both with the option of subsequent chemoradiation) in patients with ECOG 
PS 0 to 1 (NCCN guidelines Version 1.2020. Pancreatic adenocarcinoma). 
There have been recent advances in treatments for this high medical need group of 
patients, including targeted and biomarker-driven treatments. Erlotinib, an epidermal 
growth factor receptor inhibitor, is approved in the United States (US) in combination with 
gemcitabine for the first-line treatment of patients with locally advanced, unresectable or 
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metastatic pancreatic cancer. Patients with metastatic pancreatic adenocarcinoma with 
germline BRCA mutations also have the option of maintenance olaparib treatment. The 
poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor extended PFS vs 
placebo treated patients from 3.8 to 7.4 months in a randomized, double-blind Phase III 
trial, although no benefit to OS was detected in the interim analysis (Golan et al. 2019). 
Despite these advances, this remains a patient population with a high unmet medical 
need. BNT141 could potentially benefit the subpopulation of tumors with CLDN18.2-
positive pancreatic adenocarcinoma. The sponsor aims to accelerate the clinical 
development of BNT141 in this indication by establishing a safe dose to be carried forward 
with the SOC (chemotherapy) during the FIH trial. 
2.2.3.3 
Biliary tract cancers 
Biliary tract cancers comprise a group of rare epithelial tumors, and include gallbladder 
cancer and intrahepatic and extrahepatic bile duct cancer (cholangiocarcinoma). Together, 
they constitute approximately 1% of adult cancers worldwide, and are associated with poor 
survival rates, in general due to late-stage diagnosis (Athauda et al. 2020). The 5-year 
survival rate for gallbladder cancer and cholangiocarcinoma is 19% and 8%, respectively 
(ACS 2020b, ACS 2020c). 
Treatments for biliary tract cancers are stratified according to the stage of the disease. 
Surgical resection and adjuvant chemotherapy remain the mainstay of cure for localized 
disease, although this represents a small minority of patients (10 to 40%), as disease is 
typically diagnosed in patients with an advanced stage or unresectable disease (Cidon 
2016). For the first-line treatment of advanced disease, the Phase III trial ABC-02 
confirmed the superiority of the combination of gemcitabine and cisplatin over single-agent 
gemcitabine (Valle et al. 2010). 
Anti-tumor activity was also suggested for first-line therapy with weekly gemcitabine plus 
nab-paclitaxel in advanced or metastatic cholangiocarcinoma. The ORR was 30%, median 
PFS was 7.7 months, and median OS was 12.4 months. The most common Grade 3 or 
worse treatment-related AEs were neutropenia (43%) and fatigue (14%) (Sahai et al. 
2018). 
Several clinical trials are also exploring targeted therapies and immunotherapy for biliary 
tract cancers, but their use is yet to be established (Athauda et al. 2020). Although the 
therapeutic landscape for this disease is improving, there is an urgent need for more 
optimal, personalized management of biliary tract cancer in order to achieve durable 
clinical benefit. 
2.2.4 
Introduction to the investigational treatment 
Trial treatment includes both investigational medicinal product (IMP) and non-
investigational medicinal products (NIMP). The IMP under evaluation in this trial is 
BNT141; all other combination anti-cancer agents are part of SOC and are considered 
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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. 
2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) applicable for this trial are given in the BNT141 
Investigator’s Brochure. 
2.3.1 
Risk assessment of BNT141 as monotherapy (Part 1A) 
As this trial will be the first time BNT141 will be tested in humans, all precautions indicated 
when testing a new systemically active compound in a FIH trial will be taken, including 
choosing a high medical need patient population. There will be a minimum of 48 h 
between the first and second patient, and between the second and third patient, in each 
dose cohort in Parts 1A and 1B in order to account for any acute safety signals in each 
new dose level. To further augment patient safety, there will be a minimum of 14 d 
between the first, second and third patient enrolled in the first dosing cohort in each of the 
monotherapy (Part 1A) and the combination (Part 1B) escalation parts of the trial. The trial 
will be conducted at sites experienced in FIH trials, and trial-related procedures will only be 
performed by qualified physicians and trained nurses. The sponsor will also prepare and 
train the investigators to closely monitor, dose delay, or withdraw patients if AEs occur 
after administration of BNT141 in monotherapy and in combination. 
Furthermore, regular safety data reviews will be performed by the sponsor and by the SRC 
to identify and evaluate 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 has performed a risk assessment to identify and assess risks 
specific to BNT141 related to either the translated proteins, i.e., RiboMab
 antibody, or to 
the formulation of the RNA drug substance within LNPs. In particular, the following data 
sources were used: (i) the preclinical data package obtained for BNT141, and (ii) non-
clinical and (iii) clinical literature data published on other similar therapies either still in 
development or approved. 
One of the identified risks is associated with the intended target of BNT141, which is 
CLDN18.2, which may present as “on-target/off-tumor” toxicity, resulting from a direct 
interaction with normal tissues that express the targeted antigen. The stomach is the only 
human, NHP and murine organ in which CLDN18.2 is expressed in healthy tissues. 
 
 Furthermore, BNT141 does 
not bind to any other claudin family member, including the closely related splice variant 
CLDN18.1, that is predominantly expressed in the lung (Sahin et al. 2008). In summary, 
potential risk for “on-target/off-tumor” toxicity is low and will be mitigated by close clinical 
observation in patients including regular safety laboratory assessments. 
Previous clinical trials using IV administered LNP-formulated RNA mixtures have reported 
incidence of mild to moderate infusion-related reactions (IRRs) at relatively higher 
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administered doses (Coelho et al. 2013, Tabernero et al. 2013). These reactions readily 
responded to temporary interruption of the infusion and resumption of drug administration 
at a slower rate, and associated in some cases with transient elevation of pro-inflammatory 
cytokines (interleukin [IL]-6, tumor necrosis factor-α). Since the risk of IRRs cannot be 
excluded due to the given limited experience with BNT141, in the FIH trial BNT141-01, 
BNT141 will be administered 
 
 
 
. In addition, treatment guidelines for the 
management of IRRs are provided in Section 6.6.3.1 and cytokine measurements are 
included in the scheduled assessments. 
 
 
 
 
 
 
 
 
 
 
Another potential risk associated with BNT141 is the induction of ADA against RiboMab
. 
This potential risk could affect the exposure of the antibody translating in a decrease of 
efficacy. This clinical trial protocol will further monitor this potential risk with ADA 
measurements in accordance with regulatory guidelines. 
In conclusion, the non-clinical and literature data collected so far do not show any potential 
unacceptable toxicities that cannot be mitigated or managed in the clinical setting. The 
anticipated benefits of BNT141 in patient populations with high, unmet medical needs 
outweigh the potential risks with the compound. 
2.3.2 
Risk assessment of BNT141 in combination with nab-paclitaxel 
and gemcitabine (Part 1B and Part 2) 
As this is an FIH trial, the risk of synergistic and/or potentiating toxicities when BNT141 is 
combined with nab-paclitaxel and gemcitabine cannot be completely ruled out. 
 
 
 
 
 
 
 
 
 
 
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Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 4 1  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
4  
T RI A L D E SI G N  
4. 1  
O v er all  d e si g n  
T hi s tri al i s a n o p e n -l a b el, m ulti-sit e , P h a s e I/Iia d o s e e s c al ati o n, s af et y, a n d P K tri al of 
B N T 1 4 1 f oll o w e d b y e x p a n si o n c o h ort s i n p ati e nt s wit h C L D N 1 8. 2 -p o siti v e t u m or s. 
C L D N 1 8. 2 p o siti vit y will b e d et er mi n e d b y a c e ntr al l a b or at or y d uri n g t h e pr e -s cr e e ni n g 
p h a s e u si n g a v ali d at e d i m m u n o hi st o c h e mi str y a s s a y, a n d i s d efi n e d a s m o d er at e -t o-
str o n g C L D N 1 8. 2 e x pr e s si o n.  
T h e tri al d e si g n c o n si st s of t hr e e p art s:  
• 
P art  1 A i s a d o s e e s c al ati o n of B N T 1 4 1 a s m o n ot h er a p y  i n p ati e nt s wit h 
a d v a n c e d u nr e s e ct a bl e or m et a st ati c C L D N 1 8. 2 -p o siti v e s oli d t u m or s  f or w hi c h 
t h er e i s n o a v ail a bl e st a n d ar d t h er a p y li k el y t o c o nf er cli ni c al b e n efit, or t h e p ati e nt 
i s n ot a c a n di d at e f or s u c h a v ail a bl e t h er a p y. P ati e nt s m u st h a v e r e c ei v e d all 
a v ail a bl e st a n d ar d t h er a pi e s a n d f ail e d at l e a st fir st -li n e S O C  t h er a p y pri or t o 
e nr ol m e nt . T h e d o s e of B N T 1 4 1 will b e e s c al at e d u ntil t h e M T D a n d/ or R P 2 D of 
B N T 1 4 1 a s m o n ot h er a p y ar e d efi n e d.  O n c e t h e M T D i s r e a c h e d, u p t o 1 0 
a d diti o n al p ati e nt s  wit h C L D N 1 8. 2 e x pr e s si n g p a n cr e ati c a n d bili ar y tr a ct c a n c er s 
will b e e nr oll e d at t h e M T D l e v el t o o bt ai n a d diti o n al d at a o n s af et y, P K  a n d P D . 
Eli gi bl e t u m or t y p e s ar e g a stri c c a n c er, g a str o e s o p h a g e al j u n cti o n ( G E J) a n d 
e s o p h a g e al a d e n o c ar ci n o m a, p a n cr e ati c, bili ar y tr a ct ( c h ol a n gi o c ar ci n o m a a n d 
g all bl a d d er c a n c er), a n d m u ci n o u s o v ari a n c a n c er s. A d diti o n all y, p ati e nt s wit h 
s p e cifi c t u m or s ( i n cl u di n g c ol or e ct al c a n c er, n o n -s m all -c ell l u n g c a n c er, g a stri c 
s u bt y p e of e n d o c er vi c al a d e n o c ar ci n o m a) w h er e t h er e i s s ci e ntifi c e vi d e n c e t h at 
t h e C L D N 1 8.2 c o ul d b e el e v at e d c a n b e t e st e d f or C L D N 1 8. 2 e x pr e s si o n.   
• 
P art  1 B i s a d o s e e s c al ati o n of B N T 1 4 1 i n c o m bi n ati o n wit h n a b -p a clit a x el 
a n d g e m cit a bi n e  i n p ati e nt s wit h l o c all y a d v a n c e d u nr e s e ct a bl e or m et a st ati c 
C L D N 1 8 . 2-p o siti v e  p a n cr e ati c a d e n o c ar ci n o m a or c h ol a n gi o c ar ci n o m a w h o ar e 
eli gi bl e f or tr e at m e nt wit h n a b -p a clit a x el a n d g e m cit a bi n e . P art  1 B i nt e n d s t o d efi n e 
t h e M T D a n d/ or R P 2 D of t h e c o m bi n ati o n. O n c e t h e M T D i s r e a c h e d, u p t o 1 0 
a d diti o n al p ati e nt s  wit h C L D N 1 8. 2 -e x pr e s si n g p a n cr e ati c a d e n o c ar ci n o m a or 
c h ol a n gi o c ar ci n o m a  will b e e nr oll e d at t h e M T D l e v el t o o bt ai n a d diti o n al d at a o n 
s af et y, P K  a n d P D . T h e M T D of B N T 1 4 1 i n c o m bi n ati o n wit h n a b -p a clit a x el a n d 
g e m cit a bi n e i n P art  1 B will n ot e x c e e d t h e m o n ot h er a p y B N T 1 4 1 M T D d et er mi n e d 
i n P art 1 A.  
• 
P art  2 ( E x p a n si o n) c o n si st s of t h e f oll o wi n g pr e -d efi n e d e x p a n si o n c o h ort s:  
 
 
  
 
 
  
T h e s a m pl e si z e a n d d e si g n i n P art  2 will b e f urt h er d et er mi n e d b a s e d o n c ar ef ul 
e v al u ati o n of all a v ail a bl e s af et y, P K a n d P D , a n d effi c a c y d at a g e n er at e d i n P art s  1 A a n d 
1 B b y t h e S R C a n d will b e f urt h er d efi n e d vi a a n a m e n d m e nt.  
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Section 1.2 depicts the overall trial design. Details of Part 1A are described in 
Section 4.1.4.1. 
Dose escalation in Part 1A and Part 1B will follow a classical 3+3 design. In each dose 
level, 3 to 6 DLT-evaluable patients will be enrolled (2 patients where 2 DLTs have 
occurred). There will be a minimum of 48 h between the first and second patient, and 
between the second and third patient, in each dose cohort to account for any acute safety 
signals in each new dose level. To further augment patient safety, there will be a minimum 
of 14 d between the first, second and third patient enrolled in the first dosing cohort in each 
of the monotherapy (Part 1A) and the combination (Part 1B) escalation parts of the trial. 
Part 1A monotherapy dose escalation will be initiated first. In Part 1A, a pharmacology 
guided dose escalation (PGDE) approach will be taken into consideration for guiding the 
dose range of BNT141, where anti-tumor activity is expected, and the timing of Part 1B 
initiation. 
 
 
 Based on extrapolation from preclinical in vitro data and considering patient 
variability, a Ctrough of 
 is considered as pharmacologically active and able to 
trigger the MoA-mediated anti-tumor activity in all patients throughout the treatment cycle. 
Part 1B dose escalation of BNT141 in combination with nab-paclitaxel and gemcitabine is 
planned to start before the MTD/RP2D is reached in Part 1A or at latest at the MTD dose 
level using a bifurcated trial design. Bifurcation in Part 1B is planned to start when a dose 
level with the target Ctrough is reached in Part 1A and after this dose level is fully evaluated 
and deemed safe as monotherapy in the 3+3 design. 
 
 
 The 
sponsor together with the SRC may explore intermediate dose levels to bifurcate from 
monotherapy to combination dose escalation based on safety, PK, PD and preliminary 
efficacy data generated. For further understanding of the safety, tolerability and PK of 
BNT141, up to 6 additional patients may be enrolled at preceding dose levels or to 
intermediate dose levels in Parts 1A and 1B, while proceeding with further dose escalation 
or even thereafter. 
The dose level of BNT141 
 
 
 This shall lead to the timely optimization of the combination schedule that 
will be taken to Part 2 (Expansion). At the same time, patient safety is safeguarded by 
generating sufficient monotherapy data before bifurcation, and clear rules for parallel dose 
escalations are outlined. 
In Part 2, two pre-defined expansion cohorts will be opened. The sample size and 
statistical design of those cohorts will be further defined via an amendment, based on 
careful evaluation of all available safety, PK and PD, and efficacy data obtained in 
Parts 1A and 1B. 
 
 
 
 
 
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 Furthermore, more expansion cohorts to test 
safety, as well as to confirm the treatment dose and schedule may be opened and 
operationalized according to a protocol amendment. The decision to have additional 
cohorts will be based on the totality of data generated in Parts 1A and 1B of the trial. All 
decisions for cohort expansion will be endorsed by the SRC.  
In Part 1A, efficacy will be assessed by on-treatment imaging assessed locally by the 
investigator at Week 6 (±7 d), every 6 weeks (±7 d) for 24 weeks, and every 12 weeks 
(±7 d) thereafter. In Part 1B efficacy will be assessed by on-treatment imaging at Week 8 
(±7 d), every 8 weeks (±7 d) for 24 weeks, and every 12 weeks (±7 d) thereafter. Efficacy 
assessments will continue until disease progression is assessed by the investigator, 
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 and stored to the 
central imaging vendor.  
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. 
Safety will be assessed on a regular basis by means of clinical and laboratory parameters, 
as defined in the SoA.  
PK and various PD markers, which might act as anti-tumor, and safety indicators of activity 
of BNT141 monotherapy and in combination with nab-paclitaxel and gemcitabine, will be 
evaluated, as defined in the SoA. 
The overall trial design is shown in Section 1.2. 
4.1.1 
MTD, MAD and RP2D definitions 
The MTD is defined as the highest tolerated dose. The MAD is defined as the highest dose 
administered, where all dose levels were tolerated during dose escalation. 
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 not exceed the MTD.  
Toxicities other than DLTs will be considered, including: TEAEs assessed as related to 
BNT141 treatment but not considered dose-limiting, the nature and frequency of toxicities, 
and the emergence of any specific category of toxicities. Further data will be considered, 
including:  
• 
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 preceding dose levels or to intermediate 
dose levels for up to six 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 
Pre-screening 
The pre-screening is intended to identify patients with CLDN18.2-positive tumors, before 
they sign the trial-specific informed consent and they enter into trial screening. Patients will 
sign a pre-screening ICF to specifically allow the collection and testing of tumor tissue by a 
validated immunohistochemistry assay. Patients undergoing pre-screening must have 
tumor types eligible for the trial, as defined in Part 1A, Part 1B and Part 2 eligibility criteria. 
Tumor tissue must be obtained from each patient. Both fresh and archival biopsies will be 
accepted. Both biopsies should be sent preferably as slides from FFPE or as FFPE blocks. 
Bone biopsies are not allowed. Cytology specimens (including fine needle aspirates 
(FNA)) will not be accepted for this trial. 
After completion of the pre-screening assay, the remaining (unused) part of a sample will 
be either banked for future research (optional), destroyed or, in case tumor blocks were 
sent, returned to trial sites upon request.  
Demographic information including sex, year of birth/age, and self-reported race/ethnicity 
will be also collected during pre-screening. 
4.1.3 
Screening 
Screening will occur ≤ 21 d prior to Visit C1. Patients will sign an ICF prior to any 
screening related procedures. 
Eligibility status will be determined and be provided to the physician that submitted the 
patient’s tissue for testing. 
Medical history includes cancer history (including but not limited to, prior cancer therapies 
and procedures and tumor characteristics such as mutation status, cancer related somatic 
genomic alterations and germline status, other clinically relevant diseases, surgeries, use 
of alcohol and/or drugs abuse and reproductive status).Refer to Section 1.3 for the 
assessments to be performed at screening. 
4.1.4 
Dose escalation part 
4.1.4.1 
Part 1A: monotherapy dose escalation 
Monotherapy dose escalation (Part 1A) will follow a classical 3+3 design. In each dose 
level, 3 to 6 DLT-evaluable patients will be enrolled (2 patients where 2 DLTs have 
occurred). There will be a minimum of 48 h between the first and second patient, and 
between the second and third patient, in each dose cohort to account for any acute safety 
signals in each new dose level. To further augment patient safety, there will be a minimum 
of 14 d between the first, second and third patient enrolled in the first dosing cohort in 
Part 1A of the trial. 
Hospitalization 
 in Cycle 
 for all patients is at the discretion of the 
investigator. For the assessment of each cohort, the DLTs will be collected for the first 
treatment cycle, i.e., a DLT evaluation period of 21 d. 
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 7). 
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Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 4 6  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
 w e e x p e ct t h at a p h ar m a c ol o gi c all y a cti v e d o s e 
c a n b e d eli v er e d at t h e s af e st arti n g d o s e of 0. 1 5  m g/ k g, c orr e s p o n di n g t o a p pr o xi m at el y 
7  μ g/ m L Ri b o M a b 0 1 at C m a x . F urt h er, 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, i niti al d o s e d o u bli n g or tri pli n g i s p er mitt e d. 
 
 
 F urt h er m or e, t h e s p o n s or 
pr o p o s e s  
 o pti o n al, i nt er m e di at e d o s e l e v el s at 
 0. 4 5,
 
 m g/ k g.  O n c e t h e M T D i s r e a c h e d, u p t o 1 0 a d diti o n al p ati e nt s  wit h C L D N 1 8. 2 -
e x pr e s si n g p a n cr e ati c a n d bili ar y tr a ct c a n c er s will b e e nr oll e d at t h e M T D l e v el t o o bt ai n 
a d diti o n al d at a o n s af et y, P K  a n d P D . 
T o b e eli gi bl e f or D L T a s s e s s m e nt, p at i e nt s s h o ul d r e c ei v e o n e a d mi ni str ati o n of B N T 1 4 1 
d uri n g C y cl e 1 ( D L T a s s e s s m e nt p eri o d). P ati e nt s w h o will n ot b e a bl e t o f ulfil l t h e crit eri a 
f or t h e D L T a s s e s s m e nt will b e r e pl a c e d (t hi 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). R e pl a c e d p a ti e nt s c a n c o nti n u e wit h B N T 1 4 1 tr e at m e nt a n d f oll o w t h e 
s a m e tri al pr o c e d ur e s e x c e pt f or D L T a s s e s s m e nt u ntil t h e y m e et t h e pr ot o c ol -d efi n e d 
tr e at m e nt di s c o nti n u ati o n crit eri a. 
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 a t 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, a n d a v ail a bl e 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. 4. 2  
D o s e e s c al ati o n i n P art  1 B  
T h e r ul e s a n d d et ail s o n t h e bif ur c at e d d e si g n ar e o utli n e d i n S e cti o n  4. 1 . P art  1 B will 
i n v ol v e do s e e s c al ati o n of B N T 1 4 1 i n c o m bi n ati o n wit h n a b -p a clit a x el a n d g e m cit a bi n e i n 
p ati e nt s wit h C L D N 1 8 . 2-p o siti v e  u nr e s e ct a bl e l o c all y a d v a n c e d or m et a st ati c p a n cr e ati c 
a d e n o c ar ci n o m a a n d c h ol a n gi o c ar ci n o m a w h o ar e eli gi bl e f or tr e at m e nt wit h n a b -
p a clit a x el a n d g e m cit a bi n e , u ntil t h e M T D a n d/ or R P 2 D ar e d efi n e d.  
T h e d o s e e s c al ati o n i n P art  1 B f oll o w s t h e cl a s s i c al 3 + 3 d e si g n a s d e s cri b e d a b o v e i n 
S e cti o n  4. 1. 4. 1 . I n e a c h d o s e l e v el, 3 t o 6 D L T-e v al u a bl e p ati e nt s will b e e nr oll e d 
( 2 p ati e nt s w h er e 2 D L T s h a v e o c c urr e d) . T h er e will b e a mi ni m u m of 4 8  h b et w e e n t h e 
fir st a n d s e c o n d p ati e nt, a n d b et w e e n t h e s e c o n d a n d t hir d p ati e nt, i n e a c h d o s e c o h ort t o 
a c c o u nt f or a n y a c ut e s af et y si g n al s i n e a c h n e w d o s e l e v el. T o f urt h er a u g m e nt p ati e nt 
s af et y, t h er e wil l b e a mi ni m u m of 1 4  d b et w e e n t h e fir st, s e c o n d a n d t hir d p ati e nt  e nr oll e d 
i n t h e fir st d o si n g c o h ort i n P art  1 B of t h e tri al. 
Bif ur c ati o n i n P art  1 B i s pl a n n e d t o st art w h e n a B N T 1 4 1 d o s e l e v el wit h t h e t ar g et C tr o u g h 
i s r e a c h e d i n P art  1 A d o s e e s c al ati o n, a n d aft er t hi s d o s e l e v el i s f ull y e v al u at e d a n d 
d e e m e d s af e a s m o n ot h er a p y i n t h e 3 + 3 d e si g n.  At t hi s p oi nt, P art  1 B m a y st art 
 
 
 
 N a b -p a clit a x el a n d g e m cit a bi n e will b e a d mi ni st er e d a s S O C r e gi m e n. B N T 1 4 1 will 
b e s u b s e q u e ntl y e s c al at e d t o d efi n e t h e M T D a n d/ or R P 2 D of t h e c o m bi n ati o n. D o s e 
e s c al ati o n will f oll o w a cl a s s i c al 3 + 3 d e si g n a n d c o nti n u e u ntil D L T s ar e o b s er v e d i n 2/ 3 or 
2/ 6 p ati e nt s a s o utli n e d  i n T a bl e  8 . O n c e t h e M T D i s r e a c h e d, u p t o 1 0 a d diti o n al p ati e nt s  
wit h C L D N 1 8. 2 -e x pr e s si n g p a n cr e ati c a d e n o c ar ci n o m a or c h ol a n gi o c ar ci n o m a  will b e 
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enrolled at the MTD level to obtain additional data on safety, PK and PD. The MTD of 
BNT141 in combination with nab-paclitaxel and gemcitabine in Part 1B will not exceed the 
monotherapy BNT141 MTD determined in Part 1A. 
Hospitalization 
 in Cycle 1 
 for all patients is at the discretion of the 
investigator. For the assessment of each cohort, the DLTs will be collected for the first 
treatment cycle, i.e., a DLT evaluation period of 28 d. BNT141 will be administered IV 
 
 of the first 28-day cycle and Q3W thereafter. Nab-paclitaxel and 
gemcitabine will be administered IV on 
 of each 28-day cycle. The days of 
administration of BNT141 and nab-paclitaxel and gemcitabine are shown in Table 9 and 
the recommended doses in Section 6.1.2. Based on Part 1B PK, PD, PK/PD modeling and 
clinical data, 
 
. In the event that a dose level in Part 1B meets the 
classification for MTD, dosing in Part 1B will stop. To be eligible for DLT assessment, 
patients should receive: 
 
 
  
 
 
 
 
 
 
  
Patients who will not be able to fulfill the criteria for the DLT assessment will be replaced 
(this only applies to patients who do not experience a DLT). Replaced patients can 
continue with BNT141 treatment and follow the same trial procedures except for DLT 
assessment until they meet the protocol-defined treatment discontinuation criteria. 
The monotherapy dose escalation in Part 1A can proceed independently of Part 1B until 
MTD and/or RP2D of BNT141 monotherapy are established. Refer to Section 6.6.4 for 
safety stopping criteria. 
4.1.5 
Expansion part 
Once Parts 1A and 1B are completed, the trial will proceed with Part 2 (Expansion). This 
will be conducted in the two following indication-specific cohorts:  
• 
CLDN18.2-positive 
 
 eligible for treatment with nab-paclitaxel and gemcitabine.  
• 
CLDN18.2-positive 
 
 eligible for treatment with nab-paclitaxel and gemcitabine.  
The sample size and statistical design of Part 2 will be further defined via an amendment, 
based on careful evaluation of all available safety, PK and PD, and efficacy obtained in 
Parts 1A and 1B.  
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4.1.6 
Safety follow-up period 
Safety monitoring assessments will be performed from the last dose of BNT141 or nab-
paclitaxel and gemcitabine until 60 d after and the last Safety Follow-up Visit. 
4.1.7 
Survival follow-up 
Information on survival follow-up, new anti-cancer therapy (including targeted therapy and 
immunotherapy) and cancer-related procedures will be collected for all patients via 
telephone calls, patient medical records, and/or clinic visits from BNT141 treatment 
discontinuation and approximately every 12 weeks until death (unless the patient 
withdraws consent or the sponsor terminates the trial). If the patient withdraws from trial, 
the trial staff may use a public information source (e.g., county records) to obtain 
information about survival status only. 
4.1.8 
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 will only be introduced via an amendment to this protocol. 
• 
Addition or removal of PK time points depending on emerging data on BNT141 can 
be performed based on SRC recommendation. Samples at various time points 
post-injection may be added based on emerging data from this trial. If the PK data 
are uninformative, one or more time points may be removed. 
• 
Addition or removal of safety time points depending on emerging data on BNT141 
can be performed based on SRC recommendation. 
• 
Time points for measurement of correlative and PD assays may be added or 
reduced at the sponsor’s discretion. 
• 
For further understanding of the safety, tolerability and PK of BNT141, up to 6 
additional patients may be enrolled at preceding dose levels or to intermediate 
dose levels in Parts 1A and 1B, while proceeding with further dose escalation or 
even thereafter. However, the data collected will not influence the determination of 
MTD in the leading dose escalation part of the trial. 
• 
Intermediate dose levels or an alternative dosing schedule can be implemented 
based on SRC recommendation. 
• 
Based on careful evaluation of PK and PD data, PK/PD modeling and after 
endorsement by the SRC committee, an alternative dosing schedule of BNT141 
may be investigated, 
 
 
 
4.1.9 
Planned number of patients 
The sample size for trial Part 1A and Part 1B is driven by the classical 3+3 trial design and 
will range from three to six DLT-evaluable patients per cohort depending on the 
occurrence of DLTs. In both trial Parts 1A and 1B, the sample size will be up to 48 DLT-
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Bi o N T e c h S E  
C o nfi d e nti al  
C LI NI C A L T RI A L P R O T O C O L  
B N T 1 4 1 -0 1  
P a g e 4 9  of 1 2 2  
V er si o n: 4. 0  
D at e: 1 3 J U N 2 0 2 2  
 
e v al u a bl e p ati e nt s i n e a c h p art d e p e n di n g o n t h e D L T s, w hi c h m a y o c c ur. O n c e t h e M T D 
i s r e a c h e d, u p t o 1 0 a d diti o n al p ati e nt s  wit h C L D N 1 8. 2 e x pr e s si n g p a n cr e ati c a n d bili ar y 
tr a ct c a n c er s will b e e nroll e d at t h e M T D l e v el i n P art s 1 A a n d u p t o 1 0 a d diti o n al p ati e nt s 
wit h C L D N 1 8. 2 e x pr e s si n g p a n cr e ati c a d e n o c ar ci n o m a a n d c h ol a n gi o c ar ci n o m a i n 
P art  1 B r e s p e cti v el y, t o o bt ai n a d diti o n al d at a o n s af et y, P K  a n d P D . N o n -D L T -e v al u a bl e 
p ati e nt s will b e r e pl a c e d. T h e s a m pl e si z e a n d d e si g n i n P art  2 will b e f urt h er d et er mi n e d 
aft er c ar ef ul e v al u ati o n of all a v ail a bl e s af et y, P K a n d P D , a n d effi c a c y d at a g e n er at e d i n 
P art s  1 A a n d 1 B b y t h e S R C a n d will b e f urt h er d efi n e d vi a a n a m e n d m e nt.  
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  
P art  1 A of t hi s tri al i s a n  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 4 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 C L D N 1 8 . 2-p o siti v e  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 pr eli mi n ar y effi c a c y  of B N T 1 4 1. P art  1 B ai m s t o d et er mi n e 
t h e s af et y pr ofil e, P K a n d pr eli mi n ar y effi c a c y of B N T 1 4 1 i n c o m bi n ati o n wit h n a b -
p a clit a x el a n d g e m cit a bi n e . T h e tri al c o nti n u e s wit h t h e e x p a n si o n p h a s e (P art  2) t o 
e x pl or e f urt h er B N T 1 4 1 i n c o m bi n ati o n wit h n a b -p a cl it a x el a n d g e m cit a bi n e i n s el e ct e d 
t u m or i n di c ati o n s. 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.  
4. 2. 1  
Tri al d e si g n r ati o n al e f or P art  1 A: M o n ot h er a p y d o s e e s c al ati o n  
I n t h e m o n ot h er a p y d o s e e s c al ati o n P art  1 A, a P G D E a p pr o a c h will b e t a k e n i nt o 
c o n si d er ati o n f or g ui di n g t h e d o s e r a n g e of B N T 1 4 1 w h er e a nti -t u m or a cti vit y i s e x p e ct e d, 
a n d t h e ti mi n g of P art  1 B i niti ati o n . 
 
 
B a s e d o n e xtr a p ol ati o n fr o m t h e s e d at a t h e t ar g et P K p ar a m et er t o i nf or m f urt h er d o s e 
e s c al ati o n f or P art  1 A i s C tr o u g h a n d i s s et t o 
 ( s e e S e cti o n  4. 3 ). 
 
 
 
 T h e t ar g et Ctr o u g h of 
 s h o ul d b e 
hi g h e n o u g h t o tri g g er  
 i n all p ati e nt s t hr o u g h o ut t h e 2 1 -d a y d o si n g c y cl e, 
c o n si d eri n g p ati e nt v ari a bilit y, w hil e  li miti n g p ot e nti al t o xi cit y wit h t h e hi g h er d o s e t h at m a y 
b e r el at e d t o t h e L N P -f or m ul at e d R N A dr u g pr o d u ct. 
 
 
  
 
 
 
 
 
F urt h er m or e, t h e P G D E m et h o d i s a p pr o pri at e b e c a u s e:  
• 
R e al -ti m e P K r e s ult s will b e o bt ai n e d, w hi c h ar e r e q uir e d t o d et er mi n e t h e s af et y of 
t h e s u b s e q u e nt d o s e e s c al ati o n. 
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• 
 
 
 
 
• 
Since the structure of the expressed RiboMab
 is based on an 
 antibody, its 
metabolism is similar to that of endogenous 
 molecules.  
The approach is also in line with the EMA Guideline on strategies to identify and mitigate 
risks for FIH and early clinical trials with investigational medicinal products. 
4.2.2 
Trial design rationale for bifurcated design 
The development rationale for combination therapy is to leverage many different pathways 
to target both safe and effective tumor cell death. This is to be achieved by combining 
BNT141 with an already efficient but not durable cytotoxic treatment. Therefore, rapid 
triggering of combination testing is desired where BNT141 upon target binding mediates 
cell killing by ADCC and CDC. One of the common approaches to assess the effect of 
combining an IMP with another drug early on in clinical development, is to use a bifurcated 
design, which is used in Part 1 of this trial.  
This approach will allow for rapid and safe combination dose escalation for timely 
optimization of the combination schedule that will be taken into the Part 2 part of the trial. 
At the same time, patient safety is safeguarded by generating enough monotherapy data 
before bifurcation. In addition, clear rules for parallel dose escalations are outlined. 
4.2.3 
Trial design rationale for Part 2: Expansion Phase 
The trial design in the expansion cohorts will be either a Simon two-stage design or a 
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 
useful for trials of novel agents (where little is known about the treatment) or for rare 
disorders, where it is appropriate to minimize the sample size. 
4.3 
Justification for dose 
The proposed starting dose for the FIH trial of BNT141 is 0.15 mg/kg every 3 weeks. This 
is based on a comprehensive evaluation of the toxicology program in mice and NHP 
supporting 1.5 mg/kg once weekly as a safe dose, a safety margin of 10 to account for 
unexpected toxicities, and the utilization of a less frequent dosing regimen of BNT141 in 
the clinic (every 3 weeks as compared to the once weekly schedule utilized in the 
toxicology studies), which is anticipated to provide benefit based on the pharmacokinetic 
properties of the intact translated protein RiboMab
. For further details on dose 
justification, please refer to Section 4.1.4. 
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4.4
End of trial definition
The trial is considered completed when all patients: 
•
have had at least 12 months survival follow up OR 
•
are lost to follow up OR
•
have withdrawn consent OR
•
have died
OR the sponsor discontinues the trial. 
However, the maximum trial duration is 3 years after the last subject’s first treatment in the 
trial.
A patient is considered to have completed the trial if they have discontinued BNT141 
treatment and have completed safety follow up (Day 60). 
5
TRIAL POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion criteria
Each patient who meets all of the following criteria is eligible to enroll in the trial.
5.1.1
Disease-specific inclusion criteria
For all parts 
Metastatic or unresectable solid tumor.
Histological or cytological documentation of a solid tumor via a pathology report.
CLDN18.2-positive tumor sample defined as moderate-to-strong CLDN18.2 protein 
expression defined as intermediate (2+) to strong (3+) staining intensity in ≥50% of 
tumor cells as assessed by central testing using a CLIA-validated 
immunohistochemistry assay in FFPE neoplastic tissues. New biopsies and archival 
bio-samples are allowed. Bone biopsies are not allowed. Cytology specimens 
(including fine needle aspirates) will not be accepted for CLDN18.2 examination. If 
archival tissue samples from several points of time are available, the most recent one 
is preferred. Patients with a lower expression level or with CLDN18.2-negative cancers 
are not eligible. 
Trial part-specific inclusion criteria:
•
For Part 1A: Patients with unresectable or metastatic histologically or cytologically 
confirmed solid tumors for which there is no available standard therapy to confer 
clinical benefit, or the patient is not a candidate for such available therapy. Patients 
must have received all available standard therapies and failed at least first-line 
SOC therapy prior to enrolment. Measurable or evaluable disease per RECIST 1.1.
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esophageal adenocarcinoma, pancreatic, biliary tract (cholangiocarcinoma and 
gallbladder cancer), and mucinous ovarian cancers. Additionally, patients with 
specific tumors (including colorectal cancer, non-small-cell lung cancer, gastric 
subtype of endocervical adenocarcinoma) where there is scientific evidence that 
the CLDN18.2 could be elevated can be tested for CLDN18.2 expression.
•
For Part 1B: Patients with histologically confirmed advanced unresectable or 
metastatic pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for 
treatment with nab-paclitaxel and gemcitabine. Measurable or evaluable disease 
per RECIST 1.1.
•
For Part 2: 
−
Cohort 1 –
eligible for 
treatment with nab-paclitaxel and gemcitabine. Measurable disease per 
RECIST 1.1.
−
Cohort 2 –
eligible for treatment with nab-
paclitaxel and gemcitabine. Measurable disease per RECIST 1.1.
5.1.2
Other inclusion criteria
For all parts 
Signed an ICF prior to any trial-related assessments or procedures indicating that he 
or she understands the purpose of and procedures required for the trial and is willing to 
participate in the trial. 
ECOG PS of 0 to 2.
Life expectancy of at least 3 months.
≥18 years of age.
Adequate coagulation function at screening as determined by:
−
International normalized ratio (INR) or prothrombin time ≤1.5 x upper limit 
normal (ULN; unless on therapeutic anticoagulants with values within 
therapeutic window). 
−
Activated partial thromboplastin time (aPTT) ≤1.5 x ULN (unless on therapeutic 
anticoagulants with values within therapeutic window).
Adequate hematologic function at screening as determined by:
−
White blood count (WBC) ≥3 × 109/L.
−
Absolute neutrophil count (ANC) ≥1.5 × 109/L (patient may not use granulocyte
colony stimulating factor or granulocyte-macrophage colony stimulating factor 
to achieve these WBC and ANC levels in the past 7 d).
−
Platelet count ≥100 × 109/L.
−
Hemoglobin ≥8.5 g/dL (may not transfuse or use erythropoietin to obtain this 
level in the past 7 d).
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Adequate hepatic function at screening as determined by:
−
Total bilirubin ≤1.5 mg/dL (or ≤3.0 mg/dL for patients with known Gilbert’s 
syndrome or liver metastasis).
−
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x ULN; ≤3 ULN for patients with liver metastasis.
−
Albumin ≥25 g/L
Adequate renal function at screening as determined by:
−
Glomerular filtration rate 30 mL/min/1.73 m² – according to the abbreviated 
Modification of Diet in Renal Disease equation:
Glomerular filtration rate (GFR) = 186 × (Screatinin-1.154) × (age-0.203)
(where the serum creatinine level is expressed in mg/dL; multiply it by 0.742 if the 
patient is female; multiply it by 1.212, if the patient is African-American [Levey et al. 
1999]).
Able to attend trial visits as required by the protocol.
Women of childbearing potential (WOCBP) must have a negative serum (beta-human 
chorionic gonadotropin) at screening. For a definition of WOCBP, see Section 10.4.
Unless practicing true sexual abstinence, WOCBP must agree to practice one highly 
effective form of contraception during the trial and for 6 months after receiving the last 
dose of BNT141. WOCBP will also be recommended to use one acceptable method of 
contraception in addition. For definitions of highly effective and acceptable methods of 
contraception, see Section 10.4.2.
WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the entire trial, until 6 months after the last BNT141 treatment.
Men who are sexually active with WOCBP and who have not had a vasectomy must 
agree to use a barrier method of birth control, during the trial and for 6 months after 
receiving the last dose of BNT141 (see Section 10.4.2 for information on effective 
contraceptive methods).
Men must agree to not donate sperm during the trial and for 6 months after receiving 
the last dose of BNT141.
5.2
Exclusion criteria
A patient who meets any of the following criteria will be excluded from trial participation. 
Prior and concomitant therapy
Receiving: radiotherapy, chemotherapy, or molecularly-targeted agents within 3 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
(excluding BNT141); nitrosoureas, antibody-drug conjugates, or radioactive isotopes 
within 6 weeks of the start of trial treatment. Palliative radiotherapy will be allowed.
Receives concurrent systemic (oral or IV) steroid therapy > 10 mg prednisone daily or 
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or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment and is permitted.
Major surgery within the 4 weeks before the first dose of BNT141.
Prior treatment with a CLDN18.2 targeting mAb other than BNT141.
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 BNT141, including 
serious COVID-19 infection.
Side effects of any prior therapy or procedures for any medical condition not recovered 
to NCI-CTCAE v.5 Grade ≤1, with the exception of anorexia, fatigue, hyperthyroidism, 
hypothyroidism, and peripheral neuropathy, which must have recovered to ≤Grade 2. 
Alopecia of any grade is allowed.
Received any live vaccine within 30 days prior to the start of trial treatment.
Medical conditions
Current evidence of new or growing brain or leptomeningeal metastases during 
screening. Patients with known brain or leptomeningeal metastases may be eligible if 
they have: 
−
Radiotherapy, surgery or stereotactic surgery for the brain or leptomeningeal 
metastases.
−
No neurological symptoms (excluding Grade ≤2 neuropathy).
−
Stable brain or leptomeningeal disease on the computer tomography (CT) or 
MRI scan within 4 weeks before signing the informed consent.
−
Not undergoing acute corticosteroid therapy or steroid taper.
Notes: Patients with central nervous system 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.
History of seizures other than isolated febrile seizure during childhood; has a history of 
a cerebrovascular accident or transient ischemic attack less than 6 months before 
Screening.
Active immunologic disorder requiring immunosuppression with steroids or other 
immunosuppressive agents (e.g., azathioprine, cyclosporine A).
Known history of seropositivity for human immunodeficiency virus with CD4+ T-cell 
counts < 350 cells/µL and with a history of acquired immunodeficiency syndrome-
defining opportunistic infections.
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 viral load below the limit of quantification.
Active hepatitis C virus (HCV) infection; patients who have completed curative antiviral 
treatment with HCV load below the limit of quantification are allowed.
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Another primary malignancy that has not been in remission for at least 2 years, with 
the exception of those with a negligible risk of metastasis or death (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized 
prostate cancer, or ductal carcinoma in situ).
Other comorbidities
Abnormal electrocardiograms that are clinically significant, such as Fridericia-corrected 
QT prolongation > 480 ms.
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 (New York Heart Association 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.
−
Arterial thromboembolic event within the previous 6 months.
−
Significant pulmonary disease (shortness of breath at rest or on mild exertion) 
for example due concurrent severe obstructive pulmonary disease.
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 and compliance with the protocol-
required visits and procedures.
Pregnant or breastfeeding.
Concurrent enrolment in another clinical trial, unless it is a non-interventional clinical 
study.
5.3
Lifestyle considerations
Patients should avoid using drugs of abuse throughout their time of enrolment in the trial
unless such drugs are specifically prescribed (e.g., morphine).
5.3.1
Meals and dietary restrictions
There are no meals or dietary restrictions.
5.3.2
Caffeine, alcohol, and tobacco
Patients should refrain from alcohol for a minimum of 24 h prior to each visit. Patients 
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5.3.3 
Activity restrictions 
Patients should refrain from vigorous exercise for 24 h prior to blood chemistry testing. 
5.4 
Screen failures 
Pre-screening failures are patients who consent to have their tumor tissue tested for 
CLDN18.2-positivity, but do not show the desired expression level of CLDN18.2 antigen 
per protocol. They will not proceed further to the screening phase as they are not eligible 
for the trial. Pre-screening failures may be rescreened once, in cases where the tumor 
CLDN18.2-positivity could not be assessed. Patients must re-sign the pre-screening ICF 
prior to repeated pre-screening in case an additional biopsy is needed. 
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 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). 
Screen failures may be rescreened. Patients who fail their first screening for trial eligibility 
may qualify for two re-screening opportunities (for a total of three screenings per patient) 
at the investigator’s discretion. Patients must re-sign the ICF prior to any re-screening. 
Rescreened patients will be assigned a new patient number. 
6 
TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatments intended to be administered to 
a trial patient according to the trial protocol. 
6.1 
Trial treatments administered 
6.1.1 
Investigational medicinal product 
The IMP in all parts of the trial is BNT141. The IMP is 
 
 for IV administration. Each vial is intended 
for single use. Detailed information will be given in the Pharmacy Manual. 
In Part 1A, BNT141 will be administered IV as monotherapy 
 of 
each 3-week treatment cycle (21 d/Q3W) after all required procedures and assessments 
before administration have been completed. Trial visits will be performed weekly for the 
first 4 cycles (Days 1, 8, 15). After the first 4 cycles, trial visits will be performed at Day 1 of 
each subsequent cycle. 
Patients will be administered BNT141 in Part 1A according to dose levels outlined in 
Table 8. 
 
. 
When given in combination with nab-paclitaxel and gemcitabine in Part 1B, BNT141 will be 
administered as an IV infusion 
 for the first 
two dose levels (0.15 and 0.3 mg/kg) and at a minimum of 
 before the first infusion of 
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cytotoxic therapy. The SRC should decide about the minimal infusion time / maximal 
infusion speed for further cohorts after careful analysis of collected safety data. BNT141 
will be further administered every three weeks and chemotherapy will follow the approved 
schedule according to local guidelines. Each cycle in Part 1B will be 28 d. Based on 
Part 1B PK, PD, PK/PD modeling and clinical data, 
 
 
 The days of administration of BNT141 and nab-
paclitaxel and gemcitabine are shown in Table 9. 
 
Table 9: 
Days of administration of BNT141 and nab-paclitaxel and gemcitabine in Part 1B 
 
For each dose of BNT141, patients will be monitored for at least 4 h post administration. 
An overnight stay at the trial site 
 
 due to the extensive PK sampling for all patients is recommended, but 
optional and depends on patient preference (e.g., with regard to travel times to the site), 
overall health status and foremost decision of the investigator based on any safety 
concerns. Trial visits will be performed weekly for the first 4 cycles (Days 1, 8, 15, 22). 
After the first 4 cycles, trial visits will be performed at the days where BNT141 and/or nab-
paclitaxel and gemcitabine are administered.  
Pre- and post-medications with antipyretics (e.g., acetaminophen, nonsteroidal anti-
inflammatory drugs), anti-emetics, histamine type 2 (H2) receptor antagonists or proton-
pump inhibitors and anxiolytics per institutional guidelines are allowed. If necessary, 
patients should be properly pre-hydrated before BNT141 treatment. Corticosteroids should 
not be used as premedication for BNT141 with the exception of patients who have 
experienced prior administration related Grade 2 or Grade 3 reactions in the trial. 
Premedication to prevent IRR in subsequent administrations may be administered at the 
investigator’s discretion according to local guidelines and if considered necessary, patients 
should receive corticosteroids at a suggested maximum dose of 100 mg prednisone or 
equivalent. 
Further details on the administration of BNT141 in additional cohorts in Part 2 will be 
provided in a protocol amendment after careful evaluation of all available safety, PK and 
PD, and efficacy data generated in Parts 1A and 1B by the SRC. 
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6.1.2 
Non-investigational medicinal product 
6.1.2.1 
Gemcitabine 
The recommended dose of gemcitabine for treatment of pancreatic cancer and 
cholangiocarcinoma is 
 over 30 min IV infusion on 
 of each 
28-day cycle (
).  
Please refer to the US Prescribing Information (USPI) or Summary of Product 
Characteristics (SmPC) for further information on gemcitabine, including dose modification 
options. 
6.1.2.2 
Nab-paclitaxel 
The recommended dose of nab-paclitaxel for treatment of pancreatic cancer and 
cholangiocarcinoma is 
 administered as an IV infusion over 30 to 40 min on 
 of each 28-day cycle. Gemcitabine should be administered immediately 
after nab-paclitaxel 
 of each 28-day cycle (
 
). 
Please refer to the USPI or SmPC for further information on nab-paclitaxel, including dose 
modification options. 
6.2 
Preparation/handling/storage/accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all trial intervention received and any discrepancies are 
reported and resolved before use of the trial intervention. 
Only patients enrolled in the trial may receive trial treatment and only authorized site staff 
may supply or administer trial intervention. All trial intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The investigator, site, or the head of the site (where applicable) is responsible for trial 
treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused trial treatment are 
provided in the Pharmacy Manual and/or Clinical Trial Supply Manual. 
6.3 
Measures to minimize bias: randomization and blinding 
This is an open-label, non-randomized trial. 
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 
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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.  
6.5 
Concomitant therapy 
Prior treatments are any medications and non-drug therapies used by the patient up to 
21 d before trial treatment initiation 
. All prior anti-cancer treatments need 
to be collected and documented in the eCRF. Concomitant medications and therapies are 
any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, or nutritional supplements) used by a patient in addition to 
protocol-mandated treatment (including prophylactic treatment after BNT141 
administration and medications as a result of an AE). Prior/Concomitant medications and 
non-drug therapies include all anti-cancer pre-treatments and all previous and on-trial 
COVID-19 vaccinations. All such medications should be reported to the investigator and 
recorded on the Prior/Concomitant Medications eCRF along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
6.5.1 
Permitted concomitant medications and therapies 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “prohibited” 
(Section 6.5.2). Administration of concomitant medications must be reported in the 
appropriate section of the eCRF. 
• 
Palliative radiotherapy during the trial will be allowed for local pain control provided 
that each of the following is satisfied: 
− 
In the opinion of the investigator, the patient does not have progressive disease 
− 
No more than 10% of the patient’s bone marrow is irradiated 
− 
The radiation field does not encompass a target lesion 
• 
Granulocyte colony stimulating factor and other hematopoietic growth factors may 
be used in the management of acute toxicity (such as febrile neutropenia) or 
prophylactically, when clinically indicated at the investigator’s discretion.  
• 
Blood cell transfusion is allowed if clinically indicated. 
• 
Systemic (oral or IV) steroid therapy ≤ 10 mg prednisone daily or its equivalent for 
an underlying condition (refer to Section 6.5.2). 
• 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency). 
• 
Bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab. 
• 
Paracetamol/acetaminophen, or acetylsalicylic acid/aspirin, at doses of less than 
2 g/day, is permitted for use at any time during the trial. 
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•
Multivitamins, vitamin D, calcium and supplements in prevention of weight loss.
The Medical Monitor should be contacted if there are any questions regarding concomitant 
or prior therapy.
See Appendix 1 and Appendix 2 for recommendations on COVID-19 vaccination during 
trial participation.
6.5.2
Prohibited concomitant therapy
Patients must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
The following medications and substances are prohibited during the trial:
•
Any other investigational therapy.
•
Antineoplastic systemic chemotherapy or biological therapy.
•
Steroid treatment for any other purpose than to manage emergency situations 
(according to institutional standards), to modulate symptoms of an IRR, or chronic 
systemic immunosuppressive corticosteroid doses (i.e., prednisone > 10 mg daily).
•
No dietary supplements are allowed during the trial period (except for 
multivitamins, vitamin D, calcium, and supplements in prevention of weight loss). 
The use of traditional/herbal medicines is not permitted.
If a patient receives any of these during the trial, the sponsor must be notified for 
evaluation of whether the patient can continue treatment or not.
6.5.3
Premedication
Pre- and post-medications should be given to mitigate potential reactions to BNT141 or the 
translated antibody per institutional guidelines and recommendation of the SRC. 
Medications for consideration for pre- and post-medication: 
Hydration: 500 mL normal saline IV over 1 hour
H1 + H2 antihistamine:
−
IV: Diphenhydramine (Benadryl®) 50 mg + Famotidine 20 mg over 20 min OR
cetirizine (Quzyttir®) 10 mg + ranitidine 50 mg OR
−
Oral: cetirizine 10 mg + ranitidine 75 mg (3 days, starting 1 day before D1)
Antipyretic oral:
−
2-3 x 1 paracetamol (Tylenol®) 650 mg (max 2 g/day) every 4-6 hours OR
−
Paracetamol 650 mg before the infusion AND 4 hours later
−
Optional 650 mg paracetamol + 300 mg aspirin if temperature > 99.5°F 
(37.5°C)
Antiemetic: as needed
−
IV: palosonetron (Alexi®) 0.25 mg OR


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Oral: ondansetron 8 mg after study drug administration, repeated as needed
Proton-pump inhibitor: as needed
−
Omeprazole 20 mg
Corticosteroids should not be used as premedication for BNT141 with the exception of 
patients who have experienced prior administration related Grade 2 or Grade 3 reactions 
in the trial. If considered necessary, patients should receive corticosteroids at a suggested 
maximum dose of 100 mg prednisone or equivalent.
6.6
Dose modifications and safety management guidelines
6.6.1
Dose-limiting toxicity
Serious AEs, non-serious Grade ≥3 non-hematological and hematological AEs as defined 
per DLT criteria and clinically significant abnormal laboratory values Grade ≥3 will be 
collected and considered a DLT if assessed by the investigator to be at least possibly 
related to BNT141 for the Part 1A of the trial, and at least possibly related to the 
combination of BNT141 and nab-paclitaxel and gemcitabine for the Part 1B of the trial. 
Toxicities clearly not related to BNT141 (e.g., PD, comorbidity, etc.) will not be considered 
a DLT. The NCI-CTCAE v.5.0 will be used to grade the intensity of Aes.
The DLT period for the BNT141 monotherapy dose escalation in Part 1A will be 21 d. The 
DLT period for the dose escalation of BNT141 in combination with nab-paclitaxel and 
gemcitabine will be 28 d.
DLT criteria are defined below:
Hematological
•
Grade 4 neutropenia (i.e., ANC < 0.5 × 109 cells/L) lasting more than 7 d.
•
Any grade febrile neutropenia (i.e., ANC < 1.0 × 109 cells/L with a single 
temperature of > 38.3°C or a sustained temperature of ≥38°C for more than one 
hour).
•
Grade 4 thrombocytopenia (≤25.0 × 109 platelets/L).
•
Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion.
•
Grade 4 anemia.
•
Grade ≥3 hematological toxicity lasting more than 7 d.
Exception:
•
Grade 3 lymphocytopenia lasting more than 7 d that has no clinical consequence.
Non-hematological
•
Any Grade 3 cytokine release syndrome (CRS), as per the American Society for 
Transplantation and Cellular Therapy (ASTCT) Consensus grading for CRS (Lee et 
al. 2019), that does not improve to Grade 2 or below within 72 h despite medical 
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6.6.2 
Dose modification guidance/rules 
BNT141 
AEs that fulfill the DLT criteria after the DLT period has ended in the dose escalation part 
of the trial (i.e., from Cycle 2 Day 1 and beyond) or during the expansion (i.e., from Cycle 1 
Day 1 and beyond) should be handled as shown in the Figure 7. 
 
First occurrence of AE fulfilling DLT criteria Grade ≥ 3: 
• 
As a first measure, administration of BNT141 needs to be held. 
• 
Investigator must contact the sponsor to discuss whether the patient should be 
withdrawn from BNT141 treatment or if the next dose should be delayed. 
 
 
 
 
 
 
 
 
 
Second occurrence of an identical AE Grade ≥ 3 after re-exposure to BNT141: 
• 
As a first measure, administration of BNT141 needs to be held. 
 
 
 
 
 
 
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− 
Re-treatment may be considered on a case-by-case basis after review by the 
SRC. Intermediate dose levels defined in the protocol may be considered. 
Third occurrence of an identical AE Grade ≥ 2 after re-exposure to BNT141: 
• 
As a first measure, administration of BNT141 needs to be held. 
 
 
 
 
 
 
 
 
Please note: 
 
 
 
• 
BNT141 must be permanently discontinued if the patient experiences an AE 
fulfilling the DLT criteria (after the DLT period has ended for the dose escalation or 
during the expansion) that fails to resolve to Grade ≤ 1 within 21 d after the 
planned dosing date unless otherwise approved by the sponsor Medical Monitor. 
 
 
• 
BNT141 must be permanently discontinued in case of a dose delay of more than 
21 d due to toxicity possibly related to BNT141 unless otherwise approved by the 
sponsor Medical Monitor. 
The investigators are encouraged to contact sponsor in case of any safety concern that 
needs thorough discussion and evaluation. 
For AEs occurring in Part 1B and Part 2 (BNT141 in combination with nab-paclitaxel and 
gemcitabine) which are considered clearly related to the chemotherapy regimen and 
require delay or discontinuation of the chemotherapy regimen, continuation of BNT141 
administration as monotherapy is permitted at the same dose level after the AE has 
resolved to Grade ≤ 1 or baseline. 
Nab-paclitaxel and gemcitabine 
Nab-paclitaxel and gemcitabine should be dose modified as per the USPI or the SmPC. 
Recommended dosage modifications for gemcitabine for myelosuppression are described 
in Table 11. 
 
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Grade ≤1 within 21 d after the planned dosing date unless otherwise approved by 
the sponsor Medical Monitor.
•
•
in case of a dose delay of more than 21 d due to toxicity possibly related to 
BNT141 unless otherwise approved by the sponsor Medical Monitor.
•
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 after they have withdrawn.
Trial stopping rules
If any of the below-listed events occurs, a prompt cumulative review of safety data will be 
conducted by the SRC to determine whether the trial will be discontinued permanently.
If, at any time, all dose levels are considered unsafe as defined by the SRC.
Any safety finding assessed as related to BNT141 that, in the opinion of the SRC, 
contraindicates further dosing of trial patients.
Any death possibly related to the IMP occurring within 30 d of receiving IMP.
The occurrence of two Grade ≥4 DLTs in two trial participants.
At any time during repeat treatment, if more than 33% of trial participants develop AEs
meeting DLT criteria, regardless if it is within or outside of the defined DLT evaluation 
window, the trial cohort shall be paused pending a safety evaluation by the SRC and 
sponsor.
For each individual patient who has already received BNT141 and is currently in the trial at 
the time the trial stopping criteria are met, the risk/benefit whether to stop or continue 
treatment will be assessed. To allow continuation of treatment, SRC consultation will be 
considered. All patients exposed to BNT141 should continue to be followed by the 
investigator for safety.
Where applicable, regulatory authorities and independent ethics committees 
(IECs)/institutional review board (IRBs) will be notified of any significant actions taken with 
the trial.
6.7
Treatment after the end of the trial
The Investigator together with the sponsor will decide on and ensure post-trial treatment 
for ongoing trial participants with a potential treatment benefit.
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7 
DISCONTINUATION OF TRIAL TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of trial treatment 
Patients will receive BNT141 treatment until one of the pre-defined discontinuation of 
treatment criteria has been met:  
• 
Radiographic disease progression per RECIST 1.1 (see Imaging Manual). If the 
investigator assesses that the patient has clinical benefit from continuation of 
the trial drug and after discussion with the sponsor, treatment can continue 
beyond progression provided that the patient is tolerating the trial drug and 
treatment beyond progression will not delay an imminent intervention to prevent 
serious complications for PD (e.g., CNS metastases requiring immediate 
treatment). 
• 
Death. 
• 
Unacceptable AEs requiring BNT141 discontinuation (refer to safety stopping 
criteria Section 6.6.4). 
• 
Investigator believes that it is in the best interest of the patient to stop BNT141 
treatment. 
• 
Withdrawal of consent. 
• 
Pregnancy. 
• 
Lost to follow-up. 
• 
Trial termination by the sponsor. 
If trial treatment is definitively discontinued, the patient will remain in the trial to be 
evaluated for safety and survival follow-up.  
Patients who discontinue treatment for reasons other than radiographic disease 
progression (e.g., toxicity) will continue scheduled tumor assessments at the same 
frequency as would have been followed if the patient had remained on trial treatment. 
Patients should, whenever possible, irrespective of the reason for discontinuation, be 
examined as soon as possible after withdrawal. 
See the SoA (Section 1.3) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.1 
Temporary discontinuation 
See section on safety stopping criteria (Section 6.6.4). 
7.2 
Patient discontinuation/withdrawal from the trial 
Patients will be withdrawn from the trial (dose escalation or expansion phases [Part 1A or 
Part 1B]) 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. Refer to the SoA in Section 1.3 for the 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. The trial drug assigned to the withdrawn patient may 
not be assigned to another patient. 
7.3 
Lost to follow-up 
A patient will be considered lost to follow-up if they fail to return for scheduled visits and is 
unable to be contacted by the trial site. 
The following actions must be taken if a patient fails to return to the clinic for a required 
trial visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as 
soon as possible and counsel the patient on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the patient wishes to and/or 
should continue in the trial. 
• 
Before a patient is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the patient (where possible, three 
telephone calls and, if necessary, a certified letter to the patient’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the patient’s medical record. Any knowledge of the patient status 
(progressive disease, death, etc.) also requires documentation in the patient’s files. 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
See the SoA (Section 1.3) for all planned time points for assessments. 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue trial 
treatment. 


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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 informed consent 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 (Section 1.3). 
8.1 
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.1.1 
Physical examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and 
weight will also be measured and recorded and body surface area calculated using 
the equation: 
BSA (m2) = √((height [cm] x weight [kg])/3600). 
• 
A symptom-directed examination will be based upon the symptoms displayed. 
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• 
Depending on timing (before or after signing the ICF) clinically significant 
abnormalities observed at screening will be recorded on the general Medical 
History page or on the AE page of the eCRF. At subsequent visits, examination will 
be performed and new or worsened clinically significant abnormalities will be 
recorded in the AE page of the eCRF. 
8.1.2 
Vital signs 
• 
Temperature, blood pressure (systolic and diastolic), heart rate, oxygen saturation 
and respiratory rate will be assessed. 
• 
Blood pressure and heart rate will be assessed with the patients in a seated 
position with a completely automated device. Manual techniques will be used only 
if an automated device is not available. 
• 
Vital signs assessment 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 will be assessed at the following times, in relation to the start of BNT141 
dosing: 
− 
Pre-dose (up to 30 min pre-dose); 


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− 
15 min (± 5 min); 
− 
30 min (± 5 min); 
− 
60 min (± 10 min); 
− 
90 min (± 10 min); 
− 
120 min (± 15 min);  
− 
If the infusion lasts longer than 120 min then vital signs should be performed 
every 30 min (± 5 min) until end of infusion; and 
− 
Vital signs should be monitored closely after IMP infusion until the patient 
leaves the site.  
• 
Single readings will be performed on all other days. 
8.1.3 
Electrocardiograms 
• 
Triplicate 12-lead ECGs will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc (according to Frederica) intervals. Patients should be resting in a supine 
position for at least 10 min prior to ECG recording. Triplicate ECGs should be 
performed in accordance with institutional guidance, with a time difference between 
the ECGs of ≥ 2 mins. 
8.1.4 
Clinical safety laboratory assessments 
• 
See Table 3 and Table 6 for the list, timing and frequency of clinical laboratory 
tests to be performed. Additional safety laboratory assessments can be performed 
at any time point when clinically indicated and can include assessments as 
indicated. 
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the trial in the AE section of 
the eCRF. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the patient’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the trial or within 21 d after the last dose of trial intervention should 
be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or Medical Monitor. 
− 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
− 
All protocol-required laboratory assessments, as defined in Section 10.2, must 
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− 
If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in patient 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE or dose modification), then the results must be recorded in the 
eCRF. 
Routine clinical laboratory safety tests (e.g., blood chemistry, hematology, etc.) will be 
performed in a local laboratory at the site.  
All other tests and blood biomarker panel analyses will be performed by central 
laboratories.  
A Laboratory Manual will be provided to sites which specifies the procedures for collection, 
processing, storage and shipment of samples, as well as central laboratory contact 
information, specific to this clinical research trial. 
8.2 
Adverse events and serious adverse events 
AEs will be reported by the patient (or, whenever appropriate by a caregiver, or the 
patient’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs and SAEs. 
8.2.1 
Time period and frequency for collecting AE and SAE information 
All AEs will be collected from the signing of the trial-specific ICF until the second Safety 
Follow-up Visit at the time points specified in the SoA (Section 1.3). During pre-screening 
no AEs/SAEs will be reported, with the exception of AEs/SAEs related to the procedure of 
collection of a fresh biopsy. 
All SAEs (initial and follow-up reports) will be recorded and reported to the sponsor or 
designee immediately and under no circumstance should this exceed 24 h after becoming 
aware of the event, as indicated in Section 10.3.1.10.  
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. 
8.2.2 
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 
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8.2.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts. All AEs, SAEs and DLTs will be followed until resolution, 
stabilization, the event is otherwise explained, or the patient is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.1.7. 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
If a patient dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any post mortem findings including 
histopathology if available. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to the sponsor within 24 h of receipt of 
the information as described in Section 10.3.1.7. 
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, or second safety follow-up is reached. If no final status is reached at 
second Safety Follow-up Visit, the investigator must confirm the unavailability of a final 
status. 
8.2.4 
Regulatory reporting requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
trial treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, 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 serious adverse reactions (SUSARs) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
For the IMPs, it is the sponsor’s or delegate’s responsibility to perform SUSAR reporting to 
the regulatory authority, the IRB/IEC and the other investigators as required by national 
law and applicable guidelines. 
All AEs suspected to be related to any NIMP should be sent by the investigator to the 
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legislation) or to the marketing authorization holder of the NIMP, but not to both to avoid 
duplicate submissions (ENTR/CT-3, good pharmacovigilance practices [GVP] Module VI 
EMA/873138/2011 Rev 2). 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor should 
review it and then file it together with the investigator’s brochure. If required by local 
requirements, the investigator will notify the relevant IRB/IEC. 
8.2.5 
Pregnancy 
Details of all pregnancies in female patients and, female partners of male patients will be 
collected after the start of trial intervention and until 60 d after the last dose of IMP for 
pregnant female patients and 28 d for pregnant partners of male patients. 
If a pregnancy is reported, the investigator should inform the sponsor within 24 h of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.3. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.2.6 
Cardiovascular and death events 
8.2.6.1 
Cardiovascular 
Where the cardiovascular event meets one of the conditions outlined in Section 6.6 then 
the patient should be discontinued from treatment. All clinically significant cardiovascular 
events should be reported as AEs or SAEs depending on the criteria they meet. 
8.2.6.2 
Deaths 
Any death that occurs within the observation period will be reported as an SAE. 
Exemptions to the SAE definition as defined in Section 10.3.1.4 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. 
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. 
In case of a fatal event, the event term should not be “death” but the underlying event 
which led to death (death = outcome). If there is more than one AE in a fatal case, only for 
the AE leading to death the outcome “fatal” should be selected. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, “unexplained death” should 
be documented as event term. 
In addition to reporting as SAE, the death page of the eCRF needs to be completed. 
8.2.7 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs 
The progression of underlying disease (e.g., new metastases) and symptoms related to 
disease progression during trial participation is not considered as AE.  


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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.  
The recorded disease-related events will be monitored by an SRC on a routine basis, for 
details see Section 9.6. 
8.2.8 
Adverse events of special interest 
• 
Infusion-related reactions Grade ≥ 3. 
• 
Grade ≥ 3 AST or ALT elevation lasting ≥ 7 days, at least possibly related to 
BNT141. 
• 
Grade ≥ 3 bilirubin elevation lasting ≥ 7 days, at least possibly related to BNT141. 
8.3 
Treatment of overdose 
For this trial, an overdose is defined as a patients receiving a 15% excess of the intended 
dose of BNT141 specified in this protocol. 
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
• 
Contact the Medical Monitor immediately. 
• 
Closely monitor the patient for any AE/SAE and laboratory abnormalities (at least 
21 d). 
• 
Document the quantity of the excess dose as well as the duration of the overdose 
in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.4 
Pharmacokinetics  
Planned time points for PK sampling are provided in the SoA (Section 1.3). The actual 
date and time (24-h clock time) of each sample should be recorded. Blood samples for PK 
analysis should be collected, handled, frozen and shipped as outlined in the Laboratory 
Manual.  
• 
PK samples will be analyzed by a central laboratory. All collection and storage 
tubes will be provided in laboratory sampling kits. 
• 
Intact RiboMab
 (full-length and fully assembled antibody) PK samples will be 
collected and analyzed to enable characterization of PK profile. 
• 
Lipid PK samples will be drawn to enable potential further exploratory PK 
assessments. Refer to Table 2 and Table 5. 
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8.5 
Efficacy assessments 
Planned time points for efficacy assessments are provided in the SoA (Section 1.3). There 
will be no central reading of CT and/or MRI images in this trial. The assessments will be 
done at site by a qualified radiologist experienced in RECIST 1.1 criteria according to an 
Imaging Manual where all assessments will be described. 
8.5.1 
Computer tomography/magnetic resonance imaging scans 
• 
Patients will undergo CT and/or MRI scans in order to provide images which will be 
assessed by an experienced radiologist applying RECIST 1.1 criteria. 
• 
The MRI scans will be performed using a 3-tesla whole body instrument. The same 
machine should be used for all scans for an individual patient. 
• 
The CT scans should be performed using the same machine for an individual 
patient throughout the trial. 
• 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and throughout the 
trial. 
• 
The following criteria will be used when evaluating 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.  
− 
Partial response: at least a 30% decrease in the sum of 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. 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 diameters while on trial. 
• 
Monitoring of the liver and the spleen size will be performed as described in the 
Imaging Manual. 
• 
Guidelines on the RECIST 1.1 criteria should be followed (Eisenhauer et al. 2009). 
8.5.2 
Tumor marker CA 19-9 
• 
CA 19-9 measurements will be taken to follow disease, according to the SoA 
(Section 1.3). 




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Biomarker assessments will include (but will not be limited to) blood sampling for cytokine 
analysis and for exploratory functional assays (see Section 8.6). The list of planned 
assessments may change, i.e., listed assessments may be deleted or added, depending 
on the results obtained. The exploratory biomarker data generated will be used in support 
of the defined clinical trial objectives. The exploratory biomarker data generated used in 
support of the defined clinical trial objectives will be reported in suitable biomarker reports 
and reported in accordance with the requirements of applicable regulations and laws. 
Details on the collection, processing, shipment and storage of samples will be provided in 
separate documents (e.g., sample handling sheets or lab manual). Samples may be stored 
for a maximum of 15 years (or according to local regulations) following the end of the study 
at a facility selected by the sponsor to enable further analyses. 
8.8.1 
Tumor biomarkers 
• 
Tumor samples should be sent during pre-screening, Cycle 1 Day 1 and during 
treatment (Section 1.3). Testing of pre-treatment archival or fresh tumor tissue as 
well as on-treatment tumor biopsy includes but is not limited to CLDN18.2 
expression. 
• 
An on-treatment biopsy, preferred on Cycle 2 Day 8 (± 1 d), but can be performed 
at any time during the study treatment if feasible/without a risk of complications for 
the patient.  
• 
Fresh tissue samples should be collected according to local procedures under 
either local or general anesthetic (depending on location), if feasible. 
• 
Some additional tumor tissue (preferably 10 µm thick curls) will be taken from the 
FFPE block for further exploratory research on CLDN18-ARHGAP fusion for all 
patients enrolled in the trial. Transcripts of CLDN18-ARHGAP6/26 fusion results in 
better accessibility of CLDN18.2 molecules for targeted antibody therapies by 
increasing the aberrant allocation of CLDN18.2 from the tight junction to the cell 
surface. 
• 
Some additional tumor tissue may be stored with an external vendor for future 
research, where this is agreed by the patient in the ICF. 
• 
Tumor tissue should be handled according to the Laboratory Manual.  
8.9 
Immunogenicity assessments 
Immunogenicity samples will be collected from all patients. Planned time points for 
immunogenicity sampling (anti-RiboMab
 antibodies and anti-
 lipid antibodies) are 
provided in the SoA (Section 1.3). Samples will also be collected at the final visit from 
patients who discontinued trial treatment or were withdrawn from the trial. 
An extra sample for further analysis will be taken which can be used either for re-testing or 
future analysis if required.  
All samples that were not analyzed during the trial, will be stored for up to 15 years after 
the end of the trial and then destroyed.  
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• 
Blood samples for immunogenicity analysis should be collected, handled, frozen 
and shipped as outlined in the Laboratory Manual. 
• 
Immunogenicity samples will be analyzed by a central laboratory. All collection and 
storage tubes will be provided in laboratory sampling kits. 
8.10 
Blood lipids 
Blood lipids (total cholesterol, LDL, VLDL, HDL, triglycerides and Apolipoprotein E) will be 
assessed at time points provided in the SoA (Section 1.3).  
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical hypotheses 
There is no formal statistical hypothesis being tested in this FIH trial. 
9.2 
Sample size determination 
The sample size for trial Part 1A and 1B is driven by the classical 3+3 trial design and will 
range from 2 to 6 DLT-evaluable patients per cohort depending on the occurrence of 
DLTs. In both trial Parts 1A and 1B, the sample size will be up to 48 DLT-evaluable 
patients in each part depending on the DLTs, which may occur. Non-DLT-evaluable 
patients will be replaced. 
Once the MTD is reached, up to 10 additional patients with CLDN18.2 expressing 
pancreatic and biliary tract cancers will be enrolled at the MTD level in Parts 1A and up to 
10 additional patients with CLDN18.2 expressing pancreatic adenocarcinoma and 
cholangiocarcinoma in Part 1B respectively, to obtain additional data on safety, PK and 
PD. Based on this sample size the probability to observe a particular AE with incidence of 
15% would be 80.3%. 
The sample size determination for Part 2 will be provided in a protocol amendment. 
9.3 
Analysis sets 
The analyses sets are defined in Table 19: 
 
Table 19: 
Analysis set definitions 
Analysis set 
Description 
Screened Set 
All patients who signed informed consent form. 
Treated Set 
All patients who received IMP (i.e., at least one dose of BNT141). 
Efficacy Evaluable 
Set 
All patients who are assigned to IMP and have a baseline and at least one on-
treatment/post-treatment tumor response assessment.  
This analysis set may only be used in Part 2 of the trial. 
Safety Set 
All patients who received IMP (i.e., at least one dose of BNT141). 


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Analysis set 
Description 
DLT Evaluation 
Set 
All patients from the Safety Set who either have completed the DLT evaluation 
period and meet the minimum exposure criterion or have experienced a DLT during 
the DLT evaluation period (21 d for Part 1A, 28 d for Part 1B).  
Patients who do not experience any DLT during the DLT observation period are 
considered to be evaluable if they have been observed for minimum 21 d for 
Part 1A, 28 d for Part 1B following the first target dose and are considered to have 
sufficient safety data to conclude that a DLT did not occur. A patient is considered to 
have met the minimum exposure criterion in Part 1A if the relative dose intensity of 
BNT141 in Cycle 1 is at least 80%. A patient is considered to have met the minimum 
exposure criterion in Part 1B if the relative dose intensity of BNT141, nab-paclitaxel, 
and gemcitabine in Cycle 1 is at least 90%. 
Patients who are excluded from the DLT Evaluation Set will be replaced. 
This analysis set may only be used in Part 1 of the trial. 
PD Set 
All patients with baseline and at least one valid on-treatment/post-treatment PD 
assessment. 
PK Set 
All patients with baseline and at least one valid on-treatment/post-treatment PK 
assessment. 
DLT = dose-limiting toxicity; IMP = investigational medicinal product; PD = pharmacodynamics; PK = pharmacokinetics.  
 
The DLT Evaluation Set will be used for the evaluation of DLTs in order to assess the MTD 
and RP2D. The Safety Set will be used for all other safety analyses. The Treated set and 
Efficacy Evaluable Set will be used for efficacy analyses. 
9.4 
Statistical analyses 
Statistical analyses will be performed by the BioNTech or a designated contract research 
organization (CRO). All statistical analyses will be carried out using Statistical Analysis 
System (SAS)®, Version 9.4 or higher, and/or other statistical software as required. 
The Statistical Analysis Plan (SAP) will be finalized prior to database snapshot for the 
primary analysis and it will include a more technical and detailed description of the 
statistical analyses described in this section. Any deviations from the planned analyses 
described in the final SAP will be described and justified in the clinical trial report. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1 
General considerations 
In general, data will be analyzed by cohort and/or combined across cohorts as appropriate. 
Continuous variables will be summarized by cohort using the following descriptive 
statistics: number of patients (n), mean, standard deviation, median, minimum and 
maximum.  
Categorical variables will be summarized by cohort presenting absolute and relative 
frequencies (n and %) of patients in each category.  
Time-to-event-endpoints will be analyzed using Kaplan-Meier methodology by cohort and 
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of Cancer Drugs and Biologics and the EMA Guideline on the evaluation of anti-cancer 
medicinal products in man. Censoring rules will be defined in the SAP.  
The median survival time (including 95% confidence limits according to Brookmeyer and 
Crowley) and the first and third quartile will be presented. Survival rates (including 95% 
confidence intervals (CIs) 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). 
Baseline is defined as last available value prior to first dose of IMP. 
9.4.2 
Primary endpoints 
The primary analyses of primary safety endpoints (i.e., AEs, adverse event of special 
interest [AESI], SAEs and DLTs) will be performed using the Safety Set (for AEs), and DLT 
Evaluation Set (for DLTs), respectively, and are described in Section 9.4.5. 
9.4.3 
Secondary endpoints 
PK profile of the intact BNT141-encoded protein RiboMab
 
The analyses of PK parameters will be performed using the PK analysis set. Individual and 
mean (± standard deviation) serum and plasma concentration data will be tabulated and 
plotted over time by dose level. The PK parameters will be estimated from the serum 
concentration data using a non-compartmental analysis method and will include (but are 
not limited to): Cmax, tmax, t1/2, Vd, AUC, and CL, and Ctrough. These parameters will be listed 
by individual patient and summarized using descriptive statistics (means, medians, ranges, 
standard deviations, and coefficient of variation as appropriate) by cohort, as appropriate. 
Population PK modeling approaches may be also considered and will be reported 
separately. 
Objective response rate  
Objective response rate is defined as the proportion of patients in whom a CR or PR is 
confirmed 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.  
Objective response rate will be summarized with absolute and relative frequencies along 
with 2-sided Clopper-Pearson 95% CIs. For Part 1B, a sensitivity analysis will be 
performed using the Efficacy Evaluable Set. 
Disease control rate 
Disease control rate is defined as the proportion of patients in whom a CR or PR or SD 
(SD assessed at least 6 weeks after first dose) is observed as best overall response.  
Disease control rate will be summarized with absolute and relative frequencies along with 
2-sided Clopper-Pearson 95% CIs. 
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Duration of response  
Duration of response is defined as the time from first objective response (CR or PR) to first 
occurrence of objective tumor progression, or death from any cause, whichever occurs 
first. Only patients in whom a CR or PR is confirmed will be analyzed for DOR.  
Duration of response will be analyzed using Kaplan-Meier methodology. 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 
Tertiary/exploratory endpoints 
Exploratory endpoints include but not limited to: efficacy endpoints (PFS and OS), 
potential biomarkers (CLDN18.2 expression level, cytokine concentrations, chemokine 
concentrations), ADAs (anti-
 lipid and anti-RiboMab
), PK of plasma lipids, and pre-
treatment lipid levels (total cholesterol, LDL, VLDL, HDL, triglycerides, Apolipoprotein E).  
The presence and concentration of ADAs will be reviewed to evaluate the immunogenicity 
of BNT141. Number of positive/negative cases by dose level for each cycle will be 
reported, and the PK parameters between ADA positive and negative patients will be 
compared. This approach will be applied to both anti-
 lipid antibodies and anti-
RiboMab
 antibodies. 
The analysis for the exploratory endpoints and the potential association with clinical 
response and/or exposure to trial treatment (measured by BNT141-encoded protein 
RiboMab
 level) will be described in the corresponding statistical analysis plan(s). 
9.4.5 
Safety analyses 
Safety data that will be summarized includes AEs, clinical laboratory parameters, vital 
signs and ECGs. All safety analyses will be based on the Safety Set and will be 
summarized descriptively by cohort unless otherwise stated. 
AEs 
AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA®) coding system to get a System Organ Class 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 d 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 TEAE will be summarized 
by PT nested within the System Organ Class for each of the following AE types:  
• 
Any AE 
• 
Related AE 
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• 
Grade ≥ 3 AE 
• 
Related Grade ≥ 3 AE 
• 
Any AESI 
• 
Any SAE 
• 
Related SAE 
• 
Serious AE leading to death 
• 
AEs leading to dose reduction 
• 
AEs leading to dose delay 
• 
AEs leading to permanent discontinuation of treatment 
• 
DLTs 
Moreover, the number and percentage of patients with any AE will be summarized by 
worst NCI-CTCAE grade by PT nested within System Organ Class. 
DLTs will be presented in terms of listings presenting the reported term and MedDRA PT 
and System Organ Class term, its time of onset, duration, and outcome, relationship, NCI-
CTCAE grade, and seriousness including dose exposure data. 
Laboratory parameters 
Clinical laboratory assessments to be summarized include hematology, blood chemistry, 
and urinalysis. The clinical laboratory parameters and the scheduled time points for 
assessment are tabulated in Section 1.3. 
Clinical laboratory parameters at each time point and change from baseline to each post-
baseline time point will be summarized using descriptive summary statistics for each 
parameter by cohort.  
Clinical laboratory results will be classified according to the most recent version of NCI-
CTCAE. Shift tables from baseline to worst grade on treatment will be provided for each 
laboratory parameter by cohort. 
Additionally, the occurrence of clinically significant abnormal laboratory results within a 
patient will be analyzed using descriptive summary statistics for each parameter and visit 
by cohort. 
Laboratory results will be listed along with the normal ranges and NCI-CTCAE grade. 
Laboratory values that are below or above the normal ranges will be flagged. 
Vital signs 
Vital sign parameters and the scheduled time points for assessment are presented in 
Section 1.3 and 8.1.2. 
Vital sign parameters at each time point and change from baseline to each post-baseline 
time point will be summarized using descriptive summary statistics for each parameter by 
cohort. 


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Additionally, the occurrence of abnormal vital sign results within a patient will be analyzed 
using descriptive summary statistics for each parameter and visit by cohort. 
Electrocardiogram 
Electrocardiogram parameters and the scheduled time points for assessment are 
presented in Section 1.3. 
Electrocardiograms will be judged by the investigator as clinically significant (yes/no). The 
number and percentage of patients with clinically significant ECG findings will be 
summarized by cohort for each visit. 
9.4.6 
Other analyses 
Treatment exposure 
The following dose exposure variables will be derived and analyzed for each compound 
using the DLT Evaluation Set for Part 1 limited to the DLT evaluation period (21 d) as well 
as using the Safety Set for the full treatment period: 
• 
Number of cycles. 
• 
Treatment Duration (weeks) defined as follows: (Date of last administration - Date 
of first administration + Planned Duration) / 7, whereas the Planned Duration 
(days) is defined as the planned time between two consecutive administrations. 
• 
Cumulative Dose (µg) defined as sum of all administered doses. 
• 
Dose Intensity defined as Cumulative Dose (µg) / Treatment Duration (weeks). 
• 
Relative Dose Intensity (RDI) defined as follows: 
RDI (%)=
Actual Dose Intensity ( µg
week)
Planned Dose Intensity ( µg
week)
 x 100=DI x TI x 100 
Whereas 
(Actual) Dose Intensity ( µg
week) =
(Actual) Cumulative Dose (µg)
(Actual) Treatment Duration (week) 
Planned Dose Intensity ( µg
week) =
Planned Cumulative Dose (µg)
Planned Treatment Duration (week)  
Dose Index (DI)= Total Administered Dose (µg)
Total Planned Dose (µg)
 
Time Index (TI)= Planned Treatment Duration (week)
Actual Treatment Duration (week)  
 
9.5 
Interim analyses 
A formal interim statistical analysis is not planned. 


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A final analysis will be performed when the last patient discontinued from the trial. 
9.6 
Safety Review Committee 
For details on the SRC, see Section 10.1.5. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, ethical, and trial oversight considerations 
This trial will be conducted according to this protocol, the ethical principles that have their 
origin in the Declaration of Helsinki, GCP, and applicable regulatory requirements. 
10.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• 
Applicable International Conference on Harmonisation (of technical requirements 
for registration of pharmaceuticals for human use [ICH]) GCP Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
hazard to trial patients. 
The investigator will be responsible for the following: 
• 
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 (US) Code of Federal Regulations [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 
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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. 
Patients must be informed that their participation is voluntary and must be given adequate 
time for making the decision to participate in the trial. 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 requirements, 
where applicable, and the IRB/IEC or trial site. 
The medical record must include a statement that written informed consent was obtained 
using the sponsor ICF before the patient was enrolled in the trial and the date and the time 
the written consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF during their 
participation in the trial. 
A copy of the signed ICF(s) must be provided to the patient. 
Separate ICFs will be used in this trial:  
• 
Trial-specific ICF for trial participation 
• 
Pregnant partner ICF 
• 
Progression ICF 
• 
Additional ICFs will be used if required by local regulations 
10.1.4 
Pre-screening ICF data protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal trial-related data will be used by the 
sponsor in accordance with local data protection 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 
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The patient must be informed that his/her 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 will be established to review the ongoing efficacy and safety results. The SRC will 
act according to its own written standard operating procedures described in a charter, and 
will prepare written minutes of its meetings. 
10.1.6 
Dissemination of clinical trial data 
A final report integrating all trial results will be prepared by the sponsor.  
This trial will be registered on publicly accessible trial registries and trials results publicly 
disclosed on trial registries (e.g., ClinicalTrials.gov) in accordance with the applicable 
regulations. 
Clinical trial data and documentation will be disseminated as required per applicable laws 
and regulations, e.g., the European Union (EU) Regulation No 536/2014, EU Regulation 
1049/2001, and the US Final Rule, which implements Section 801 of the Food and Drug 
Administration Amendments Act (FDAAA 801). Clinical documents under such laws 
includes protocols and protocol amendments, SAPs, ICH E3 clinical study reports. 
If this clinical trial is used to support marketing authorization packages/submissions, the 
sponsor will comply with the EU Policy 0070, the proactive publication of clinical data on 
the EMA website. Clinical data, under Phase 1 of this policy, includes clinical overviews, 
clinical summaries, ICH E3 clinical study reports, and appendices containing the protocol 
and protocol amendments, sample CRFs, and statistical methods. under Phase 2 of this 
policy, “clinical data” includes the publishing of individual patient data. 
Even if not required by applicable laws and regulations, this trial will be registered, and trial 
results be publicly posted on ClinicalTrials.gov. In addition, expert summaries of the 
outcomes for all primary and secondary outcome measures (irrespective of outcome) and 
lay summaries, will be posted on a publicly accessible website. 
The results for all primary and secondary outcome measures, irrespective of outcome, will 
be submitted for publication in academic journals (for further details, see Section 10.1.10). 
10.1.7 
Data quality assurance 
All patient data relating to the trial will be recorded on electronic CRF unless transmitted to 
the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing 
the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 


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Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other parties (e.g., CRO). 
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the 
trial is being conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must 
be retained by the investigator for 25 years after trial completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
10.1.8 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. 
Definition of what constitutes source data can be found in the source data agreement at 
each site. 
10.1.9 
Trial and site start and closure 
The trial start date is the date on which the clinical trial starts recruitment of patients. 
The first act of recruitment is the first site open and will be the trial start date. 
The sponsor designee reserves the right to close the trial site or terminate the trial at any 
time for any reason at the sole discretion of the sponsor. Trial sites will be closed upon trial 
completion. A trial site is considered closed when all required documents and trial supplies 
have been collected and a trial site closure visit has been performed. 
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. 
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• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of patients by the investigator 
• 
Discontinuation of further trial treatment development 
If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the trial of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 
10.1.10 
Publication policy 
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
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 multi-site trials only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
Clinical laboratory tests 
The parameters and day/time at which they will be analyzed are listed in Table 3 and 
Table 6. 
10.3 
Adverse events: Definitions and procedures for recording, 
evaluating, follow-up, and reporting 
10.3.1 
Definition of an AE 
AE definition 
• 
An AE is any untoward medical occurrence in a patient or clinical trial patient, 
administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
• 
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 


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administration of IMP). AEs with an onset date more than 60 d after the last 
administration of IMP will be considered as treatment-emergent only if assessed as 
related to IMP by the investigator. 
10.3.1.1 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions or worsening of pre-existing conditions detected or diagnosed after 
signing the ICF. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE. 
10.3.1.2 
Events not meeting the AE definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the patient’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
patient’s condition. 
• 
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 8.2.7. 
10.3.1.3 
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. 


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• 
The definition implies a reasonable possibility of a causal relationship between the 
event and the IMP. This means that there are facts (evidence) or arguments to 
suggest a causal relationship. 
10.3.1.4 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under trial, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
Is life-threatening 
− 
The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event. It does not refer 
to an event, which hypothetically might have caused death, if it were more 
severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
− 
Hospitalization signifies that the patient has been admitted (at least an 
overnight stay) to the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or 
outpatient setting. 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. 
− 
Hospitalization for signs/symptoms of the disease under trial including 
worsening of the disease under trial and hospice admission for palliative care 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 medically important conditions: 
− 
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 


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prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
− 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. 
10.3.1.5 
Definition SUSAR 
Any suspected serious adverse reaction (SUSAR) that is classified as unexpected by the 
sponsor. 
A suspected serious adverse reaction is classified as unexpected when the nature or 
severity is not consistent with the applicable product information (reference safety 
information [RSI], i.e., the investigator’s brochure for an unauthorized investigational 
product or SmPC for an authorized product).  
The expectedness of a suspected serious adverse reaction is determined by the sponsor 
according to the RSI. This should be done from the perspective of events previously 
observed, not based on what might be anticipated from the pharmacological properties of 
a medicinal product. 
If the RSI is contained in the investigator’s brochure, the investigator’s brochure should 
contain a clearly identified section to expected serious adverse reactions. 
10.3.1.6 
Use of the terms “severe” and “serious” 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
AE (e.g., rated as mild, moderate, or severe, or according to NCI-CTCAE; see 
Section 10.3.1.7 for guidance on the assessment of intensity; the event itself may be of 
relatively minor medical significance [such as severe headache without any further 
findings]). 
Severity and seriousness need to be assessed independently for each AE recorded on the 
eCRF. 
SAEs must be reported by the investigator to the sponsor immediately (i.e., no more than 
24 h after learning of the event; see Section 10.3.1.10 for reporting instructions). 
10.3.1.7 
Recording and follow-up of AE and/or SAE 
Adverse event 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 (starting from the ICF being 
signed until the second Safety Follow-up Visit). 
• 
Data pertaining to AEs will be collected during each trial visit, either based on the 
patient’s spontaneous description or investigator’s inquiry or discovered in the 
course of examinations done during the visit, clinical significance of any sign or 
symptom needs to be evaluated by the investigator.  


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• 
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 NCI-CTCAE v5.0;  
− 
seriousness; 
− 
outcome; 
− 
causal relationship of the AE to the trial treatment; and 
− 
any trial treatment action and/or any other action taken. 
• 
All assessments as well as AE term (diagnosis/description), start date and time of 
onset, end date and time need to be documented in the eCRF.  
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all patient identifiers, with the exception of 
the patient number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
• 
To avoid colloquial expressions, the AE should be reported in standard medical 
terminology. The investigator will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information. Whenever possible, 
the diagnosis (not the individual signs/symptoms) will be documented as the AE. If 
a definitive diagnosis is not possible, the individual signs and symptoms should be 
recorded. 
Assessment of intensity 
The intensity of an AE (i.e., severity of organ toxicity) will be graded according to the NCI-
CTCAE v 5.0. AEs that are not listed in NCI-CTCAE v 5.0 should be classified according to 
the investigator’s discretion as close as possible to NCI-CTCAE v 5.0, based on the 
comparison with the most severe case encountered in past training and clinical 
experience.  
The investigator will make an assessment of intensity for each AE and SAE reported 
during the trial and assign it to one of the following categories:  
• 
Grade 1 - Mild 
• 
Grade 2 - Moderate 
• 
Grade 3 - Severe 
• 
Grade 4 - Life-threatening consequences; urgent intervention indicated 
• 
Grade 5 - Death related to AE 
With regards to the intensity of an AE the following needs to be documented: 
• 
Initial intensity of the AE 


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• 
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 change from severe to moderate according to 
NCI-CTCAE criteria). 
• 
An event is defined as “serious” when it meets at least one of the pre-defined 
seriousness criteria as described in the definition of an SAE, NOT when it is rated 
as severe. 
Actions taken by the investigator 
Actions taken by the investigator as a result of an AE have to be documented.  
Action(s) taken with trial treatment (IMPs) by the investigator: 
• 
Dose not changed (= continuation of trial treatment administration according to the 
trial protocol) 
• 
Dose reduced (= reduction of the trial treatment dosage *) 
• 
Drug interrupted, e.g.: 
− 
Delayed administration of IMP within one treatment cycle 
− 
Delayed start of the next treatment cycle 
− 
Cancellation of administration at a given visit 
− 
Interruption of IMP administration during a given visit  
• 
Drug withdrawn 
• 
Unknown (e.g., in case the patient is lost to follow-up) 
• 
Not applicable (e.g., in case treatment with trial treatment has not yet started or 
event starts after last trial treatment administration)  
Other action(s) that may be taken by the investigator include: 
• 
None 
• 
Initiation of a concomitant medication for the treatment of the AE 
• 
Initiation/termination of a non-drug therapy for the treatment of the AE 
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) 


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• 
Recovering/resolving (= AEs which are improving but not yet resolved completely, 
e.g., decrease in an intensity grade) 
• 
Not recovered/not resolved (= AEs which are ongoing without improving or still 
present when the patient deceases due to another cause) 
• 
Recovered/resolved with sequelae* (= patient recuperated but retained 
pathological conditions resulting from the AE; the sequelae should be indicated) 
• 
Fatal** (= death due to the AE) 
• 
Unknown (e.g., in case the patient is lost to follow-up) 
* Generally, an AE is defined as recovered/resolved if all symptoms have ceased, no 
medication for treatment of the event is taken anymore and no other measures (e.g., 
hospitalization) are ongoing. 
  
If the patient has developed permanent or chronic symptoms or if the event requires long-
term medication(s), the AE is defined as recovered/resolved with sequelae as soon as no 
changes of symptoms and/or medication(s) are expected anymore.  
An AE that is documented as a worsening of a medical condition already known at 
baseline, is defined as recovered as soon as the medical condition has returned to 
baseline status. 
** In case of a fatal event, the event term should not be “death” but the underlying event 
which led to death (death = outcome). If there is more than one AE in a fatal case, only the 
AE leading to death will be attributed with the outcome “fatal”. All other AEs ongoing at the 
time of death will be attributed with the outcome “not recovered/not resolved”. A copy of an 
autopsy report should be submitted if available. 
Assessment of causality 
The investigator is obligated to assess the relationship between trial treatment/trial 
procedure and each occurrence of each AE/SAE. 
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 (either BNT141 
or in BNT141 combination with nab-paclitaxel and gemcitabine) 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. 


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• 
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 NIMP or the procedure of trial treatment 
administration. 
Relationship to trial procedures 
• 
In this trial, it cannot be excluded that during the course of the trial some 
procedures give rise to AEs which are related to the trial procedure and not to the 
trial treatment. Procedure related AE can occur at the site of injection of the trial 
treatment e.g., redness, swelling, hematoma or itching or during or after trial-
specific procedure, e.g., discomfort after blood drawing. These events have to be 
reported in the eCRF on 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 v 5.0. 
Applicable for all categories 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data to the sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a patient dies during participation in the trial or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post mortem 
findings including histopathology.  
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the sponsor within 24 h of 
receipt of the information. 


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10.3.1.8 
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 10.3.1.4). In the present trial, some 
events are excluded from the SAE definition. The following events do not need to be 
reported as SAEs: 
• 
AEs and SAEs occurring later than the second Safety Follow-up Visit must only be 
reported by the investigator to the sponsor if a relationship to trial treatment or trial 
procedure is suspected. 
• 
Hospitalizations for respite care will not be considered as reportable SAE. 
• 
Hospitalizations solely for coordination of care, including hospice arrangements, 
will not be considered as reportable SAE. 
• 
Hospitalizations that were necessary solely because of patient requirement for 
outpatient care outside of normal outpatient clinic operating hours will not be 
considered as reportable SAE. 
• 
Planned hospitalizations required by the protocol (e.g., for trial treatment 
administration or insertion of access device for trial treatment administration) will 
not be considered as reportable SAE. 
• 
Hospitalizations for procedures or interventions of a pre-existing condition of the 
patient (elective surgery = planned, non-emergency surgical procedure) will not be 
considered as a reportable SAE (unless the intervention/procedure is not caused 
by an acute worsening of the pre-existing condition during the time trial 
participation).  
− 
If it was planned and documented in patient record before the trial-specific 
patient informed consent was signed (ICF for trial participation, see 
Section 10.1.3, or 
− 
If it was scheduled during the trial when elective surgery became necessary 
and the patient has not experienced an AE. 
Nevertheless, this kind of hospitalization should be avoided during trial treatment. 
• 
The progression of underlying disease (e.g., new metastases) during trial 
participation is not considered as AE. 
• 
Routine treatment or monitoring of the underlying disease not associated with any 
deterioration in the patient’s condition. 
10.3.1.9 
Documentation of particular situations 
AEs that are secondary to other events: 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. A medically significant secondary AE that is separated in time 
from the initiating event should be documented as an independent AE in source data and 
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If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be documented as AE. 
If vomiting results in severe dehydration, both events should be documented as AEs 
separately. 
Abnormal laboratory results and vital signs values: 
Not every laboratory or vital signs abnormality needs to be documented as AE. For 
clinically significant laboratory/vital signs abnormalities the following definitions and 
documentation rules apply: 
If a laboratory/vital signs abnormality is a sign of a disease or syndrome, the 
laboratory/vital signs abnormality is clinically significant and only the diagnosis of the 
causing disease or syndrome needs to be documented as AE. 
If a laboratory/vital signs abnormality results in specific symptoms but no diagnosis of a 
disease or syndrome can be made, the laboratory/vital signs abnormality is clinically 
significant and only the symptoms need to be documented as AEs. 
If a laboratory/vital signs abnormality is not a sign of a disease or syndrome and does not 
result in specific symptoms but leads to a change in trial treatment or in a medical 
intervention, the laboratory/vital signs abnormality is clinically significant and must be 
documented as AE. 
AEs associated with an overdose or error in drug administration: 
An overdose is the accidental or intentional use of a drug in an amount (per administration 
or cumulatively) higher than the dose being studied (for the trial treatment) or higher than 
the maximum recommended dose according to the authorized product information (for 
approved concomitant medications). An overdose or incorrect administration of a drug is 
not itself an AE, but it may result in an AE.  
All AEs associated with an overdose or incorrect administration should be documented as 
AE in source data and eCRF and reported as SAE if applicable. 
10.3.1.10 
Reporting of SAEs 
All SAEs which occur in a patient during the observation period, and do not meet any of 
the above listed SAE exemptions, whether considered to be associated with trial 
medication or not, must be reported by the investigator to the sponsor within 24 h 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 the trial 
procedure. 
SAE reporting to the sponsor via paper SAE Form 
For the period of observation please refer to Section 8.2.1.  
A paper SAE Form needs to be completed and forwarded to the sponsor for all SAE that 
do not meet any of the above defined AE or SAE exemptions, and all DLTs regardless if 
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The investigator needs to complete the paper Serious Adverse Event Form which must be 
sent to the sponsor via one of the following reporting lines: 
• 
Safety Report Fax No.:   
 
• 
Safety Report E-Mail Address:  
 
Information for final description and evaluation of a case report may not be available within 
the required time frames for reporting. Nevertheless, for regulatory purposes, initial reports 
should be submitted if the following minimal information is available:  
• 
An identifiable patient (patient number) 
• 
A suspected medicinal product  
• 
An identifiable reporting source (investigator/trial site identification)  
• 
An event or outcome that can be identified as serious 
SAE follow-up information should be sent to the sponsor (indicating that this is a “follow-
up” report using the SAE Form or the Additional Information and Follow-Up Form) without 
delay as described above and accompanied by appropriate anonymous supporting 
documentation (e.g., discharge letters, medical reports or death certificates), until a final 
outcome and date are available. All confidential information (name, address, full day of 
birth) needs to be blackened before sending. In addition to a medical record, the 
investigator should complete an Additional Information and Follow-Up Form, which 
contains the SAE term and patient number. 
A copy of the submitted SAE report must be retained on file by the investigator. If explicitly 
required according to national legislation, the investigator must submit copies of the SAEs 
to the IRB/IEC or authority and retain documentation of these submissions in the 
Investigator Site File. 
In case an investigator or any other trial team member has questions on safety reporting 
the sponsor may be contacted via: 
• 
E-Mail: 
 
For medical questions, the Medical Monitor for this trial should be contacted. 
10.4 
Contraceptive guidance and collection of pregnancy 
information 
10.4.1 
Definitions 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea after chemotherapy) and a menstrual cycle cannot 
be confirmed before first dose of trial treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 


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1. Premenarchal 
2. Premenopausal female with one of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
− 
Documented bilateral tubal ligation or occlusion 
For patients with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining trial entry. 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
• 
A postmenopausal state is defined as no menses 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 postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the trial. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before trial enrolment. 
10.4.2 
Contraception guidance 
The investigator or delegate should advise the patient how to achieve highly effective 
contraception.  
The following birth control methods may be considered as highly effective: 
• 
Combined estrogen and progestogen-based hormonal contraception associated 
with inhibition of ovulation 1 (oral, intravaginal, or transdermal) 
• 
Progesterone-only contraception associated with inhibition of ovulation 1, (oral, 
injected, implanted) 2 
• 
Intrauterine device / hormone-releasing system. 2 
• 
Bilateral tubal ligation / occlusion. 2 
• 
Vasectomy (for a male patient or male partner of a female patient). 2, 3 
• 
Sexual abstinence. 4 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
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3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant 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 study 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. 
The following birth control methods may be considered as acceptable but potentially not 
highly effective methods: 
• 
Male or female condom with a spermicidal agent; both female and male condom 
should not be used together.  
• 
Cap diaphragm or sponge with a spermicidal agent.  
A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods. 
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 
intervention and until 60 d after the last dose. 
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 Safety Report 
Fax number or e-mail detailed in Section 10.3.1.10. Completed pregnancy forms must be 
signed by an investigator before faxing/mailing them to the sponsor. Blank reporting forms 
are provided to the investigator during the site initiation visit and are filed in the 
investigator’s site file (ISF). 
The investigator will collect follow-up information on the patient/patient’s partner and the 
neonate and the information will be forwarded to the sponsor. Pregnancy follow-up should 
describe the outcome of the pregnancy, including any voluntary or spontaneous 
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 a SAE and will be reported as such. 
Any post-trial pregnancy related SAE considered reasonably related to the trial 
intervention by the investigator will be reported to the sponsor. While the investigator is not 
obligated to actively seek this information in former trial patients, he or she may learn of an 
SAE through spontaneous reporting. 


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10.5 
Liver safety: Suggested actions and follow-up assessments  
Section 6.6.1 specifies which liver events will be treated as DLTs and how treatment 
should be adjusted. If liver events which do not meet the criteria of a DLT occur, then the 
investigator should treat them according to their best judgment. 
10.6 
Investigators and trial administrative structure 
10.6.1 
Investigators and trial site personnel 
There must be an investigator at each trial site. 
If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator. 
All persons assigned responsibility as principal investigator must sign a declaration of their 
responsibilities and their agreement to this protocol before any trial-related procedure is 
performed. 
Curriculum vitae and/or other relevant documents confirming the current qualification of 
the investigators must be provided to the sponsor. This should include any previous 
training in the principles of GCP, experience obtained from work with clinical trials, and 
experience with patient care. 
Documentation of all involved investigators must be maintained according to GCP and 
applicable regulatory requirements. 
10.6.2 
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. 
10.6.3 
Contract research organizations 
Documentation of all involved CRO must be maintained according to GCP and applicable 
regulatory requirements. This includes documentation of any delegation of responsibilities 
to CROs. 




















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10.10 
Data collection and management 
The trial documentation must be adequate for the reconstruction of the trial. 
10.10.1 
Case report forms 
CRFs will be completed through use of an electronic data capture system, i.e., will be 
electronic (eCRF). Trial site personnel will receive training and have access to a manual 
for appropriate CRF completion. The CRFs will be submitted electronically to the sponsor 
via the system and should be handled in accordance with instructions from the sponsor. 
The CRF is set up in accordance to the SoA, reviewed, and tested via user acceptance 
test before it is pushed to production. Different roles/accounts with different access rights 
will be set up during this process. 
All CRFs should be completed by designated, trained trial site personnel. CRFs should be 
reviewed, verified, and then electronically signed and dated by the investigator or a 
designee. 
At the end of the trial, the investigator will receive trial patient data for his/her trial site in a 
readable format that must be kept with the trial records. Acknowledgment of receipt and 
readability of the trial patient data will be required. 
10.10.2 
Patient reported outcomes 
There will be no patient reported outcome measures planned in this trial. 
10.10.3 
Data management 
The sponsor or designee is responsible for the data management of this trial. Data 
management will be performed in accordance to the respective data management plan. 
The sponsor or designee is responsible for eCRF design and development, data imports 
from external data sources (e.g., central laboratory), data reconciliations, data cleaning, 
data coding, data exports and database lock. 
Data cleaning includes quality checking the data for completeness and consistency, in 
accordance with an edit check specifications document, via programmed or manual review 
checks. In case of discrepancies, queries will be generated accordingly in the eCRF as 
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 database lock. 
Medical conditions, AEs and non-drug therapies, will be coded using MedDRA® 
throughout the trial.  
Medications will be coded using the World Health Organization Drug Dictionary (WHO-
DD). Product group/level codes will be assigned according to the anatomical, therapeutic, 
and chemical classification system. 


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Investigator’s site file and the trial master file 
The principal investigator is responsible for the filing of all essential documents in an ISF. 
The sponsor is responsible for the timely filing of all essential documents in the trial master 
file. 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 
REFERENCES 
American Cancer Society. Pancreatic Cancer 2020a. Available at: 
https://www.cancer.org/cancer/pancreatic-cancer/about.html (accessed September 2020). 
American Cancer Society. Bile Duct Cancer 2020b. Available at: 
https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-
stage.html (accessed September 2020). 
American Cancer Society. Gallbladder cancer 2020c. Available at: 
https://www.cancer.org/cancer/gallbladder-cancer/detection-diagnosis-staging/survival-
rates.html (accessed September 2020). 
Athauda A, Fong C, Lau DK, et al. Broadening the therapeutic horizon of advanced biliary 
tract cancer through molecular characterisation. Cancer Treat Rev. 2020;86:101998. 
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries [published 
correction appears in CA Cancer J Clin. 2020 Jul;70(4):313]. CA Cancer J Clin. 
2018;68(6):394–424. 
Cidon EU. Resectable cholangiocarcinoma: reviewing the role of adjuvant strategies. Clin 
Med Insights Oncol. 2016;10: CMO.S32821. 
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin 
amyloidosis. N Engl J Med. 2013;369(9):819–829. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. 
Desai A, Gainor JF, Hegde A, et al. COVID-19 vaccine guidance for patients with cancer 
participating in oncology clinical trials. Nat Rev Clin Oncol. 2021 May;18(5):313-319. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. 


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EMA (2017). Guideline on strategies to identify and mitigate risks for first-in-human and 
early clinical trials with investigational medicinal products.  
EMA (2017). Guideline on the evaluation of anticancer medicinal products in man. 
Espinoza JA, Riquelme I, Sagredo EA, et al. Mucin 5B, carbonic anhydrase 9 and claudin 
18 are potential theranostic markers of gallbladder carcinoma. Histopathology. 
2019;74(4):597–607. 
FDA (2010). Guidance for Industry. S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals. 
FDA (2018). Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics. 
Gillen S, Schuster T, Meyer Zum Buschenfelde C, et al. Preoperative/neoadjuvant therapy 
in pancreatic cancer: a systematic review and meta-analysis of response and resection 
percentages. PLoS Med. 2010;7(4):e1000267. 
Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated 
Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-327. 
doi:10.1056/NEJMoa1903387. 
Hong JY, An JY, Le J, et al. Claudin 18.2 expression in various tumor types and its role as 
a potential target in advanced gastric cancer. Translational Cancer Research. Transl 
Cancer Res. 2020;9(5):3367–3374. 
BNT141 Investigator’s Brochure, Version 1.0, December 2020. 
Karanjawala ZE, Illei PB, Ashfaq R, et al. New markers of pancreatic cancer identified 
through differential gene expression analyses: claudin 18 and annexin A8. Am J Surg 
Pathol. 2008;32(2):188–196. 
Khan I, Sarker SJ, Hackshaw A. Smaller sample sizes for phase II trials based on exact 
tests with actual error rates by trading-off their nominal levels of significance and power. Br 
J Cancer. 2012;107(11):1801–1809. 
Kleeff J, Korc M, Apte M, et al. Pancreatic Cancer. Nat Rev Dis Primers. 2016;2:16022. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol 
Blood Marrow Transplant. 2019;25(4):625–638. 
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular 
filtration rate from serum creatinine: a new prediction equation. Modification of Diet in 
Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–470. 
Luberice K, Downs D, Sadowitz B, et al. Has survival improved following resection for 
pancreatic adenocarcinoma?. Am J Surg. 2017;214(2):341–346. 
Micke P, Mattsson JS, Edlund K, et al. Aberrantly activated claudin 6 and 18.2 as potential 
therapy targets in non-small-cell lung cancer. Int J Cancer. 2014;135(9):2206–2214. 


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Neelapu SS. Managing the toxicities of CAR T-cell therapy. Hematol Oncol. 2019;37 Suppl 
1:48–52. 
Niimi T, Nagashima K, Ward JM, et al. claudin-18, a novel downstream target gene for the 
T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific 
isoforms through alternative splicing. Mol Cell Biol. 2001;21(21):7380–7390. 
Orth M, Metzger P, Gerum S, et al. Pancreatic ductal adenocarcinoma: biological 
hallmarks, current status, and future perspectives of combined modality treatment 
approaches. Radiat Oncol. 2019;14(1):141. 
 
 
 
Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target 
suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624–7634. 
 
 
 
Sahin U, Tureci Ö, Manikhas GM et al. Zolbetuximab combined with EOX as first-line 
therapy in advanced CLDN18.2+ gastric (G) and gastroesophageal junction (GEJ) 
adenocarcinoma: Updated results from the FAST trial. J Clin Oncol. 2019;37(4):16. 
Shinozaki A, Shibahara J, Noda N, et al. Claudin-18 in biliary neoplasms. Its significance 
in the classification of intrahepatic cholangiocarcinoma. Virchows Arch. 2011;459(1):73–
80. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–
30. 
 
Tabernero J, Shapiro GI, LoRusso PM, et al. First-in-humans trial of an RNA interference 
therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer 
Discov. 2013;3(4):406–417. 
Tanaka M, Shibahara J, Fukushima N, et al. Claudin-18 is an early-stage marker of 
pancreatic carcinogenesis. J Histochem Cytochem. 2011;59(10):942–952. 
 
 
Türeci Ӧ, Mitnacht-Kraus R, Wöll S, et al. Characterization of zolbetuximab in pancreatic 
cancer models. Oncoimmunology. 2018;8(1):e1523096. 
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for 
biliary tract cancer. N Engl J Med. 2010;362(14):1273–1281. 
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Waissengrin B, Agbarya A, Safadi E, Padova H, Wolf I. Short-term safety of the BNT162b2 
mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint 
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Werner J, Combs SE, Springfeld C, et al. Advanced-stage pancreatic cancer: therapy 
options. Nat Rev Clin Oncol. 2013;10(6):323–333. 
Wöll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in 
pancreatic neoplasms. Int J Cancer. 2014;134(3):731–739. 
Zhu G, Foletti D, Liu X, et al. Targeting CLDN18.2 by CD3 bispecific and ADC modalities 
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Appendix 1: 
Recommendation for COVID-19 vaccination during trial 
participation 
BioNTech as the sponsor of the BNT141-01 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 BNT oncology trials, considering also guidelines from the FDA, EMA, 
CDC, ASCO, ESMO and local agencies. COVID-19 vaccination may be performed in 
accordance with the most current guidelines. As of May 2021, these are:  
• 
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 
COVID-19 vaccine and trial treatment dose are ensured. 
• 
COVID-19 vaccination during DLT evaluation period in dose escalation trial or 
parts of the trial should be avoided to circumvent 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 BNT141-01 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 RT-
PCR before enrolment in the BNT141-01 trial should be documented in the medical 
history. 
 
 


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Appendix 2: 
Risk-benefit assessment of COVID-19 vaccination in 
BNT141-01 trial 
BNT141 encodes the antibody RiboMab
 directed against CLDN18.2. The specific 
RiboMab
 binding to CLDN18.2 on the cell surface of tumor cells mediates cell death 
through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent 
cytotoxicity (CDC). BNT141 is entering early clinical development, and the safety profile in 
humans has not been characterized.  
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 Center for Disease Control’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 7 (i.e., received any live vaccine within 30 days prior to 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 on a 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 interactions of BNT141 with all the vaccines approved in the US and EU are not 
known. However, the sponsor assesses the risk of significant side effects of BNT141 in 
combination with COVID-19 vaccine to be low. The National Comprehensive Cancer 
Network (NCCN) and American Society of Clinical Oncology (ASCO) recommend for the 
COVID-19 vaccine to be administered on the same day as oncology therapy, including 
immunotherapy. However, since no clinical data are available for BNT141 as no clinical 
trials have been performed, the protocol would recommend at least seven days interval 
between COVID-19 vaccine and administration of BNT141 as a precaution.  
However, a longer interval may be necessary during the DLT observation period. The 
oncologist should always assess the situation on an individual basis and discuss with the 
sponsor. Considering the high morbidity and mortality from COVID-19 in patients with 
cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related AE 
in patients enrolled in clinical trials (Desai et al. 2021). 
 
 
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Appendix 3: 
Recommendation for COVID-19 infection in BNT141-01 
trial 
There is no clear or specific guidance for patients enrolled in interventional oncology 
clinical trials who have COVID-19 infection. The decision should be taken on a case-by-
case basis taking into consideration the institutional guidelines and the patient’s 
symptoms, comorbidities, age, presence of lung tumor or metastasis, COVID-19-
vaccination status, etc. and should be discussed with the sponsor.  
Patients who have not been enrolled: 
Patients with serious COVID-19 infection are not eligible for the trial. 
Patients with asymptomatic or mild COVID-19 infection should not receive their first trial 
treatment until symptom resolution and a negative SARS-CoV-2 test (antigen or PCR). 
Patients with ongoing trial treatment: 
The oncologist should always assess the situation individually and discuss it with the 
sponsor. 
For asymptomatic, vaccinated patients, trial treatment continuation can be discussed. 
For symptomatic patients, trial treatment interruption should be discussed. If trial treatment 
is interrupted, a negative SARS-CoV-2 test (antigen or PCR) is recommended after 
symptom resolution to continue the trial treatment. 

SAP_003.pdf: 
 
 
Page 1 of 47 
 
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). 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
BNT141-01 
 
Version: 
Final v1.0 
Date: 
07 Sep 2023 
Sponsor: 
BioNTech SE 
 
 
 
Protocol number:  
BNT141-01 
Protocol title: 
Phase I/IIa, first-in-human, open-label, dose escalation trial with expansion cohorts 
to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy 
of BNT141 as a monotherapy and in combination with other anti-cancer agents in 
patients with CLDN18.2-positive solid tumors 
Short Title / 
Acronym 
Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy trial of 
BNT141 in patients with unresectable or metastatic CLDN18.2-positive gastric, 
pancreatic, ovarian and biliary tract tumors 
Trial Phase 
I/IIa 
Protocol version: 
4.0  
Protocol date: 
13 June 2022 
 
Compounds: 
BNT141 
SAP version: 
Final v1.0 
SAP date: 
07 September 2023 
CRO name: 
Syneos Health 
SAP author: 
 
 
PPD


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TABLE OF CONTENTS 
TABLE OF CONTENTS 
2
LIST OF TABLES 
3
1.
SAP APPROVAL 
4
2.
VERSION HISTORY 
5
3.
INTRODUCTION 
6
3.1
Objectives and endpoints 
7
3.2
Trial design 
9
3.3
Schedule of activities 
13
4.
STATISTICAL HYPOTHESES 
13
5.
INTERIM ANALYSES AND ANALYSIS SEQUENCE 
14
6.
SAMPLE SIZE DETERMINATION 
14
7.
ANALYSIS SETS AND SUBGROUPS 
14
7.1
Analysis sets 
14
7.2
Protocol deviations 
15
7.2.1
Protocol deviations due to COVID-19 
16
7.3
Subgroups 
16
8.
STATISTICAL ANALYSES 
17
8.1
General considerations 
17
8.1.1
Key definitions 
17
8.1.2
Missing data 
20
8.1.3
Visit windows 
20
8.2
Patient disposition 
20
8.3
Baseline characteristics 
21
8.3.1
Demographics and baseline characteristics 
21
8.3.2
Disease characteristics 
21
8.3.3
Medical history 
22
8.3.4
Prior anti-cancer treatments 
22
8.3.5
Prior and concomitant medication 
23
8.4
Efficacy analyses 
23
8.4.1
Primary analysis 
23
8.4.2
Supplementary analyses 
23
8.4.3
Secondary analyses 
23
8.4.4
Exploratory analyses 
23
8.4.5
Other exploratory endpoints 
23
8.5
Safety analyses 
24


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8.5.1
Primary safety endpoints 
24
8.5.2
Extent of exposure 
24
8.5.3
Adverse events 
25
8.5.4
Injection/infusion-related reactions and cytokine release syndrome 
28
8.5.5
Laboratory assessments 
29
8.5.6
Physical examination 
31
8.5.7
Vital signs 
31
8.5.8
Electrocardiogram (ECG) 
32
8.5.9
ECOG performance status 
33
8.6
Pharmacokinetics (PK) analyses 
34
8.6.1
Primary PK endpoints 
34
8.6.2
Secondary PK endpoints 
34
9.
CHANGES TO PROTOCOL-PLANNED ANALYSES 
34
10.
QUALITY CONTROL 
35
11.
REFERENCES 
35
12.
SUPPORTING DOCUMENTATION 
37
12.1
Appendix 1: List of abbreviations 
38
12.2
Appendix 2: List of PK parameters 
41
12.3
Appendix 4: Schedule of activities 
42
 
LIST OF TABLES 
Table 1:
SAP version history summary 
5
Table 2:
Objectives and endpoints 
7
Table 3:
Definitions of analysis sets 
15
Table 4:
Local laboratory assessments – overview 
30
Table 5:
Normal ranges for vital signs 
32
Table 6:
ECOG performance status 
33
 
 
 






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3. INTRODUCTION 
This is a Phase I/IIa, first-in-human, open-label, dose escalation trial with expansion cohorts 
to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of 
BNT141 as a monotherapy and in combination with other anti-cancer agents in patients with 
CLDN18.2-positive solid tumors. 
The clinical trial protocol (CTP) v5.0, released on 15 March 2023, had not been implemented 
yet when the sponsor decided to terminate the study. Therefore, the Statistical Analysis Plan 
(SAP) is based on the CTP v4.0. 
The trial was planned to consist of three parts:  
x Part 1A was a dose escalation of BNT141 as monotherapy in patients with 
unresectable or metastatic CLDN18.2-positive solid tumors for which there was no 
available standard therapy likely to confer clinical benefit, or the patient was not a 
candidate for such available therapy; patients had to have received all available 
standard therapies and failed at least first-line standard of care (SOC) therapy prior to 
enrolment; the dose of BNT141 were escalated until the maximum tolerated dose 
(MTD) and/or RP2D of BNT141 as monotherapy were defined.  
x Part 1B was planned to be a dose escalation of BNT141 in combination with nab-
paclitaxel and gemcitabine in patients with advanced unresectable or metastatic 
CLDN18.2-positive pancreatic adenocarcinoma or cholangiocarcinoma who were 
eligible for treatment with nab-paclitaxel and gemcitabine; it intended to define the 
MTD and/or RP2D of the combination.  
x Part 2 (Expansion) was planned to consist of two pre-defined expansion cohorts:  
o 
 
  
 
 
 
 
 
 
  
Part 2 was planned to be defined via an amendment after careful evaluation of all available 
safety, PK and PD, and efficacy data generated in Parts 1A and 1B by the Safety Review 
Committee (SRC). 
The sponsor stopped the study early, while only patients under Part 1A had been recruited. 
Therefore, this SAP outlines the planned analyses for Part 1A in the CTP v4.0, dated 13 
June 2023, including three amendments:  
x Amendment 1 (03 March 2021): This update was issued before first patient was 
enrolled into the trial. Minor editorial changes, such as correction of typing errors 
requested by the Food and Drug Administration (FDA). Changes has no impact on 
the planned objectives or trial conduct.  
x Amendment 2 (06 August 2021): This update was issued before first patient was 
enrolled into the trial. Specification of unique identifiers to the inclusion criteria, to 
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correct an error in the implementation of the change to DLT definitions in 
Section 6.6.1 of protocol and minor administrative changes which has no impact on 
the planned objectives or trial conduct.  
x Amendment 3 (13 June 2022): Major changes that included clarifications of PK 
endpoints, update of eligible indications to include patients with specific tumors, 
update of end of trial and patient completion definitions, definition of SAE regarding 
inpatient hospitalization or prolongation of existing hospitalization, etc. 
The last amendment 4, released on 11 April 2023, is described in the CTP v5.0. 
In addition, the SAP defines and describes the statistical methodologies to ensure complete 
and appropriate analyses and allow valid conclusions regarding the study objectives of Part 
1A in the clinical study report (CSR). It must be finalized prior to the database lock of the 
final analysis. 
The analyses to support the SRC data are not a part of this SAP.  
Up to the early trial termination decision, four dose decision meetings (DDM) were held on 
21 June 2022, 25 October 2022, 10 January 2023 and 11 April 2023. In addition, one 
investigational brochure was released on 30 March 2023 and one ad hoc analysis was 
released on 21 July 2023. 
Syneos Health will perform the statistical analyses (using SAS® software version 9.4 or 
higher, and/or other statistical software as required) and is responsible for the production 
and quality control of all tables, figures, and listings (TFLs) for the final delivery.  
PK analyses will be performed using Phoenix WinNonlin® version 8.3.4, which is validated 
by Syneos Health. Details of the PK analysis and corresponding PK tables, figures and 
listings shells are provided in a separate analysis plan.  
Templates for each unique table, figure and patient listing are provided in a separate 
document “Data Presentation Plan” (“DPP”). 
3.1 
Objectives and endpoints 
Trial objectives and endpoints are listed in Table 2. 
 
Table 2: 
Objectives and endpoints  
Objectives 
Endpoints 
Primary objectives 
Endpoints 
To assess the safety and tolerability of 
BNT141 at different dose levels. 
 
x 
Occurrence of treatment-emergent adverse events 
(TEAEs) within a patient including Grade ≥ 3, 
serious, fatal TEAE by relationship. 


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Objectives 
Endpoints 
x 
Occurrence of dose reductions and discontinuation 
of BNT141 due to TEAEs. 
To identify the maximum tolerated 
dose (MTD) or maximally administered 
dose (MAD) /recommended Phase II 
dose (RP2D) of BNT141 based on the 
occurrence of dose-limiting toxicities (DLTs) using 
the following definitions: 
x 
The MTD will be defined as the highest 
tolerated dose, where less than one-third of 
the patients experience a DLT.  
x 
The MAD is defined as the highest dose 
administered, where all dose levels were 
tolerated during dose escalation. 
x 
The RP2D will be defined based on integrated 
evaluation of safety, tolerability, clinical 
benefit, 
pharmacokinetic 
(PK), 
and 
pharmacodynamic data, for all dose levels 
tested. 
 
x 
Occurrence of DLTs within a patient during the DLT 
evaluation period 
Secondary objectives 
Endpoints 
To characterize the PK profile of the 
BNT141-encoded protein RiboMab
. 
x 
PK parameters including but not limited to area-
under-the-concentration-time 
curve 
(AUC), 
clearance (CL), volume of distribution (Vd), 
maximum concentration (Cmax), time to Cmax (tmax), 
measured concentration at the end of a dosing 
interval [taken directly before next administration] 
(Ctrough), and half-life (t½). 
To evaluate the anti-tumor activity of 
BNT141 according to Response 
Evaluation Criteria in Solid Tumors 
(RECIST) 1.1. 
x 
Objective response rate (ORR) is defined as the 
proportion of patients in whom a complete 
response (CR) or partial response (PR) per 
RECIST 1.1 is confirmed as best overall response 
(BOR). 
x 
Disease control rate (DCR) is defined as the 
proportion of patients in whom a CR or PR or 
Stable Disease (SD) per RECIST 1.1 (SD 
assessed at least 6 weeks after first dose) is 
observed as BOR. 
x 
Duration of response (DOR) is defined as the time 
from first objective response (CR or PR per 
RECIST 1.1) to first occurrence of objective tumor 
progression (PD) per RECIST 1.1 or death from 
any cause, whichever occurs first. 
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Objectives 
Endpoints 
Exploratory objectives 
Endpoints 
To evaluate the efficacy of BNT141. 
x 
Progression-free survival (PFS) defined as the time 
from first dose of BNT141 to first objective PD 
(progressive disease) per RECIST 1.1, or death 
from any cause, whichever occurs first. 
x 
Overall survival (OS) is defined as the time from 
first dose of BNT141 to death from any cause  
To assess Claudin 18.2 (CLDN18.2) expression 
level as a potential biomarker to predict clinical 
response to BNT141. 
x 
Correlation of CLDN18.2 expression level with 
clinical outcomes 
To 
assess 
potential 
Pharmacodynamic 
biomarkers of BNT141. 
x 
Evaluation 
of 
Pharmacodynamic 
biomarkers 
compared to baseline. 
To evaluate the immunogenicity of BNT141. 
x 
Anti-drug antibodies (ADAs) response. 
To assess other exploratory markers that may be 
collected in the study to better understand 
BNT141 treatment. 
x 
Evaluate pre-treatment lipid status and potential 
influence on BNT141 response. 
ADAs = Anti-drug antibodies; AUC = Area-under-the-concentration-time curve; BOR = Best overall response; CL = 
Clearance; Cmax = Maximum observed serum concentration; CR = Complete response; Ctrough = Measured concentration 
at the end of a dosing interval; DCR = disease control rate; DLTs = Dose limiting toxicities; DOR = Duration of response; 
MAD = Maximal administered dose; 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. 
3.2 
Trial design 
 
Trial design 
This trial is an open-label, multi-site, Phase I/IIa dose escalation, 
safety, and PK trial of BNT141 followed by expansion cohorts in 
patients with CLDN18.2-positive tumors. CLDN18.2 positivity will be 
determined by a central laboratory during the pre-screening phase 
using a validated immunohistochemistry assay and is defined as 
moderate-to-strong CLDN18.2 expression. 
 
The trial design was planned to consist of three parts: 
• 
Part 1A was a dose escalation of BNT141 as monotherapy 
in patients with advanced unresectable or metastatic 
CLDN18.2-positive solid tumors for which there is no available 
standard therapy likely to confer clinical benefit, or the patient 
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have received all available standard therapies and failed at 
least first-line SOC therapy prior to enrolment. The dose of 
BNT141 was escalated until the MTD and/or RP2D of BNT141 
as monotherapy were defined. Once the MTD was reached, up 
to 10 additional patients with CLDN18.2 expressing pancreatic 
and biliary tract cancers were planned to be enrolled at the 
MTD level to obtain additional data on safety, PK and PD. 
Eligible tumor types are gastric cancer, gastroesophageal 
junction (GEJ) and esophageal adenocarcinoma, pancreatic, 
biliary tract (cholangiocarcinoma and gallbladder cancer), and 
mucinous ovarian cancers. Additionally, patients with specific 
tumors (including colorectal cancer, non-small-cell lung 
cancer, gastric subtype of endocervical adenocarcinoma) 
where there was scientific evidence that the CLDN18.2 could 
be elevated could be tested for CLDN18.2 expression. 
x Part 1B was planned to consist of a dose escalation of 
BNT141 in combination with nab-paclitaxel and 
gemcitabine in patients with locally advanced unresectable or 
metastatic CLDN18.2-positive pancreatic adenocarcinoma or 
cholangiocarcinoma who were eligible for treatment with nab-
paclitaxel and gemcitabine. Part 1B intended to define the 
MTD and/or RP2D of the combination. Once the MTD was 
reached, up to 10 additional patients with CLDN18.2-
expressing pancreatic adenocarcinoma or cholangiocarcinoma 
were planned to be enrolled at the MTD level to obtain 
additional data on safety, PK and PD. The MTD of BNT141 in 
combination with nab-paclitaxel and gemcitabine in Part 1B 
had not to exceed the monotherapy BNT141 MTD determined 
in Part 1A. 
• 
Part 2 (Expansion) was planned to consist of the following 
pre-defined expansion cohorts:  
 
 
  
The trial design in the expansion cohorts was planned to be 
either a Simon two-stage design or a Khan one-stage design.  
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The same imaging method (CT/MRI) had to be used for a patient 
throughout the trial. Imaging was assessed by an experienced 
radiologist at site using RECIST 1.1 criteria.  
 
Schema (graphical representation of the trial): 
 
 
 
3.3 
Schedule of activities 
See protocol Section 1.3 for the schedule of activities (SoA) and Appendix 5 of this SAP. 
4. STATISTICAL HYPOTHESES 
There is no formal statistical hypothesis being tested in this first-in-human trial. 
The primary objectives of trial Part 1A are to assess the safety and tolerability and to identify 
the MTD and/or RP2D of BNT141.  
The primary objective of trial Part 1B was planned to assess the safety and tolerability, and 
to identify the MTD and/or RP2D of BNT141 in combination with nab-paclitaxel and 
gemcitabine.  
For Part 2, statistical hypotheses were planned to be defined in a protocol amendment.  
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5. INTERIM ANALYSES AND ANALYSIS SEQUENCE 
A formal interim statistical analysis was not planned for Part 1 of the study. 
However, data were reviewed for each dose escalation cohort in Part 1A by the SRC. 
Up to the early trial termination decision, four DDMs were held on 21 June 2022, 25 October 
2022, 10 January 2023 and 11 April 2023. In addition, one investigational brochure was 
released on 30 March 2023 and one ad hoc analysis was released on 21 July 2023. 
6. SAMPLE SIZE DETERMINATION 
The sample size for trial Part 1A and 1B was driven by the classical 3+3 trial design and 
ranged from 2 to 6 DLT-evaluable patients per cohort depending on the occurrence of DLTs. 
In both trial Parts 1A and 1B, the sample size was up to 48 DLT-evaluable patients in each 
part depending on the DLTs, which may occur. Non-DLT-evaluable patients were replaced.  
Once the MTD was reached, up to 10 additional patients with CLDN18.2 expressing 
pancreatic or biliary tract cancers were planned to be enrolled at the MTD level in Parts 1A 
and up to 10 additional patients with CLDN18.2 expressing pancreatic adenocarcinoma and 
cholangiocarcinoma in Part 1B respectively, to obtain additional data on safety, PK, and PD. 
Based on this sample size the probability to observe a particular AE with incidence of 15% 
would be 80.3%. 
The final Part 2 sample size calculations was planned to be provided through an amendment 
when Part 2 design is available in the BNT141 CTP. 
7. ANALYSIS SETS AND SUBGROUPS 
7.1 
Analysis sets 
The following analysis sets are defined: 
 


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Table 3: 
Definitions of analysis sets 
Analysis set 
Description 
Screened Set 
All patients who signed informed consent form. 
Treated Set 
All patients who received IMP (i.e., at least one dose of BNT141).  
Safety Set 
All patients who received IMP (i.e., at least one dose of BNT141). 
DLT Evaluation Set 
All patients from the Safety Set who either have completed the DLT evaluation period 
and meet the minimum exposure criterion or have experienced a DLT during the DLT 
evaluation period (21 d for Part 1A,). 
Patients who do not experience any DLT during the DLT observation period are 
considered to be evaluable if they have been observed for minimum 21 d for Part 1A 
following the first target dose and are considered to have sufficient safety data to 
conclude that a DLT did not occur. A patient is considered to have met the minimum 
exposure criterion in Part 1A if the relative dose intensity of BNT141 in Cycle 1 is at 
least 80%.  
Patients who are excluded from the DLT Evaluation Set will be replaced.  
This analysis set may only be used in Part 1 of the trial. 
Pharmacodynamic 
Set 
All patients with baseline and at least one valid on-treatment/post-treatment 
pharmacodynamic assessment.  
Pharmacokinetic  
Set 
All patients with baseline and at least one valid on-treatment/post-treatment PK 
assessment. 
DLT = Dose limiting toxicity; IMP = Investigational medicinal product. 
The DLT Evaluation Set will be used for the evaluation of DLTs in order to assess the MTD 
and RP2D. The Safety Set will be used for all other safety analyses. The Treated Set 
includes all patients who received at least one complete/partial dose of BNT141. The 
Treated Set will be used for demographics, disease characteristics, medical history, prior 
and concomitant medication, other medical procedures, and efficacy analyses. The 
Screened Set and Treated Set will be used for disposition as applicable. 
7.2 
Protocol deviations 
Protocol deviation management for this study is detailed in the trial specific Protocol 
Deviation and Non-compliance Management Plan. According to this plan, protocol 
deviations or site non-compliance are documented concisely in the Medidata Clinical Trial 
Management System (CTMS) and periodically reviewed as part of the project oversight by 
a wider trial team. 
Protocol deviations are failures to adhere to the inclusion/exclusion criteria and protocol 
requirements and will be classified into major protocol deviations and minor issues. 
x Major protocol deviations are a subset of protocol deviations that may significantly 
affect the completeness, accuracy, and/or reliability of the trial data or that may 
significantly affect a patient’s rights, safety, or well-being. For example, major protocol 


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deviations may include enrolling patients in violation of key eligibility criteria designed 
to ensure a specific patient population or failing to collect data necessary to interpret 
primary endpoints, as this may comprise the scientific value of the trial. 
x Minor issues are any non-compliance that does not adversely affect the study or 
process (i.e., does not meet the definition of major).  
x Major protocol deviations will be identified by trial team review during the Data Review 
Meeting (DRM) prior to database lock. 
Additional major protocol deviations may be defined at the Data Review Meeting (DRM) prior 
to database lock. During the DRM, protocol deviations as specified in this section of the SAP 
and all protocol deviations as reported in the CTMS system will be evaluated. 
Major protocol deviations will be summarized by dose cohort, country, site, and deviation 
type for the Treated Set.  
All major protocol deviations will be listed. 
7.2.1 
Protocol deviations due to COVID-19 
Protocol deviations related to COVID-19 are documented in the CTMS with the preface 
“COVID-19” in the deviation description. 
COVID-19 related protocol deviations are, for example: 
x COVID-19, Visit xx on date xx of patient not conducted due to site facility re-
organization related to COVID-19 disruption. 
x COVID-19, missing Visit xx due to patient affected by COVID-19 
The following listings of protocol deviations due to COVID-19 will be generated for the 
Treated Set to report the impact of COVID-19 on patients enrolled in this study: 
x Patients impacted by COVID-19 related trial disruption. 
x Missing visits due to COVID-19. 
7.3 
Subgroups 
No subgroup analysis is planned for Parts 1A. This section was planned to further describe 
potential subgroup analysis for Part 2 through amendment when Part 2 design is available 
in the BNT141 CTP. 


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8. STATISTICAL ANALYSES 
8.1 
General considerations 
In general, statistical analysis will be performed by dose cohort for Part 1A according to the 
IMP dose level 
.  
Continuous variables will be summarized using the following descriptive statistics: number 
of patients (n), mean, standard deviation, median, minimum, and maximum.  
Categorical variables will be summarized using absolute and relative frequencies (n and %) 
of patients in each category. A “missing”’ category will be presented where applicable, if 
there is one or more missing value, with exception of by-visit summaries. 
Baseline is defined as last available value prior to first dose of IMP. 
Generally, only measurements at scheduled visits will be summarized and included in the 
tables by visit. Measurements at unscheduled visits will be included only in the listings, 
unless specified otherwise.  
All enrolled patients will be included in the final analysis. 
All relevant data will be listed. The listings will be sorted by dose level, patient number and 
date/time of assessment/event (if applicable). Unscheduled measurements will be included 
in the listings. 
Programming considerations of planned summary tables, figures and listings and templates 
for each unique table and patient listing are provided in a separate document “DPP”.  
8.1.1 
Key definitions 
Date/time of first IMP dose: 
Is defined as date/time of first administration of BNT141. 
DLT evaluation period: 
The DLT evaluation period is defined as Cycle 1, i.e., 21 days for Part 1A.  
For detailed definition of DLT see protocol Section 6.6.1. 
Baseline Definition: 
Baseline is defined as last available value prior to first dose of IMP (i.e., prior to the date and 
time of the first administration of IMP). Unscheduled measurements prior to the first dose of 
IMP will be considered in the derivation of the baseline values.  
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Change from baseline: 
Change from baseline will be calculated as follows:  
x Change from baseline = post-baseline assessment value – baseline assessment 
value. 
Change from pre-treatment: 
Change from pre-treatment will be calculated as follows:  
x Change from pre-treatment = post-treatment assessment value at visit X – pre-treatment 
assessment value at visit X. Will be defined for each post-treatment assessment.  
Age (in years) at date of informed consent: 
Age is derived in the database based on the collected Year of birth as follows: 
Age = (Informed consent Date – (01July + Year of birth)) / 365.25. 
Age as derived in the database will be analyzed. 
Body mass index (BMI): 
BMI will be calculated as follows: 
BMI (kq/m2) = Weight (kg) / Height (m2). 
Duration: 
Duration will be calculated as follows:  
Duration (days) = last observation date – first observation date + 1 
For conversion of days to months or years the following rules will be applied: 
x 1 month = 30.4375 days 
x 1 year = 365.25 days 
Time from initial diagnosis to enrollment (in months): 
Date of initial diagnosis is collected in Month/Year. Missing day will be replaced with the first 
day of the month. In case month is not reported, month and date will be replaced with July, 
1st. 
Time from initial diagnosis to enrollment (months) will be calculated as: 
(Informed consent date – imputed date of initial diagnosis) / 30.4375  
Trial day:  
Trial day is defined as follows:  


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If date of assessment is on or after the date of first IMP dose:  
x Date of assessment/event – date of first IMP dose +1 
If date of assessment is before date of first IMP dose: 
x Date of assessment/event – date of first IMP dose 
Laboratory values with “< xx” or “> xx”: 
Any laboratory assessment values given as “< xx” or “> xx” in the database will be imputed 
with the numeric value of xx without the sign for the calculation of descriptive statistics and 
the changes from baseline (e.g., a value of < 1 will be imputed as 1 for the calculations).  
Start of Follow-up Period: 
Patients discontinuing from treatment for any reason had safety follow-up visits 30 days (+5 
days) and 60 days (±7 days) after the patient receives the last dose of BNT141. If the patient 
initiated new anti-cancer treatment within 60 days of the last dose of trial treatment, the 
safety follow-up visit was performed prior to starting new anti-cancer treatment. Once new 
anti˗cancer treatment was initiated, the patient moved into Survival follow-up. 
Information on survival follow-up, new anti-cancer therapy (including targeted therapy and 
immunotherapy) and cancer-related procedures were collected for all patients via telephone 
calls, patient medical records, and/or clinic visits from BNT141 treatment discontinuation 
and approximately every 12 weeks until death (unless the patient withdraws consent, or the 
sponsor terminates the trial). 
Planned time points for safety and survival follow-up are provided in the schedule of 
activities, see protocol Section 1.3. 
Pooling of centers: 
No pooling of centers is planned for this trial. 
Conventions for imputing missing/partially missing dates:  
When computations on dates are to be performed, incomplete/missing dates will be imputed 
using the following rules, 
x Missing day, month/year present: If the month/year is the same as the month/year of 
the first IMP administration date, then impute missing start dates with first IMP dose 
date. Otherwise, for dates corresponding to a start date, impute with the first day of 
the month and, for dates corresponding to a stop date, impute with the last day of the 
month. 
x Missing month/day, year present: If the year is the same as the year of the first IMP 
dose date, then impute missing start dates with first IMP dose date. Otherwise, for 


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dates corresponding to a start date, impute with the first day of the year and, for dates 
corresponding to a stop date, impute with the last day of the year. 
x Missing month/day/year: no imputation. 
x In the case imputed start date is after stop date, imputed start date is further adjusted 
to be equal to stop date. 
This imputation method will be applied to the following dates: 
x Onset date of AEs (for identification of treatment-emergent AEs purpose), incomplete 
AE end dates. 
x Medical history start or end date to define prior medical history and concomitant 
diseases. 
x Date of prior/concomitant medication (start dates) to define prior and concomitant 
medication, incomplete stop dates of prior/concomitant medications. 
8.1.2 
Missing data 
All reasonable efforts will be made to obtain complete data for all patients. However, missing 
observations may occur due to patients lost to follow-up or to noncompliance with required 
trial visits and/or assessments. Missing data will not be imputed, and data analysis will be 
performed based on the observed values, unless otherwise specified. 
8.1.3 
Visit windows 
Every attempt was made to perform evaluations at the designated time point/visit. Visit 
windows for visits per cycles and for follow-up (FU) visits are defined in the SoA tables (see 
protocol Section 1.3 and Appendix 5). All visits will be summarized according to the nominal 
visit. 
8.2 
Patient disposition 
For the Screened Set, the number of patients screened, the number and percentage of 
patients who were eligible, those who were treated will be summarized by country, and site. 
For the Treated Set, the number and percentage of treated patients included in each 
analysis set (i.e., Safety Set, DLT Evaluation Set, PK Set and PD set), the number and 
percentage of patients being excluded and the reasons for exclusion will be summarized by 
dose cohort.  
For the Treated Set, the treatment status will be reported by dose cohort, including the 
number and percentage of patients having prematurely discontinued and the primary reason 
for premature treatment discontinuation of the IMP (e.g., AEs, disease progression, death, 
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Further, the number and percentage of patients entered safety follow-up period and survival 
follow-up period as well as end of trial and the primary reason for discontinuation from the 
trial will be summarized by dose cohort. Total number of deaths will be presented by dose 
cohort. 
All patient disposition data will be listed. Patients excluded from any of the analysis sets and 
the reason for exclusion from the analysis sets will be listed. In addition, screening failures 
patients along with their reason of screening failure will be listed. A listing of all inclusion and 
exclusion criteria that were not met, based on the Screened Set will be generated as well. 
8.3 
Baseline characteristics 
8.3.1 
Demographics and baseline characteristics 
Demographic and baseline variables will be summarized for patients in the Treated Set. Age 
(years), weight (kg), height (cm), body mass index (kg/m2), BSA (m2) and Glomerular 
filtration rate (mL/min/1.73 m2) will be summarized as continuous data. Age (<65 years, ≥65 
years, ≥65 - <75 years, ≥75 years), Sex (male or female), Ethnicity (Hispanic or Latino, Not 
Hispanic or Latino, Not Reportable, Unknown), race (Black or African American, American 
Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, White, Not 
Reported), BMI categories (<18 kg/m2, ≥18 kg/m2 - <25 kg/m2, ≥25 kg/m2 - <30 kg/m2, ≥30 
kg/m2) and substance use as current alcohol use (yes, no) and current other drug abuse 
(yes, no) will be summarized as categorical data by dose cohort.  
A listing of demographics and baseline characteristics will be provided for the Treated Set. 
8.3.2 
Disease characteristics 
Disease characteristics will be summarized for patients in the Treated Set.  
Time from initial diagnosis to enrollment (month), and time from most recent disease 
progression to first IMP dose (month) will be summarized as continuous data by dose cohort.  
Cancer type, cancer grade, tumor stage (American Joint Committee on Cancer [AJCC], 
current version) at initial diagnosis, Tumor, Nodes and Metastasis (TNM) classification at 
initial diagnosis, Tumor status at trial entry, and Eastern Cooperative Oncology Group 
performance status (ECOG PS) at baseline will be summarized as categorical data by dose 
cohort.  
Further, on the basis of the initial tumor assessment (based on RECIST 1.1) reported at the 
Screening visit, the following variables will be reported: 
x Disease characteristics – Imaging: target lesions (absent/present), non-target lesions 
(absent/present), location of target lesions and sum of target lesion diameters. 


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The tumor type concerning the CLDN18.2 expression level at screening will be summarized 
as follows: IC form signed for CLDN18.2 expression (yes/no), percentage of tumor cells with 
a CLDN18.2 expression of 2+/3+ (%) both as continuous and as categorical data (<50.0%, 
50.0% - 75.9%, 76.0% - 90.0%, >90.0%), sample type (Fresh tumor biopsy / Archival FFPE 
tumor tissue), Anatomical location where the sample was collected (Colon / Esophagus / 
Liver / Lung, etc.), laterality (Left / Right) and type of biopsy (Core / Punch / Excisional). 
Disease characteristics data will be listed for the Treated Set. 
8.3.3 
Medical history 
Medical history data will be coded using MedDRA (version 25.0 or later version). The 
number and percentage of patients with a medical history will be summarized by System 
Organ Class (SOC) and Preferred Term (PT) in the Treated Set, without distinguishing 
between prior medical history and concomitant diseases. 
A listing of medical history data will be provided for the Treated Set. 
8.3.4 
Prior anti-cancer treatments 
Prior cancer surgeries will be coded using MedDRA version 25.0 or later version. 
Prior systemic cancer therapies will be coded using the World Health Organization Drug 
Dictionary (WHO-DD) drug codes of the most recent version (WHO-DD Global B3 Sep2021 
or later version) resulting in Anatomical-Therapeutic-Chemical (ATC) codes indicating 
therapeutic classification. 
A table “Prior Systemic Cancer Therapies” will be generated for the line (number) of prior 
systemic cancer therapies and the following information of the last systemic therapy: 
x setting (adjuvant, neoadjuvant, metastatic, maintenance, unknown), 
x best response (CR, PR, PD, SD/Non-PD, NE, Unknown, Not Applicable), 
x disease status at the end of therapy (CR, PR, PD, SD/Non-PD, NE, Unknown, Not 
Applicable), 
x reasons for termination of the therapy (Toxicity/Intolerance, Disease Progression, 
Other, Unknown, Completion of therapy)  
Prior cancer surgery, prior cancer radiotherapy and prior systemic cancer therapy will be 
listed for the Treated Set. In addition, a listing of systemic cancer therapy, including ATC 
therapeutic class (ATC level 2), ATC pharmacological class (ATC level 3), and chemical 
class (ATC level 4) will be generated. 


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8.3.5 
Prior and concomitant medication 
All medications will be coded using the WHO-DD drug codes of the most recent version 
(WHO-DD Global B3 Sep2021, or later version) resulting in ATC codes indicating 
therapeutic classification. 
Prior and concomitant medications will be defined using start and stop dates recorded 
relative to the first and last IMP administration dates.  
Prior medications will be defined as any therapy taken prior up to (but not including) the 
start date of first IMP administration.  
Concomitant medications will be defined as any medication either ongoing at the start 
date of first IMP administration or with a start date on or after the first IMP administration 
date, including those taken during safety follow-up.  
Concomitant medications will be summarized by ATC therapeutic class (ATC level 2), ATC 
pharmacological class (ATC level 3), and chemical class (ATC level 4). 
All medications will be listed and flagged as “Prior” or “Concomitant” for the Treated Set, 
including ATC therapeutic class (ATC level 2), ATC pharmacological class (ATC level 3), 
and chemical class (ATC level 4).  
8.4 
Efficacy analyses 
No efficacy analysis is planned for Part 1A.  
8.4.1 
Primary analysis 
No primary efficacy endpoints are specified for this study. The analysis of the primary safety 
endpoints is described in Section 8.5.1.  
8.4.2 
Supplementary analyses 
Not applicable. 
8.4.3 
Secondary analyses 
Not applicable. 
8.4.4 
Exploratory analyses 
No analysis of PFS and OS is planned for Part 1A.  
8.4.5 
Other exploratory endpoints 
Cytokine assessment data will be listed. The other exploratory endpoints such as ADAs and 
PK lipids will be elaborated in the “Pharmacokinetic and pharmacodynamic analysis plan”. 


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8.5 
Safety analyses 
Safety analysis will be limited to Part 1A. 
Safety data analyses include extent of exposure to trial treatment, AEs, occurrence of DLTs 
during dose escalation in Part 1A, clinical laboratory assessments, physical examination, 
vital signs, ECGs and ECOG performance status.  
All safety analyses will be based on the Safety Set and will be summarized by dose cohort, 
except for the DLT(s) analysis which will be based on the DLT Evaluation Set. 
All safety data will be listed for the Safety Set. 
8.5.1 
Primary safety endpoints 
The primary safety endpoints are the occurrence of DLTs, treatment-emergent adverse 
events (TEAEs), adverse events of special interest (AESI) and serious adverse events 
(SAE) reported by causal relationship to trial treatment, grade, and seriousness according 
to NCI CTCAE v5.0. The number and percentage of patients with any DLT, TEAEs, AESIs 
and/or SAEs will be presented.  
Moreover, a patient listing will be provided with all dose exposure data of all patients 
enrolled, and a listing of all recorded DLTs and/or adverse events (AE) will be presented 
including the reported term and SOC and PT terms coded using MedDRA®, start date/time 
and stop date/time, causal relationship, NCI CTCAE grade, and seriousness including dose 
exposure data. 
8.5.2 
Extent of exposure 
Exposure to BNT141 (for Part 1A) will be analyzed by dose cohort using the safety set as 
well as the DLT Evaluation set for the following dose exposure variables: 
x Number of cycles 
x Actual treatment duration (week) defined as follows: 
(date of last dose - date of first dose + planned duration per cycle) / 7, where the 
planned duration (days) is defined as the planned time between two consecutive 
administrations. 
Actual treatment duration (month) defined as follows: 
(date of last dose administration - date of first dose administration + planned duration 
per cycle) / 30.4375, where the planned duration (days) is defined as the planned 
time between two consecutive administrations. 
Planned treatment duration (week) is defined as follows: 


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(number of cycles × planned duration per cycle) / 7, irrespectively if patient was 
treated or not, with the exception of the last cycle which will be counted only when a 
patient at least partially receives an assigned dose. 
x For BNT141 planned duration per cycle is 21d for Part 1A. Actual cumulative dose 
 is defined as: 
sum of all administered doses.  
x Planned cumulative dose 
 is defined as: 
sum of all planned doses, irrespectively if patient was treated at cycle or not. 
x Dose intensity 
 is defined as: 
actual cumulative dose
 / actual treatment duration (week) 
x Planned dose intensity 
 is defined as: 
planned cumulative dose 
 / planned treatment duration (week) 
x Relative dose intensity (RDI) (%) is defined as: 
Dose intensity 
 / planned dose intensity 
 x 100 
RDI will be presented as continuous parameters as well as categorically as follows: number 
and percentage of patients with RDI of < 60%, 60 - < 80%, ≥ 80%. 
Moreover, the number and percentage of patients with any dose modification, with any dose 
delay, with any dose reduction, and any drug interruption will be presented.  
All study drug administration data will be listed. All the above-mentioned variables related to 
actual exposure will be listed as well. 
8.5.3 
Adverse events 
AEs will be coded using the MedDRA® coding system (version 25.0 or later version) to get 
a SOC and 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 
TEAEs only if assessed as related to IMP by the investigator. TEAEs will be summarized by 
dose cohort as well as overall.  
AEs started prior to first administration of IMP or after last administration of IMP + 60 days 
and not assessed as related to IMP (follow-up AEs) will be included only in the AE listings. 
AE leading to permanent study treatment discontinuation 
CCI
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AE leading to discontinuation are the AEs with the items “Action taken” ticked “Drug 
withdrawn”. 
AE leading to dose rate reduction 
AE leading to dose rate reduction are the AEs with the items “Action taken” ticked “Dose 
rate reduced”. 
AE leading to dose reduction  
AE leading to dose reduction are the AEs with the items “Action taken” ticked “Dose 
reduced”. 
AE leading to drug interruption 
AE leading to drug interruption are the AEs with the items “Action taken” ticked “Drug 
interrupted”. 
In case a patient has an AE with missing relationship status, the event will be assumed to 
be related and associated with the treatment received in the summaries (will be listed as 
collected in the listings). No imputation for missing NCI-CTCAE grades and missing 
seriousness will be performed.  
Dose limiting toxicities 
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 the purpose of dose escalation, the DLT monitoring period will be the 21 days of Cycle 
1 per CTP v4.0.  
Dose-limiting toxicities are outlined in protocol section 6.6.1. Serious AEs, non-serious 
Grade ≥ 3 non-hematological and hematological AEs as defined per DLT criteria and 
clinically significant abnormal laboratory values Grade ≥ 3 will be collected and considered 
as a DLT if assessed by the investigator to be at least possibly related to BNT141 for the 
Part 1A of the trial. Toxicities clearly not related to BNT141 (e.g., PD, comorbidity, etc.) will 
not be considered a DLT. The NCI-CTCAE v.5.0 will be used to grade the intensity of AEs. 
DLT will be presented in a listing. 
Overall summary of adverse events 
The number and percentage of patients reporting at least one TEAE will be summarized for 
each of the following AE types: 
• 
Any AE 
• 
AE related to BNT141 
• 
Grade ≥3 AE  


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• 
Grade ≥3 AE related to BNT141 
• 
AE related to trial procedure  
• 
DLT 
• 
AESI 
o Infusion-related reactions (IRR) 
o AESI related to liver function (AST, ALT, bilirubin) 
• 
SAE 
• 
SAE related to BNT141 
• 
SAE leading to death 
• 
Related SAE leading to death 
• 
AE leading to permanent treatment discontinuation of BNT141 
• 
AE leading to drug interruption of BNT141 
• 
AE leading to dose rate reduction of BNT141 
• 
AE leading to dose reduction of BNT141 
• 
Related AE leading to permanent treatment discontinuation of BNT141 
• 
Related AE leading to drug interruption of BNT141 
• 
Related AE leading to dose rate reduction of BNT141 
• 
Related AE leading to dose reduction of BNT141 
Adverse events by SOC and PT 
The number and percentage of patients will be summarized by SOC and PT as per 
MedDRA. If a SOC/PT is reported more than once for a patient, the patient will only be 
counted once for this SOC/PT. All AE summary tables will be sorted by descending 
frequency (%) by SOC, by PT within SOC, and count of events where applicable in the 
“Total” column. If the frequencies tie, the alphabetic order will be applied. The number of AE 
events will be summarized in the same table.  
The following tables for TEAEs by SOC and PT will be generated: 
• 
Any AE  
• 
AE related to BNT141 
• 
AE related to trial procedure  
• 
Any SAE 


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• 
SAE related to BNT141  
• 
Related SAE leading to death  
• 
Any non-serious AE 
• 
AE leading to drug interruption of BNT141 
• 
Related AE leading to drug interruption of BNT141 
In addition, the most frequent TEAEs concerning PT will be summarized by number and 
percentage of patients as well as number of events; most frequent is defined as TEAEs for 
PTs which occur in at least 10% of the patients in any of the displayed dose cohorts. 
Adverse events by worst NCI-CTCAE grade 
The number and percentage of patients with any TEAE will be summarized by worst NCI 
CTCAE grade by PT nested within SOC. If a TEAE is reported more than once by a patient 
for an SOC/PT, the patient will be counted for the worst grade for this SOC/PT. AEs with a 
missing grade will be presented in the summary table as a grade category of “missing”. 
TEAEs related to treatment will be analyzed by the worst NCI CTCAE grade as well.  
The following tables for TEAEs by worst NCI CTCAE grade by PT nested within SOC will 
be generated: 
• 
Any AE  
• 
AE related to BNT141 
Deaths 
Treatment-emergent AEs leading to death will be listed. All deaths will be listed as well. 
Deaths within 30 days of last dose of trial treatment will be flagged.  
Adverse events listings 
All AEs will be listed. Further, all deaths, SAEs, all SAEs leading to death, AEs leading to 
permanent discontinuation of treatment and AESIs will be listed.  
All DLTs will be presented with the reported term, PT and SOC, its time of onset, duration, 
and outcome, causal relationship, NCI CTCAE grade, and seriousness based on the DLT 
Evaluation Set. 
8.5.4 
Injection/infusion-related reactions and cytokine release 
syndrome 
Injection/infusion-related reactions (IRRs) and cytokine release syndromes (CRS) will be 
listed. 


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8.5.5 
Laboratory assessments 
Clinical laboratory data to be summarized include hematology, blood chemistry, coagulation 
factors, urinalysis, and endocrine tests. The clinical laboratory parameters to be assessed 
are listed in Table 4.  
All laboratory parameters are reported in the clinical database using local safety laboratories. 
Measurements and corresponding Low and High ranges will be converted into Standard 
International (SI) units. Values outside the normal ranges are classified as “Not clinically 
significant” or “Clinically significant” by the investigator. 
The last available assessment on treatment is defined as the assessment at End of 
Treatment Visit or the last safety assessment on treatment in case of treatment 
discontinuation due to death or withdrawal of consent.  
The last available assessment is defined as the assessment either at Safety FU-D30, Safety 
FU-D60 visit or the last safety assessment before discontinuation from trial.  
Continuous clinical laboratory parameters at each scheduled visit and change from baseline 
to each post-baseline time point will be summarized using descriptive summary statistics for 
each parameter by dose cohort. These summaries will apply to hematology, blood 
chemistry, coagulation factors, endocrine tests and blood lipids. 
The number and percentage of patients reporting markedly abnormal clinical laboratory 
values as reported by the investigator at any point on the trial will be summarized for each 
parameter by visit and dose cohort using the following categories as applicable: Clinically 
significant low, Low, Normal, High, Clinically significant high. These summaries will apply to 
hematology, blood chemistry, and coagulation factors. 
Urinalysis dipstick results will be reported only by number of patients and percentage for 
each parameter by visit and dose cohort.  
All clinical laboratory data will be presented in the data listings. Abnormal clinical laboratory 
values and clinically significant values as reported by the investigator will be flagged in the 
listing. Blood lipids, pregnancy assessment (including childbearing potential), and Hepatitis 
B and C data will be listed as well. 
 




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ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; aPTT = Activated partial thromboplastin time; AST = 
Aspartate aminotransferase; BUN = Blood urea nitrogen; CA 19-9 = Cancer antigen 19-9; CRP = C-reactive protein; 
eGFR = Estimated glomerular filtration rate; EOT = End of treatment; FU = Follow-up; HbsAg = Hepatitis B surface 
antigen; HCV = hepatitis C virus; HDL = High density lipoprotein; INR = International normalized ratio; LDH = Lactate 
dehydrogenase; LDL = Low-density lipoprotein; PCR = Polymerase chain reaction; PT = Prothrombin; RBC = Red blood 
cell count; RNA = Ribonucleic acid; T3 = Triiodothyronine; T4 = thyroxine; TSH = Thyroid stimulating hormone; VLDL = 
Very low-density lipoprotein; WBC = White blood cell. 
8.5.6 
Physical examination 
The complete physical examination includes, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  
Weight (kg) is measured and body surface area (BSA) calculated, based on height at 
screening, using the equation: 
BSA (m2) = √((height [cm] x weight [kg])/3600). 
The symptom-directed examination is based upon the symptoms displayed, i.e on any new 
or worsened clinically significant abnormalities since previous assessment [Y/N]. 
The scheduled visits and time points for assessments are presented in the SoA (see protocol 
Section 1.3). 
All physical examination data will be listed. 
Note: depending on timing (before or after signing the ICF for trial participation), the clinically 
significant findings of the physical examination are recorded as medical/surgical history or 
as AEs. 
8.5.7 
Vital signs 
Vital sign parameters are diastolic blood pressure (mmHg), systolic blood pressure (mmHg), 
oxygen saturation (%), pulse rate (beats/min), respiratory rate (breaths/min) and body 
temperature (oC). The scheduled visits and time for assessments are presented in the SoA 
(see protocol Section 1.3 and Appendix 5). 
Vital sign parameters at each time point, change from baseline to each post-baseline time 
point will be summarized using descriptive statistics for each dose cohort. Change in vital 
sign parameters from pre-treatment to each time point post treatment will be summarized 
as well.  
The last available assessment on treatment is defined as the assessment at End of 
Treatment Visit or the last safety assessment on treatment in case of treatment 
discontinuation due to death or withdrawal of consent.  
The last available assessment on trial is defined as the assessment either at Safety FU-
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Vital sign values for each parameter will be assigned an LNH classification according to 
whether the value is lower (L), within (N) or higher (H) the reference range for that parameter 
(Table 5).  
 
Table 5: 
Normal ranges for vital signs 
Parameter 
Range  
Systolic blood pressure 
90-140 mmHg 
Diastolic blood pressure 
40-90 mmHg 
Oxygen saturation 
95 - 100% 
Respiratory rate 
10-22 Breaths/min 
Pulse rate 
60-100 bpm 
Temperature 
≤ 38 °C 
 
All vital sign data and assigned LNH flag will be presented in the data listings. 
8.5.8 
Electrocardiogram (ECG) 
ECGs parameters and the scheduled visits for assessment are presented in the SoA (see 
protocol Section 1.3 and Appendix 5). 
ECG parameters, i.e., ventricular heart rate (HR) [bpm]), pulse rate (PR) [msec], QRS 
duration [msec], QT interval [msec], and corrected QT (QTc) interval (according to 
Frederica) [msec], at each visit and change from baseline to each post-baseline visit will be 
summarized using descriptive statistics by dose cohort. The mean of the triplicates at each 
visit will be applied.  
In addition, investigators´ interpretations of ECG parameters will be summarized by visit, 
and the worst-case abnormality (1=Abnormality, CS / 2=Abnormality, NCS / 3=Normal) by 
visit will be used. The worst-case abnormality at one visit is considered Abnormality, CS, if 
at least one of the triplicates at the visit is Abnormality, CS. Otherwise, the worst-case 
abnormality is considered Abnormality, NCS, if at least one of the triplicates is Abnormality, 
NCS and there is no Abnormality, CS. The worst case is Normal, if none of the triplicates is 
abnormal. 
QTc interval according to Frederica values will be classified according to the NCI CTCAE 
v5.0 where possible, and summarized once as a categorical variable over all treatment visits, 
including unscheduled visits. 
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8.6 
Pharmacokinetics (PK) analyses 
8.6.1 
Primary PK endpoints 
No primary PK endpoints are specified. 
8.6.2 
Secondary PK endpoints 
PK profile of intact BNT141-encoded protein RiboMab
 
The analyses of PK parameters will be performed using the PK analysis set. Individual and 
mean (± standard deviation) serum and plasma concentration data will be tabulated and 
plotted over time by dose level. 
PK parameters will be estimated from the serum concentration data using a non-
compartmental analysis method and will include (but are not limited to): Cmax, tmax, t1/2, 
Vd, AUC0-t, and CL, and Ctrough. (see definitions in Appendix 3). These parameters will be 
listed by individual patient and summarized using descriptive statistics (means, medians, 
ranges, standard deviations, and coefficient of variation as appropriate) by cohort, as 
appropriate. Details of the PK analysis will be provided in “Pharmacokinetic and 
pharmacodynamic analysis plan”. 
Population PK modeling approaches may be also considered and will be reported 
separately. 
9. CHANGES TO PROTOCOL-PLANNED ANALYSES 
As of the trial termination, patients have been recruited only to Part 1A per CTP v4.0, dated 
on 13 June 2022.  
Therefore, this SAP describes the planned analysis and statistical methods for Part 1A only. 
The other major changes to the analyses planned in the CTP v4.0 are as follows,  
x The analyses of shift from baseline to the worst post-baseline NCI-CTCAE grade in 
the clinical laboratory parameters were removed. 
x The analyses of secondary efficacy endpoints were removed.  
x The analyses of exploratory endpoints were removed, with the exception that 
cytokine, anti-drug antibody and PK lipids data will be listed.  
 
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10. QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, 
data listings, figures or statistical analyses. An overview of the development of programs is 
detailed in Syneos Health Developing Statistical Programs SOP (3907). 
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of 
Biostatistical Deliverables SOP (3908) and the SAS Programming and Validation Plan 
(version 3.0, dated 25 AUG 2021) describes the quality control procedures that are 
performed for all SAS programs and output. Quality control (QC) is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce 
the output by checking for their logic, efficiency and commenting and by review of the 
produced output.  
11. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika 26: 404-413, 1934. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
European Medicines Agency, Guideline on the evaluation of anti˗cancer medicinal products 
in man (available at https://www.ema.europa.eu/en/documents/scientific-guideline/draft-
guideline-evaluation-anticancer-medicinal-products-man-revision-6_en.pdf). 
Khan I, Sarker SJ, Hackshaw A. Smaller sample sizes for phase II trials based on exact 
tests with actual error rates by trading-off their nominal levels of significance and power. Br 
J Cancer. 2012;107(11):1801–1809. 
Kaplan E. L., Meier P. Nonparametric estimation of incomplete observations. Journal of the 
American Statistical Association. 1958;53:457-481. 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
Simon R. Optimal two-stage designs for Phase II clinical trials. Control Clin. Trials. 
1989;10(1):1-10. 
U.S. Department of Health and Human Services, Food and Drug Administration, Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics (available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryIn
formation/Guidances/). 


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U.S. 
National 
Comprehensive 
Cancer 
Network 
(NCCN 
2020; 
available 
at 
https//www.nccn.org/professionals/physician_gls/pdf/prostate.pdf). 
 
 


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12. 
SUPPORTING DOCUMENTATION 


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12.1 
Appendix 1: List of abbreviations 
 
Abbreviation Definition 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ApoE 
Apolipoprotein E 
aPPT 
Activated partial thromboplastin time 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area-under-the-concentration-time curve 
BMI 
Body Mass Index 
bpm 
beats per minute 
BSA 
Body surface area 
C 
Cycle 
CA 19-9  
Cancer antigen 19-9 
CI 
Confidence Interval 
CLDN18.2 
Claudin 18.2 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CRS 
Cytokine release syndrome 
CS 
Clinically Significant 
CT 
Computer tomography 
CTC 
Common Toxicity Criteria 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events, version 5.0 
CTMS 
Clinical Trail Management System 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
D 
Day of cycle 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 


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DPP 
Data presentation plan 
DRM 
Data Review Meeting 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group Performance Status 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FFPE 
(Fresh) formalin-fixed paraffin-embedded 
FU 
Follow-up 
GEJ 
Gastroesophageal junction 
h 
Hour 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRR 
Injection/infusion-related reaction 
LNH 
Low, Normal, High 
LNP 
Lipid nanoparticles 
MAD 
Maximally administered dose 
Max 
Maximum 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
 
Min 
Minimum 
mmHg 
millimeter of mercury 
MRI 
Magnetic resonance imaging 
MTD 
Maximally tolerated dose 
N 
Number of Patients 
n 
Number of Observations 
NA 
Not Applicable 
NCI 
National Cancer Institute 
NCS 
Not Clinically Significant 
NE 
Not Evaluable 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events 
ORR 
Objective Response Rate 
CCI


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OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Preferred Term 
PS 
Performance status 
QC 
Quality Control 
RBC 
Red Blood Cell 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Stable Disease; Standard Deviation 
SI 
International System of Units 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables, Figures and Listings 
TMF 
Trial Master File 
TSH 
Thyroid Stimulating Hormones 
V 
Visit 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 


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12.2 
Appendix 2: List of PK parameters 
 
 
 
 
 
Parameter 
Definition 
AUC0-t 
Area under the concentration versus time curve from time 0 to time t 
AUC0-inf 
Area under the drug concentration-time curve, from time zero to infinity 
AUC0-504 
Area under the drug concentration-time curve, from time zero to 504 hours after 
the start of the infusion 
AUC0-tau 
Area under the drug concentration-time curve, from time zero over the dosing 
interval at steady-state (Tau = 504 hours corresponding to 3-weeks 
administration) after the start of the infusion 
CL 
Clearance 
Cmax 
Maximum observed concentration 
Cmin 
Minimum concentration of a drug observed 
Cmax, ss 
Maximum observed concentration at steady-state 
Cmin, ss 
Minimum concentration of a drug observed 
Ctrough 
Concentration prior to next dose 
Kel 
Apparent terminal elimination rate constant, estimated by linear regression of the 
terminal elimination phase of the log-linear drug concentration-time curve 
tmax 
Time to reach the maximum observed concentration Cmax 
tmax, ss 
Time to maximum observed concentration at steady-state 
t1/2 
Terminal half-life 
Vss 
Volume of distribution, estimated as MRTinf * CL 
CLss 
Apparent clearance at steady state 
Vss 
Volume of distribution at steady state 
RAUC 
Accumulation ratio for AUC 
RCmax 
Accumulation ratio for Cmax 






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