Conditions: Pancreatic Ductal Adenocarcinoma Colorectal Cancer Gastric Cancer Squamous Cell Carcinoma of the Head and Neck Bone Cancer Advanced Cancer Recurrent Disease Metastatic Tumours
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This study was conducted to advance new treatment for patients with metastatic or locally advanced cancers expressing Neurotensin receptor 1 (NTSR1). This study was the first time the investigational drug called 177Lu-3BP-227 was administered to patients under controlled conditions of a clinical study.

The purpose of this study was to evaluate how safe the investigational drug is as well to verify how well it is tolerated by patients after several intravenous administrations. In addition, the effect of the study drug on tumoral lesions and how it distributes throughout the body and at which rate it is removed from the body was evaluated. Since 177Lu-3BP-227 is a radio-labelled drug, it also measured how the emitted radiation is distributed throughout the body (dosimetry).

The study consisted of a phase I dose escalation part. The study originally planned to include a phase II study however due to early termination (not due to safety concerns) the study did not progress to phase II and was stopped during phase I. For the phase I dose escalation part, it was anticipated that approximately 30 subjects will be included, in up to six escalation steps. No expansion cohorts were implemented.

Detailed description:

Arms:
arm 1: Screening: 177Lu-IPN01087 - 25 µg 3BP-227 (IPN01087) per 1 GBq of 177Lu. 1 GBq in a total volume of 10 mL.

Treatment phase: 177Lu-IPN01087 - 2.5 to 7.5 GBq escalation dose of 177Lu-3BP-227 (IPN01087) in a total volume of 20 mL for each cycle of administration (2 cycles plus 4 optional additional).

Interventions: intervention 1: 177Lu-3BP-227 (also called 177Lu-IPN01087)
Intervention descriptions: intervention 1: The cumulative activity of the treatment investigational medicinal product (IMP) formulation will be administered in two intravenous (i.v.) infusions separated by at least 4 weeks (28 days). Up to 6 administrations can be given (2 cycles plus 4 optional additional)

Protocol document:
Prot_000.pdf: 
 
 
 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 1 of 167 
 
STUDY PROTOCOL 
 
AN INTERNATIONAL MULTICENTRE, OPEN-LABEL FIRST IN HUMAN 
PHASE I/II STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
BIODISTRIBUTION AND ANTITUMOUR ACTIVITY OF 177LU-3BP-227 FOR THE 
TREATMENT OF SUBJECTS WITH SOLID TUMOURS EXPRESSING 
NEUROTENSIN RECEPTOR 1  
 
Study Number D-FR-01087-001  
Protocol Version 8.0, dated 12 June 2020 
 
EUDRACT Number 2017-001263-20 
IND # Not Applicable 
 
Sponsor 
Ipsen Pharma SAS  
65, quai Georges Gorse 
92100 Boulogne-Billancourt, France 
 
Serious Adverse Event Reporting 
Fax Number: 
 
USA and Latin America Fax Number: 
 
Email: 
 
 
Pharmacovigilance/Emergency Contact 
 Ipsen Innovation 
ZI de Courtaboeuf – 5 Avenue du Canada 
91940 Les Ulis, France 
Phone: 
 (Ipsen Biopharm Ltd, 102 Park Drive, Milton Park, Abingdon, 
OX14 4RY, United Kingdom) 
Mobile: 
 (for emergencies) 
The person listed above is medically designated by the sponsor as the first point of contact for 
emergency situations. 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any purpose other 
than that contemplated herein without the sponsor’s prior written authorisation 
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 2 of 167 
 
Sponsor Authorised Protocol Approver 
Name, Title: 
 
Address: 
Ipsen Biopharm Ltd, 102 Park Drive, Milton Park, Abingdon, OX14 4RY, 
United Kingdom 
 
Sponsor Medical Monitor 
Qualified physician designated by the sponsor who is responsible for all study-site related 
medical decisions that have to be taken. 
Name, Title: 
  
Address: 
Ipsen Biopharm Ltd, 102 Park Drive, Milton Park, Abingdon, OX14 4RY, 
United Kingdom 
Mobile: 
 
Email: 
 
 
Sponsor Clinical Pharmacologist 
Name, Title: 
 
Address: 
Ipsen Innovation, 5 avenue du Canada, 91940 Les Ulis Cedex, France 
Phone: 
 
Fax: 
 
Email: 
 
 
Coordinating Investigator 
Name, Title: 
 
 
Address: 
CHU-Hôtel Dieu, 1 place Alexis-Ricordeau, 44093 Nantes Cedex 1, France 
Phone:  
 
Mobile: 
 
Fax:  
 
Email: 
 
 
Project Management and Monitoring Office 
Address:  
Aepodia France SARL, 3 avenue du Canada, 91940 Les Ulis, France 
Phone:  
 
Fax: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 3 of 167 
 
AGREEMENT – SIGNATURE PAGE 
Protocol Title:  
 
AN INTERNATIONAL MULTICENTRE, OPEN-LABEL FIRST IN HUMAN 
PHASE I/II STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
BIODISTRIBUTION AND ANTITUMOUR ACTIVITY OF 177LU-3BP-227 FOR THE 
TREATMENT OF SUBJECTS WITH SOLID TUMOURS EXPRESSING 
NEUROTENSIN RECEPTOR 1 
 
Protocol Version 8.0, dated 12 June 2020 
 
By signing below, I hereby confirm that I have read, discussed and understood the above 
mentioned version of the protocol and the background information concerning the study drug. 
I attest that I will carry out the study according to this protocol. 
I also agree that the work will be performed according to Good Clinical Practice (GCP) 
guidelines, the ethical principles, as referenced in Section 13, and all currently applicable laws 
and regulations of the country(ies) where the study will be conducted. 
 
Coordinating Investigator 
Name 
 
Title: 
 
Date: 
 
Signature: 
 
 
 
 
Sponsor 
 
Name 
 
Title: 
 
 
Date: 
 
Signature: 
 
 
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 4 of 167 
 
SYNOPSIS 
Sponsor name 
Ipsen Pharma SAS 
Name of finished product 
177Lu-3BP-227 
Name of active ingredient 
177Lu-3BP-227 
Title of the study 
AN INTERNATIONAL MULTICENTRE, OPEN-LABEL FIRST IN HUMAN 
PHASE I/II STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
BIODISTRIBUTION AND ANTITUMOUR ACTIVITY OF 177LU-3BP-227 
FOR THE TREATMENT OF SUBJECTS WITH SOLID TUMOURS 
EXPRESSING NEUROTENSIN RECEPTOR 1 
Sponsor study number 
D-FR-01087-001 
EUDRACT number 
2017-001263-20 
IND Reference 
Not applicable 
Type of study/ 
Phase of development 
Phase I / phase II 
Number of planned centres 
Approximately eight centres in Europe and three centres in the United States of 
America for the phase I (dose escalation) and additional centres in Europe and 
the United States of America for the potential phase I dose expansion and 
phase II. 
Study hypothesis and 
objectives 
STUDY HYPOTHESIS 
The present study consists of two parts that aim to test the following hypotheses: 
Phase I 
177Lu-3BP-227 is sufficiently well-tolerated to permit clinical investigation in 
phase II. 
Phase II 
177Lu-3BP-227 yields higher objective response rates in subjects who have 
Neurotensin Receptor 1 (NTSR1) expressing cancers that are unresectable, 
locally advanced or metastatic, based on Response Evaluation Criteria in Solid 
Tumours (RECIST) version 1.1 by central review and as compared with the 
historical objective response rate (ORR) obtained with current standard-of-care 
treatment for each tumour type. 
 
STUDY OBJECTIVES 
Primary objectives 
Phase I 
To establish the safety and tolerability of fractionated intravenous (i.v.) 
administrations of 177Lu-3BP-227 in subjects with unresectable, locally 
advanced or metastatic cancers expressing NTSR1. 
Phase II 
To estimate ORR of fractionated i.v. administrations of 177Lu-3BP-227 in 
subjects with unresectable, locally advanced or metastatic cancers expressing 
NTSR1. 
 
Secondary objectives 
Phase I 
a) 
To determine the whole-body distribution of 177Lu-3BP-227 and 
pharmacokinetics (PK) of both 177Lu-3BP-227 and 3BP-227. 
b) 
To determine the radiation dosimetry of 177Lu-3BP-227 (organ exposure 
to radiation). 
c) 
To describe the preliminary antitumour activity of 177Lu-3BP-227. 
Phase II 
a) 
To further evaluate the safety profile of 177Lu-3BP-227 at the 
radioactivity recommended by the phase I results. 
b) 
To further assess the response to treatment with 177Lu-3BP-227 using 
RECIST version 1.1 and/or positron emission tomography (PET) 
Response Criteria in Solid Tumours (PERCIST) version 1.0 criteria. 
c) 
To further characterise the whole-body distribution and dosimetry of 
177Lu-3BP-227 and PK of both 177Lu-3BP-227 and 3BP-227. 
d) 
To describe the influence of 177Lu-3BP-227 on the health-related quality 
of life of treated subjects. 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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Exploratory objectives 
Phase I/II 
a) 
To explore the correlation between the tumour uptake of 177Lu-3BP-227 
and the NTSR1 expression on tumours. 
b) 
To explore renal safety by measuring urinary specific biomarkers. 
c) 
To evaluate the tumour microenvironment, transcriptomics, and other 
markers of interest for the disease through assessment of tumour 
biopsies. 
d) 
To explore genomic alterations in circulating cell-free DNA (cfDNA) 
and in germline DNA. 
e) 
To collect gene mutation status for correlation with clinical outcome. 
f) 
To collect biobank samples for future analysis of circulating markers 
(optional, additional informed consent required). 
g) 
To generate a model integrating PK, dosimetry, antitumour activity and 
safety data. 
Study design 
This is a multicentre, open-label phase I/II study of 177Lu-3BP-227 in subjects 
with unresectable, locally advanced or metastatic solid tumours expressing 
NTSR1 who have exhausted their available standard-of-care treatment options 
and/or are deemed suitable for treatment with 177Lu-3BP-227 as per the 
investigator’s clinical assessment and/or their individual disease state. The study 
consists of a phase I with a dose escalation part (and potential expansion cohorts) 
and a phase II either in selected or over multiple indications in a basket approach. 
 
Phase I  
During phase I, it is planned to enrol subjects with unresectable, locally 
advanced or metastatic tumours expressing NTSR1 originating from either the: 
x 
Pancreas (pancreatic ductal adenocarcinoma, PDAC) 
x 
Colon and rectum (colorectal cancer, CRC) 
x 
Stomach (gastric cancer, GC) 
x 
Gastrointestinal stromal tumours (GIST) 
x 
Head and neck region (squamous-cell carcinoma of head and neck, 
SCCHN) 
x 
Bone (Ewing Sarcoma, ES) 
 
For the dose escalation part, 
 
 
Following eligibility confirmation, it is 
anticipated that a maximum of 30 subjects will receive the 177Lu-3BP-227 
therapeutic dose in up to six cohorts with four escalation steps. Three to five 
subjects will be treated per cohort in order to yield a minimum of three evaluable 
subjects per radioactivity level, treated at the full planned radioactivity amount 
fractionated into two administrations. Once five subjects are enrolled in a cohort, 
the enrolment will be stopped in that cohort. Once the dose escalation part has 
been completed, the maximum tolerated cumulative activity (MTCA) level may 
be repeated in an additional cohort. 
 
The cumulative starting activity will be 5 GBq fractionated into two 
administrations (2×2.5 GBq). The cumulative maximum activity will be 15 GBq 
activity (2×7.5 GBq). However, if the MTCA is not reached and if limiting organ 
dose levels are not exceeded, an additional cohort with three administrations at 
7.5 GBq may be added, leading to a cumulative activity of 22.5 GBq. 
 
Of note, for each cohort in the dose escalation part, if a subject has clinical 
benefit and an acceptable tolerability profile, and if the organ dose limits are not 
exceeded, up to four additional cycles of 177Lu-3BP-227 can be administered 
every 4 weeks after the end of the core trial (EOCT). The safety data evaluation 
will be conducted by the sponsor. The decision to administer additional cycles 
is based on the investigator’s judgement and subject’s discretion and must be 
discussed with and agreed upon by the sponsor.  
 
CCI


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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The MTCA is defined as the maximum tolerated cumulative activity that may 
be administered following fractionated i.v. administrations of at least 4 weeks 
apart, so that:  
x 
No more than 33% of the subjects experience a dose limiting toxicity 
(DLT) during Cycles 1 and/or 2 and 
x 
The cumulative radiation in each target organ does not exceed the 
acceptability limits. 
The DLTs are defined for any of the following IMP-related AEs according to 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) scale version 5.0, that occur during the defined DLT assessment 
period (from the first administration of 177Lu-3BP-227 to EOCT/ED): 
x 
Grade 4 neutropenia for seven or more consecutive days; 
x 
Febrile neutropenia or neutropenic infection (defined as a documented 
infection with neutrophil count decreased Grade 3 or 4); 
x 
Grade 3 or 4 thrombocytopenia (platelet count decreased) with  clinically 
meaningful bleeding (i.e. requiring urgent hospitalisation or transfusion 
to manage the bleeding); 
x 
Grade 4 thrombocytopenia for seven or more consecutive days; 
x 
Any Grade 3 anaemia (Hb<8.0 g/dL; transfusion indicated) or Grade 4 
anaemia (life-threatening consequences; urgent intervention indicated); 
x 
Any Grade 3 or higher laboratory abnormalities in aspartate 
aminotransferase/alanine 
aminotransferase 
(AST/ALT) 
with 
accompanying Grade 2 or higher bilirubin (Hy’s law); 
x 
Any Grade 3 or higher renal injury/toxicity (estimated glomerular 
filtration rate (eGFR) <30 mL/min/1.73 m2); 
x 
Any Grade 3 or higher GI AE, not resolved to Grade ≤2 within 48 hours 
despite optimal adequate medical management, with the following 
specifications: 
- 
Grade 3 nausea, vomiting (inadequate oral caloric or fluid intake; 
tube feeding, total parenteral nutrition or hospitalisation 
indicated) 
- 
Grade 3 diarrhoea (increase of ≥7 stools per day over baseline; 
hospitalisation indicated; severe increase in ostomy output 
compared to baseline; limiting self-care activities of daily living 
(ADL)) or Grade 4 diarrhoea (life-threatening consequences; 
urgent intervention indicated) 
- 
Grade 3 constipation (obstipation with manual evacuation 
indicated; limiting self-care ADL) or Grade 4 constipation 
(life-threatening consequences; urgent intervention indicated); 
x 
Any toxicity related to 177Lu-3BP-227 resulting in a treatment delay of 
more than four weeks due to either delayed recovery to baseline or 
resolution of any AE to Grade ≤2 (with the exception of alopecia and 
lymphopenia). 
x 
Grade 5 toxicity (death) 
Study design following phase I dose escalation results 
Upon completion of the phase I dose escalation or upon reaching the MTCA and 
confirmed jointly by the safety review committee (SRC) and the sponsor, and in 
consideration of the accumulated subject data, cohorts of subjects will be studied 
to further characterise the safety and efficacy of 177Lu-3BP-227. 
In the case of acceptable tolerability and evident antitumour activity across all 
enrolled subjects in phase I, a phase II basket trial design will be utilised to study 
the antitumour activity of 177Lu-3BP-227 in subjects with NTSR1 expressing 
tumours. Sample size estimations for this design will be provided as part of a 
protocol amendment. However, if the antitumour activity is driven by a type of 
tumour, tumour-specific phase II cohort(s) will be initiated utilising an Optimal 
Simon’s Two Stage design (see Phase II). 
If safety evaluation and dose schedules of 177Lu-3BP-227 cannot be fully 
explored during the phase I dose escalation part, the expansion part will serve to 
accomplish this objective including, but not limited to, schedules of high loading 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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doses followed by fractionated lower doses or evaluation of 177Lu-3BP-227 in 
combination with other antitumoral treatments (to be defined). The expansion 
part will also serve to clarify any uncertainties of antitumour responses. 
The number of cohorts and subjects will be determined based on emerging data 
from the dose escalation part and the modelling and simulation approach. 
Phase II 
Phase II study will be conducted either with a basket design trial or 
indication-specific cohorts with an Optimal Simon’s Two Stage design, 
according to the scenarios described above. 
 
 
 
One or two further 
cohorts may be opened (subject to results emerging from ongoing preclinical 
studies and antitumour efficacy seen during dose escalation and amending the 
current protocol) likely to enrol subjects with GC and/or SCCHN. 
x 
The PDAC cohort will enrol approximately 55 subjects and will 
investigate whether 177Lu-3BP-227 attains an ORR superior to a 
clinically accepted historical threshold of current standard-of-care 
treatment for subjects with unresectable, locally advanced or metastatic 
disease.  
x 
The CRC cohort will enrol approximately 70 subjects and will 
investigate whether 177Lu-3BP-227 attains an ORR superior to a 
clinically accepted historical threshold of current standard-of-care for 
subjects with unresectable, locally advanced or metastatic disease.  
The current protocol will be amended at the end of the phase I to document the 
rationale of the phase II design. In any case, the cumulative activity administered 
during phase II will not exceed the MTCA determined during phase I. 
Number of subjects 
During the phase I escalation part, 
 up to 30 subjects will receive the 177Lu-3BP-227 
therapeutic dose. For the phase II, approximately 125 subjects (55 PDAC and 70 
CRC subjects) are planned to be enrolled for Optimal Simon’s Two Stage design. 
In case of the implementation of phase I expansion cohorts, up to 45 additional 
subjects will be enrolled. Similarly, if additional cohorts of subjects with GC, 
ES or SCCHN in the phase II are to be studied, approximately 120 additional 
subjects will be enrolled. In total, the phase I/II study would therefore enrol up 
to 320 subjects evaluable for safety and/or efficacy. 
For a single-arm basket trial approach, sample size justification will be provided 
as part of a protocol amendment. 
Main eligibility criteria 
Inclusion criteria: 
Eligible subjects must fulfil all the following inclusion criteria: 
Phase I 
(1) 
Signed informed consent form prior to all study procedures. 
(2) 
Aged 18 years or older. 
(3) 
Histologically or cytologically confirmed unresectable, locally advanced 
or metastatic disease and has received prior lines of standard-of-care 
chemotherapy/treatment and has no further suitable treatment options 
and a documented decision by a multidisciplinary oncology board 
including a specialist of the concerned pathology.  
(4) 
Subjects have: 
(a) 
PDAC, or 
(b) 
CRC (colorectal adenocarcinoma), or 
(c) 
GC (gastric adenocarcinoma), or 
(d) 
Gastrointestinal Stromal Tumours (GIST), or 
(e) 
SCCHN, or 
(f) 
ES. 
(5) 
Tumours showing:  
(a) 
uptake of 177Lu-3BP-227 (screening formulation) in known 
primary or metastatic sites as judged by the investigator to be 
greater than background; or 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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(b) 
uptake of 111In-3BP-227 in known primary or metastatic sites 
(for subjects who participated in Study D-FR-01087-002) as 
judged by the investigator to be greater than background. 
(6) 
Measurable disease (based on RECIST version 1.1). 
(7) 
Criterion 7 is removed by protocol amendment.  
(8) 
Documentation of progressive disease in the 6 months prior to study start 
(treatment). 
(9) 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 (unless if disability is related to surgery in ES and agreed with the 
sponsor). 
(10) 
Adequate organ function as evidenced by: 
(a) 
Leukocytes ≥ 3000/μL 
(b) 
Absolute neutrophil count ≥1500/μL 
(c) 
Platelets ≥75,000/μL 
(d) 
Hb >9g/dL or >10 g/dL (if history of cardiac disease) 
(e) 
Total serum bilirubin ≤2×upper normal institutional limits 
(ULN) 
(f) 
Aspartate aminotransferase/alanine aminotransferase ≤2.5×ULN 
(≤5×ULN if subject has liver metastases) 
(g) 
Estimated glomerular filtration rate ≥55mL/min. 
(11) 
Estimated life expectancy of >3 months. 
(12) 
Female subjects must not be pregnant or lactating at study entry and 
during the course of the study and must not become pregnant for at least 
6 months following the last study treatment. Women of childbearing 
potential must agree to use a highly effective method of contraception 
(see note below).  
(13) 
Male subjects must not father children during the study and for at least 6 
months after the last study treatment and in addition must agree to use a 
condom for this period to protect his partner from contamination with the 
IMP. For males with partners who are of child bearing potential, effective 
contraception is a combination of male condom with either cap, 
diaphragm or sponge with spermicide (double barrier methods), but these 
are not considered to be highly effective. A man is considered to be 
infertile if he has had bilateral orchidectomy or successful vasectomy. 
Effective contraception includes a female partner of childbearing 
potential if she is using highly efficacious contraception (see note below), 
but the male subject must agree to use a condom to protect his partner as 
described above. 
(14) 
Must be willing and able to comply with study restrictions and to remain 
at the clinic for the required time during the study period and willing to 
return to the clinic for the follow-up evaluation, as specified in the 
protocol. 
Note: Highly effective methods of contraception that result in a low failure rate 
(i.e., <1% per year) when used consistently and correctly include combined 
(oestrogen and progestogen containing) hormonal contraception associated 
with 
inhibition 
of 
ovulation 
(oral, 
intravaginal, 
or 
transdermal), 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable), intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner (the 
vasectomised partner has received medical assessment of the surgical success 
at least 6 months prior to the first study treatment and provided that partner is 
the sole sexual partner of the female subject of childbearing potential trial 
participant), or sexual abstinence; 
True abstinence, when in line with the preferred and usual lifestyle of the subject, 
is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of study treatment and for 6 
months after the last dose of 177Lu-3BP-227. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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ovulation, symptothermal, and post-ovulation method) and withdrawal are not 
acceptable methods of contraception; 
Female subject is considered of childbearing potential i.e. fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. 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. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
For male subjects, acceptable methods of effective contraception include sexual 
abstinence, successful vasectomy, bilateral orchidectomy and barrier methods 
(i.e. condom). In addition, male subjects should not donate sperm and female 
subjects should not donate eggs for at least 2 years after the last study treatment.   
Phase II 
The inclusion criteria for phase II will be revised based on the scenario adopted 
and indication(s) selected for investigation based on the results from phase I and 
will be documented as part of a protocol amendment. 
 
Exclusion criteria: 
Eligible subjects must not have any of the following: 
Phase I/II 
(1) 
Prior treatment received 
(a) 
Any antitumour treatment since last documented disease 
progression 
(b) 
Any chemotherapy within 3 weeks or nitrosourea within 6 weeks 
prior to first treatment investigational medicinal product (IMP) 
administration 
(c) 
Any curative radiotherapy within 4 weeks or palliative 
radiotherapy within 7 days prior to first treatment IMP 
administration 
(d) 
Any, monoclonal antibodies within 4 weeks or tyrosine kinases 
inhibitors within 2 weeks prior to the first treatment IMP 
administration 
(e) 
Any other IMP within 2 weeks prior to first treatment IMP 
administration, if the previous compound is a mechanism-based 
molecularly targeted agent whose half-life (t1/2) is not 
well-characterised. 
(2) 
Brain metastases. 
(3) 
Nephrectomy, renal transplant or concomitant nephrotoxic therapy 
putting the subject at high risk of renal toxicity during the study. 
(4) 
Only nonmeasurable metastatic bone lesions. 
(5) 
Existing or planned colostomy during study participation. 
(6) 
Any history of inflammatory bowel disease. 
(7) 
Any uncontrolled significant medical, psychiatric or surgical condition 
or laboratory finding, that would pose a risk to subject safety or interfere 
with study participation or interpretation of individual subject results. 
(8) 
Clinically significant abnormalities on electrocardiogram (ECG) at 
screening including corrected QT interval (Fridericia's formula) 
>450 msec for males or 470 msec for females at screening. 
(9) 
Previously received external beam irradiation to a field that includes 
more than 30% of the bone marrow or kidneys. 
(10) 
Criterion 10 is removed by protocol amendment. 
(11) 
Any unresolved NCI-CTCAE Grade 2 or higher (except alopecia) from 
previous 
antitumour 
treatment 
and/or 
medical/surgical 
procedures/interventions. 
(12) 
Known allergy to IMP or its excipients administered in this study, 
including imaging contrast media. 
(13) 
Positive pregnancy test (female subjects). 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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(14) 
Likely to be uncompliant or uncooperative during the study, in the 
judgment of the investigator. 
(15) 
Unable to understand the nature, scope and possible consequences of the 
study, in the judgment of the investigator. 
(16) 
Sponsor employees or investigator site personnel directly affiliated with 
this study, and their immediate families. Immediate family is defined as 
a spouse, parent, child or sibling, whether biological or legally adopted. 
Treatment: route, strength, 
regimen 
For both screening and treatment formulations, the specific activity of the IMP 
is 25 μg 3BP-227 per 1 GBq of 177Lu. 
The screening IMP formulation consists of 1 GBq in a total volume of 10 mL. 
The treatment IMP formulation consists of 2.5 to 7.5 GBq of 177Lu-3BP-227 in 
a total volume of 20 mL. 
The total radioactivity of the treatment IMP formulation will be fractionated and 
administered in two i.v. infusions separated by at least 4 weeks (28 days). A 
100 mL saline solution will be administered intravenously over a period of 
30 minutes concomitantly with every IMP administration. The subject will be 
instructed to drink water (at least 1.5 L/24 hours) on the days following each 
IMP administration. 
Reference treatment: route, 
strength, regimen 
Not applicable  
Criteria for evaluation 
(endpoints) 
STUDY ENDPOINTS  
Primary endpoints 
Phase I 
For the dose escalation, the primary endpoint is MTCA or the maximum 
administered cumulative activity (MACA), if the MTCA is not identified during 
the dose escalation part. The primary variables used for the MTCA 
determination will be the incidence of DLTs (as defined above) and the organ 
exposure to radiation during two cycles of treatment. The DLT period for the 
determination of the primary endpoint starts at the first administration of 
177Lu-3BP-227 to EOCT/ED. 
Safety evaluation will encompass DLTs, frequency and nature of adverse events 
(AEs), abnormal findings from physical examination, vital signs, 12-lead ECG 
and 24-hour 3-lead ECG Holter, ECOG performance status treatment related 
deterioration and clinical laboratory tests abnormalities (including haematology, 
blood biochemistry, hormone analysis, urinalysis and pregnancy test). 
In case the phase I dose expansion cohorts are implemented, the primary 
endpoint will be safety and tolerability measured by the type, severity, 
expectedness and frequency of AEs. 
 
Phase II 
The primary endpoint is ORR measured by CT or MRI using RECIST 
version 1.1. Tumour response assessments are performed every 8 weeks or at the 
time of occurrence of first clinical signs of disease progression as determined by 
the investigator. 
 
Secondary endpoints 
Phase I  
Pharmacokinetics, biodistribution and dosimetry 
For biodistribution and dosimetry of 177Lu-3BP-227, the secondary endpoints 
are:  
a) 
Maximal uptake (%); maximal concentration achieved (Cmax); time post 
injection to achieve maximal concentration (Tmax); area under the curve 
(AUC) at the target lesions, discernible organs and blood; terminal t1/2 of 
activity concentrations in blood. 
b) 
Highest absorbed dose, specific absorbed dose to the target lesions 
(Gy/GBq), specific absorbed dose per organ (Gy/GBq) and cumulative 
absorbed organ doses (Gy). 
For PK of 3BP-227, the secondary endpoints are: 
c) 
Pharmacokinetic parameters including, but not limited to, Cmax, AUC, 
t1/2, clearance (CL), volume of distribution (Vd), cumulative amount of 


 
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unchanged drug excreted into the urine (Ae), renal clearance of the drug 
from plasma (CLR), as measured in plasma and urine at defined 
timepoints. 
 
Pharmacodynamic/efficacy 
a) 
Objective response rate and disease control rate (DCR), as determined 
by RECIST version 1.1 in subjects who received IMP.  
b) 
Progression-free survival (PFS) and overall survival (OS) rates as 
determined from start of study treatment until occurrence of event and/or 
end of observation period. 
c) 
Evaluation of metabolic tumour response using PERCIST (version 1.0) 
or practical PERCIST. 
d) 
Changes in serum tumour markers relevant and specific to the underlying 
tumour disease from Day of the first treatment administration to EOCT, 
which is planned 6 weeks after the second 177Lu-3BP-227 dose 
administration. 
 
Phase II 
Efficacy 
a) 
Disease control rate, time to progression, time to response, duration of 
response as per RECIST version 1.1. 
b) 
Qualitative and quantitative changes in tumour-to-background uptake 
using PERCIST version 1.0. 
c) 
Progression-free survival (PFS) and OS as determined from start of study 
treatment until occurrence of event and/or 6 and 12 months after start of 
study treatment. 
d) 
Changes in serum tumour markers relevant and specific to the underlying 
tumour disease from baseline to EOCT. 
Subject Reported Outcomes 
a) 
Changes in health-related quality of life scores from baseline to EOCT 
measured by validated questionnaires. 
Safety 
a) 
Safety and tolerability measured by the type, severity, expectedness and 
frequency of AEs. 
 
Pharmacokinetics, biodistribution and dosimetry 
a) 
For PK, biodistribution and dosimetry, the endpoints will be similar as 
for phase I. 
 
Exploratory endpoints  
Phase I/II 
a) 
Tumour uptake of 177Lu-3BP-227 and the correlation with NTSR1 
expression on tumour biopsies. 
b) 
If applicable, tumour microenvironment and other markers of interest 
(such as NTSR1 expression, Ki67, gene expression and DNA damage) 
in tumour biopsies taken at baseline, at EOCT visit or at disease 
progression, whichever occurs earlier. 
c) 
Genomic profiling in circulating cfDNA and in germline DNA. 
d) 
Gene mutation status in correlation with clinical outcome. 
e) 
Specific renal safety biomarkers specific for proximal tubulus toxicity. 
Biobanking (optional): 
Serum and whole blood ribonucleic acid samples will be stored for further 
biomarker analysis after the end of the study. Analysis of additional biomarkers 
from the biobank samples will be performed outside the scope of the main study 
and reported separately. 
Statistical methodology 
Statistical methodology in phase I 
Safety 
Continued monitoring of DLTs and toxicities will be performed during dose 
escalation. At the time of the SRC, an interim analysis of the DLTs, toxicities 


 
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and selected organ absorbed doses (kidney, liver and bone marrow) will be 
performed to guide the dose selection during the dose escalation part. 
 
Biodistribution, radiation dosimetry, PK of 177Lu-3BP-227 
Descriptive summaries of PK and biodistribution parameters will be presented 
for each cohort over the treatment period. 
 
Pharmacokinetics of 3BP-227 
If 3BP-227 levels are measurable in plasma and urine, PK parameters of 
3BP-227 will be derived using a noncompartmental approach. An attempt to 
build an integrated model taking into account PK, dosimetry, antitumour and 
safety data will be made. 
 
Pharmacodynamics/Efficacy Analysis 
In order to perform preliminary antitumour activity, ORR and DCR will be 
tabulated. Tumour response will be evaluated by the site investigator. 
Independent review of tumour assessment may be requested at the discretion of 
the sponsor. In both cases, response and progression will be evaluated using the 
revised RECIST guideline (version 1.1). Only subjects with measurable disease 
at baseline, who have received at least two administrations of 177Lu-3BP-227 and 
reached the end of Cycle 2 or EOCT visit will be considered evaluable for 
response. 
 
Statistical methodology in phase II 
Efficacy Analysis 
For phase II cohorts, tumour response will be assessed in imaging modalities of 
CT or MRI scans after Cycle 2 and subsequently every 8 weeks for the first 
6 months and every 12 weeks thereafter. Images will be reviewed by an 
independent central review core laboratory. ORR, best overall response (BOR) 
and other efficacy parameters will be tabulated. Objective response rate will be 
calculated combining the number of subjects with a BOR of confirmed complete 
response (CR) or partial response (PR) per RECIST version 1.1. 
 
For the Simon Two-Stage design, the hypotheses that will be tested for each 
cohort are: H0: ORR≤ORR0 versus the alternative H1: ORR>ORR0 where ORR 
is the true objective response rate following 177Lu-3BP-227 treatment that 
warrants further clinical development, and ORR0 is the minimum objective 
response rate to be excluded from further clinical development. The thresholds 
for ORR and ORR0 may be updated based on results from phase I and the 
evolving scientific knowledge. 
Objective response rate will be analysed at the end of Stage 1 (and no later than 
after the 16-week visit of the last evaluable subject of the Stage 1 cohort for each 
PDAC and CRC cohort). If the observed number of responders is below a 
predefined threshold, the respective study cohort will be stopped for futility. 
Otherwise, additional subjects will be treated to complete the planned enrolment. 
At the end of Stage 2, the null hypothesis will be rejected depending on the total 
observed number of responders based on a predefined threshold. 
 
At the end of phase II, descriptive summaries will be provided for all primary 
and secondary efficacy endpoints. For the primary endpoint, final analysis will 
take into account the sequential sampling procedure of the design and the 
underlying binomial distribution assumed by the Simon Two-Stage design. 
 
Safety 
Descriptive statistics will be calculated on the safety parameters. No formal 
statistical analyses of safety data are planned. 
 
Biodistribution, radiation dosimetry, PK of 177Lu-3BP-227 and 3BP-227 
Analysis will be performed as for phase I. 


 
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TABLE OF CONTENTS 
RATIONALE FOR PROTOCOL AMENDMENT #7 ....................................................... 19 
LIST OF DEFINITIONS AND ABBREVIATIONS........................................................... 22 
1 
BACKGROUND INFORMATION ............................................................................ 27 
1.1 
Introduction ................................................................................................................... 27 
1.2 
Name and Description of the Investigational Medicinal Product ............................ 27 
1.3 
Nonclinical Data ............................................................................................................ 27 
1.3.1 
In Vitro Studies ........................................................................................... 27 
1.3.2 
Toxicology ................................................................................................... 27 
1.3.3 
Pharmacokinetic Properties of Unlabelled 3BP-227 ................................. 27 
1.3.4 
Biodistribution and Dosimetry of Radiolabelled 3BP-227 ........................ 28 
1.3.5 
Pharmacodynamic Effect In Vivo Study .................................................... 29 
1.4 
Clinical Data .................................................................................................................. 29 
1.5 
Rationale for the Study ................................................................................................. 30 
1.6 
Selection of Dosage ........................................................................................................ 32 
1.7 
Population to be Studied .............................................................................................. 34 
1.8 
Known and Potential Risks to Human Subjects ........................................................ 35 
2 
STUDY HYPOTHESIS ................................................................................................ 37 
2.1 
Phase I ............................................................................................................................ 37 
2.2 
Phase II .......................................................................................................................... 37 
3 
STUDY OBJECTIVES ................................................................................................. 38 
3.1 
Primary Objectives ....................................................................................................... 38 
3.1.1 
Phase I ......................................................................................................... 38 
3.1.2 
Phase II ....................................................................................................... 38 
3.2 
Secondary Objectives ................................................................................................... 38 
3.2.1 
Phase I ......................................................................................................... 38 
3.2.2 
Phase II ....................................................................................................... 38 
3.3 
Exploratory Objectives ................................................................................................. 38 
3.3.1 
Phase I/II ..................................................................................................... 38 
4 
INVESTIGATIONAL PLAN ...................................................................................... 38 
4.1 
Overall Study Design and Plan .................................................................................... 38 
4.2 
Phase I ............................................................................................................................ 39 
4.2.1 
Dose Escalation ........................................................................................... 39 
4.2.1.1 
Definition of the MTCA ................................................................................ 40 
4.2.1.2 
Cohorts Description ..................................................................................... 40 
4.2.1.3 
Dose Escalation Mode ................................................................................. 41 
4.2.1.4 
Safety Review Committee ............................................................................. 41 
4.2.2 
Dose Expansion ........................................................................................... 43 
4.3 
Phase II .......................................................................................................................... 43 
4.4 
Study Endpoints ............................................................................................................ 43 
4.4.1 
Primary Endpoint ........................................................................................ 43 


 
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4.4.1.1 
Phase I ......................................................................................................... 43 
4.4.1.2 
Phase II ........................................................................................................ 44 
4.4.2 
Secondary Endpoints .................................................................................. 44 
4.4.2.1 
Phase I ......................................................................................................... 44 
4.4.2.2 
Phase II ........................................................................................................ 44 
4.4.3 
Exploratory Endpoints ................................................................................ 45 
4.5 
Study Duration .............................................................................................................. 45 
4.6 
Randomisation and Blinding ....................................................................................... 45 
4.6.1 
Method of Randomisation .......................................................................... 45 
4.6.1.1 
Subject Unique Identifier ............................................................................. 45 
4.6.1.2 
Randomisation Number ............................................................................... 45 
4.6.2 
Blinding ....................................................................................................... 45 
4.6.3 
Code-break .................................................................................................. 45 
4.7 
Discontinuation Rules ................................................................................................... 46 
4.7.1 
Individual Discontinuation Rules .............................................................. 46 
4.7.1.1 
Definition of Dose Limiting Toxicity (Dose Escalation) .............................. 46 
4.7.1.2 
Procedures for Subject Discontinuation ...................................................... 47 
4.7.1.3 
Replacement Rules ....................................................................................... 47 
4.7.2 
Discontinuation of a Cohort or a Site or Study Termination .................... 47 
5 
SELECTION OF SUBJECTS ..................................................................................... 49 
5.1 
Inclusion Criteria .......................................................................................................... 49 
5.1.1 
Phase I ......................................................................................................... 49 
5.1.2 
Phase II ....................................................................................................... 50 
5.2 
Exclusion Criteria (Phase I/II) ..................................................................................... 50 
5.3 
Rationale for Specific Inclusion/Exclusion Criteria .................................................. 51 
6 
STUDY CONDUCT ...................................................................................................... 52 
6.1 
Study Schedule of Assessments .................................................................................... 52 
6.2 
Study Visits and Procedures ........................................................................................ 52 
6.2.1 
Screening ..................................................................................................... 52 
6.2.1.1 
Informed Consent ......................................................................................... 52 
6.2.1.2 
Screening Procedures .................................................................................. 52 
6.2.2 
Treatment Period and Additional Cycles for Phase I Dose Escalation .... 53 
6.2.2.1 
Early Discontinuation or End of Core Trial Visit ....................................... 53 
6.2.2.2 
End of Additional Cycles ............................................................................. 53 
6.2.2.3 
End of Study ................................................................................................. 54 
6.2.3 
Long-term Follow-up .................................................................................. 54 
6.2.4 
Unscheduled Visits ...................................................................................... 54 
6.3 
Study Restrictions ......................................................................................................... 54 
6.3.1 
Concomitant Medications ........................................................................... 54 
7 
STUDY TREATMENT ................................................................................................ 57 
7.1 
Investigational Medicinal Product .............................................................................. 57 


 
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7.1.1 
Dosage Form and Strength ......................................................................... 57 
7.1.1.1 
Decentralized Supply Dosage Form and Strength ....................................... 57 
7.1.1.2 
Centralized Supply Dosage Form and Strength .......................................... 57 
7.1.2 
Supplies, Packaging and Labelling ............................................................ 57 
7.1.3 
Storage ......................................................................................................... 57 
7.1.4 
Preparation, Dispensing and Administration Procedures......................... 58 
7.1.4.1 
Route of Administration ............................................................................... 58 
7.1.4.2 
Dosing Regimen in Phase I .......................................................................... 58 
7.1.4.3 
Dosing Regimen in Phase II ........................................................................ 58 
7.1.5 
Accountability .............................................................................................. 58 
7.1.6 
Spillage ........................................................................................................ 58 
7.2 
Product Complaints ...................................................................................................... 59 
8 
SAFETY ASSESSMENTS ........................................................................................... 60 
8.1 
Adverse Events .............................................................................................................. 60 
8.1.1 
Definition of an Adverse Event .................................................................. 60 
8.1.2 
Adverse Events Categorisation, Recording, and Follow-up ...................... 61 
8.1.2.1 
Assessment of Expectedness ......................................................................... 61 
8.1.2.2 
Follow-up of Adverse Events ....................................................................... 61 
8.1.2.3 
Reporting of Adverse Events ........................................................................ 62 
8.1.3 
Serious Adverse Event Assessment and Reporting to Sponsor ................. 62 
8.1.4 
Suspected Unexpected Serious Adverse Reactions .................................... 63 
8.1.5 
Pregnancy .................................................................................................... 63 
8.1.6 
Adverse Events of Special Interest ............................................................. 64 
8.1.7 
Deaths .......................................................................................................... 64 
8.1.8 
Reporting to Competent Authorities, IECs/IRBs and other Investigators 64 
8.2 
Specific Safety Assessments ......................................................................................... 64 
8.2.1 
Physical Examinations ............................................................................... 64 
8.2.2 
Vital Signs ................................................................................................... 65 
8.2.3 
Height and Weight ...................................................................................... 65 
8.2.4 
Electrocardiograms ..................................................................................... 65 
8.2.5 
Performance Status ..................................................................................... 66 
8.2.6 
Clinical Laboratory Tests ............................................................................ 66 
8.2.6.1 
Blood Analyses ............................................................................................. 67 
8.2.6.2 
Urinalysis ..................................................................................................... 67 
8.2.6.3 
Pregnancy Test ............................................................................................. 68 
8.2.7 
Specific Renal Safety Biomarkers .............................................................. 68 
9 
PHARMACOKINETIC ASSESSMENTS ................................................................. 69 
9.1 
Pharmacokinetics of 177Lu-3BP-227 ............................................................................ 69 
9.1.1 
Blood Sample Collection ............................................................................. 69 
9.1.2 
Urine Sample Collection ............................................................................. 69 
9.2 
Nuclear Medicine Imaging for Dosimetry .................................................................. 70 


 
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9.3 
Pharmacokinetics of 3BP-227 ...................................................................................... 70 
9.3.1 
Blood Sample Collection ............................................................................. 70 
9.3.2 
Urine Sample Collection ............................................................................. 71 
10 
PHARMACODYNAMIC/EFFICACY ASSESSMENTS ......................................... 72 
10.1 Imaging Assessments .................................................................................................... 72 
10.1.1 
Screening Imaging Assessments ................................................................ 72 
10.1.2 
Phase I Imaging Assessments..................................................................... 72 
10.1.3 
Phase II Imaging Assessments ................................................................... 73 
10.2 Quality of Life Questionnaire ...................................................................................... 73 
10.3 Tumour Markers .......................................................................................................... 74 
10.4 Genomic Profiling in Circulating Cell-free DNA and Germline DNA .................... 74 
10.5 Gene Mutation Status ................................................................................................... 74 
10.6 Tumour Biopsy .............................................................................................................. 74 
11 
BIOBANKING .............................................................................................................. 76 
12 
STATISTICAL ANALYSES ....................................................................................... 77 
12.1 Analysis Sets .................................................................................................................. 77 
12.2 Statistical Methodology for Phase I ............................................................................ 77 
12.2.1 
Sample Size Calculation ............................................................................. 77 
12.2.1.1 
Dose Escalation ........................................................................................... 77 
12.2.1.2 
Dose Expansion ........................................................................................... 77 
12.2.2 
Statistical Methods ...................................................................................... 77 
12.2.3 
Demographic and Other Baseline Characteristics .................................... 78 
12.2.4 
Maximum Tolerated Single and Cumulative Activity ............................... 78 
12.2.5 
Safety Evaluation ........................................................................................ 78 
12.2.6 
Pharmacokinetics, Biodistribution and Dosimetry .................................... 79 
12.2.6.1 
Biodistribution and Pharmacokinetic Analysis of 177Lu-3BP-227 ............... 79 
12.2.6.2 
Radiation Dosimetry Analysis of 177Lu-3BP-227 ......................................... 79 
12.2.6.3 
Pharmacokinetic Analysis of 3BP-227 ........................................................ 80 
12.2.7 
Pharmacodynamic/Efficacy Evaluation .................................................... 80 
12.2.8 
Interim Analysis/Safety Review Committee ............................................... 81 
12.2.9 
Clinical Study Report .................................................................................. 82 
12.3 Statistical Methodology for Phase II ........................................................................... 82 
12.3.1 
Sample Size Calculation ............................................................................. 82 
12.3.2 
Analysis Sets ................................................................................................ 83 
12.3.3 
Demographic and Other Baseline Characteristics .................................... 83 
12.3.4 
Efficacy Evaluation ..................................................................................... 83 
12.3.5 
Safety Evaluation ........................................................................................ 84 
13 
DATA HANDLING AND RECORD KEEPING ....................................................... 85 
13.1 Data Collection .............................................................................................................. 85 
13.2 Data Reporting .............................................................................................................. 85 
13.3 Data Management ......................................................................................................... 85 


 
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13.4 Record Keeping ............................................................................................................. 86 
14 
REGULATORY AND ETHICAL CONSIDERATIONS ......................................... 87 
14.1 Regulatory Considerations ........................................................................................... 87 
14.2 Ethical Review Considerations .................................................................................... 87 
14.3 Subject Information Sheet and Consent ..................................................................... 87 
14.4 Final Report Signature ................................................................................................. 88 
15 
INSURANCE AND FINANCE .................................................................................... 89 
15.1 Insurance ....................................................................................................................... 89 
15.2 Financial Agreement ..................................................................................................... 89 
16 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 90 
16.1 Protocol Amendments and Protocol Deviations and Exceptions ............................. 90 
16.1.1 
Protocol Amendments ................................................................................. 90 
16.1.2 
Protocol Deviations and Exceptions........................................................... 90 
16.1.3 
Information to Study Personnel ................................................................. 91 
16.2 Monitoring ..................................................................................................................... 91 
16.3 Investigator’s Regulatory Obligations ........................................................................ 92 
16.3.1 
Audit and Inspection ................................................................................... 92 
16.3.2 
Data Quality Assurance .............................................................................. 92 
17 
PUBLICATION POLICY ............................................................................................ 93 
18 
REFERENCES .............................................................................................................. 94 
19 
ATTACHMENTS ......................................................................................................... 97 
19.1 Attachment 1 – Study Schedule of Assessments for Phase I Dose Escalation ......... 97 
19.2 Attachment 2 – Blood Sampling Summary .............................................................. 104 
19.3 Attachment 3 – Clinical Laboratory Tests ............................................................... 105 
19.4 Attachment 4 – RECIST Version 1.1 Guidelines ..................................................... 107 
19.5 Attachment 5 – Statistical Details and Simulation Results for Implementation of 
Adaptive Bayesian Dose Escalation Design .............................................................. 126 
19.5.1 
Statistical Model ........................................................................................ 126 
19.5.2 
Trial Simulation Details ............................................................................ 128 
19.5.3 
Simulation Scenarios ................................................................................ 129 
19.5.4 
Operational Characteristics ...................................................................... 130 
19.5.5 
Simulation Results .................................................................................... 131 
19.6 Attachment 6 – RECIST to PERCIST ...................................................................... 136 
19.7 Attachment 7 – Protocol Amendment #7 Summary ................................................ 138 
 


 
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LIST OF TABLES 
Table 1 
Radiation Dose Estimates for Adult Humans based on Dosimetry Studies in 
Rat and Dogs ........................................................................................................ 29 
Table 2 
Estimated Safety Margin in Study/Species based on Human Equivalent 
Dose Calculated Based on Body Surface Area ................................................. 33 
Table 3 
Radiochemical Physical Characteristics of 177Lutetium .................................. 34 
Table 4 
Preliminary NTSR1 Expression Profile in Targeted Tumours ....................... 35 
Table 5 
Cohorts and Radioactivity Escalation Plan ...................................................... 41 
Table 6 
Timepoints and Replicates of 12-lead ECG Recordings .................................. 66 
Table 7 
Schedule of Assessments for Phase I – For Subjects who are Screen Failures 
after IMP Screening Administration ................................................................. 98 
Table 8 
Schedule of Assessments for Phase I – Dose Escalation ................................... 99 
Table 9 
Schedule of Assessments for Additional Cycles in Case of Clinical Benefit 
and Good Tolerability ....................................................................................... 103 
Table 10 
Prior Probability Distribution of MTSA ......................................................... 127 
Table 11 
Prior Probability Distribution of MTCA ........................................................ 127 
Table 12 
Simulated Dose-DLT Probabilities .................................................................. 130 
Table 13 
Main Operational Characteristics for the Five Trial Simulation Scenarios 132 
 
LIST OF FIGURES 
Figure 1 
Phase I Study Design Scheme ............................................................................. 40 
Figure 2 
Flow of Dose Escalation Cohorts and SRC Meetings....................................... 42 
Figure 3 
40 Random Observations (Curves) from the Prior Distribution .................. 127 
Figure 4 
Dose versus DLT Rates After Cycle 1 and Cycle 2 Simulation Scenarios ... 130 
Figure 5 
Mean (SD) Sample Size per Single or Cumulative Dose Level for the Five 
Simulation Scenarios ......................................................................................... 133 
Figure 6 
Boxplot of Total Number of Subjects During Cycle 1 for the Five Simulation 
Scenarios ............................................................................................................. 134 
Figure 7 
Boxplot of Total Number of Subjects During Cycle 2 for the Five Simulation 
Scenarios ............................................................................................................. 134 
Figure 8 
Boxplot of Total Number of Cohorts for the Five Simulation Scenarios ..... 135 
 


 
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RATIONALE FOR PROTOCOL AMENDMENT #7 
The protocol was amended to update the following:  
• 
Clarification of the inclusion criteria for subject selection as follows: 
- 
to clearly state nonresectable locally advanced disease  
- 
to clearly state that no further suitable treatment options are available for subjects 
eligible for the study 
• 
Allow subjects screened and found positive for NTSR1 in the 111In-IPN01087 phase I 
diagnostic study to take part in this study without having the diagnostic dose of 
177Lu-IPN01087 during the screening phase 
• 
Extend the long-term follow-up period from 2 years to a maximum of 5 years or until 
lost to follow-up, withdrawal of consent or death, whichever occurs first. 
• 
Revision of the DLT criteria (Section 4.7.1.1) to adequately describe the grading as stated 
in the CTCAE 5.0 dictionary 
• 
Revision of the subject discontinuation rules so if there are life threatening toxicities 
outside of the DLT period, treatment is discontinued 
• 
Optimise the dosimetry evaluation through adaptation of the imaging schedule 
• 
Clarification of biopsy collection 
• 
Clarification about COVID-19 added following the recent pandemic 
• 
  
• 
Make various clarifications and minor corrections for consistency 
All modifications (except minor changes) are presented in Attachment 19.7. 
PROTOCOL HISTORY 
Protocol version 
Rationale for amendment 
V1.0, 02AUG2017 
NA – initial version 
V2.0, 16OCT2017, 
Amendment #1 
To update tumour biopsy inclusion criteria as per Ethical Committee 
review. 
V3.0, 09NOV17, 
Amendment #2 
To incorporate changes to inclusion criteria, dose escalation part, 
physical examination and ECG assessments as per review by the 
Health Authorities in France. 
V4.0, 6DEC2017 
Amendment #3 
To include Ewing Sarcoma as an additional indication in the phase 
I/II study and to provide updated information regarding the IMP. 
In addition, some inconsistencies in the protocol have been corrected. 
V5.0, 02MAR2018 
Amendment #4 
To give precision on the calculation of the TGR, information about 
drug-drug interactions, clarification of discontinuation process, 
information about infusion rate in response to adverse events and 
increase time for use of contraception for females in the inclusion 
criteria from 30 days to 6 months, as well as information about 
spillages. 
In addition, some administration changes and minor inconsistencies 
in the protocol have been corrected. 
V6.0, 17 July 2018 
Amendment #5 
The protocol has been amended to improve the determination of the 
biokinetics of 177Lu-3BP-227 and perform an absolute quantification 
of radioactivity in target organs. Whole body scans (planar 
CCI


 
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Protocol version 
Rationale for amendment 
scintigraphy) have been added to single photon emission computed 
tomography (SPECT /CT) during treatment period. Whole body scans 
will allow the calculation of whole body time-integrated activity 
coefficient (“residence time”) that is needed for dosimetry analysis as 
it accounts for nonspecific activity in the body. Inclusion criteria n°3 
has been updated to enable the recruitment of patients who do not have 
a compelling standard-of-care option. 
In addition, some administration changes and minor corrections have 
been added. 
V7.0, 20 June 2019 
Amendment #6 
The protocol was amended to update personnel (the sponsor 
authorised protocol approver and sponsor medical monitor), to update 
the background information, especially new nonclinical toxicology 
data, to update the number of subjects receiving screening and 
therapeutic dose, 
 and add genomic 
alterations in circulating cell-free DNA and gene mutation status as 
exploratory objectives and endpoints, to change pharmacokinetic 
timepoints to improve the clinical feasibility, to specify the biopsy 
conditions and put them as optional assessments, to remove tumour 
markers assessments for gastric cancer (CA72-4) and squamous-cell 
carcinoma of head and neck (TPA), to refine the exclusion criteria 
regarding body weight, to clarify discontinuation rules, to clarify the 
duration of the safety follow-up period after the IMP screening dose 
administration and the reporting of AE collection after the last IMP 
administration, to specify that death due to disease progression will be 
reported as an SAE, to specify details on the preparation of the CSR, 
to add schedule of assessments for screen failure subjects and to make 
various clarifications and corrections for consistency. 
Following local competent authority feedback, the sponsor was 
requested to provide an updated study protocol including only highly 
effective methods of contraception for female subjects and female 
partner of male participants. Additionally, the sponsor was requested 
to: 
• 
Clarify the duration of use of effective contraception for male 
subjects 
• 
Clarify the maximum number of subjects participating in the 
study  
• 
Amend the study protocol so that only subjects who fulfil all of 
the inclusion criteria are included in the clinical study by 
clarifying the major protocol deviation definition 
• 
Specify in detail under which conditions re-screening of 
subjects will be possible 
• 
Clarify that all AEs during the core trial will be followed up 
until resolution or stabilisation independent of the level of 
severity or causality for treated subjects 
CCI


 
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Protocol version 
Rationale for amendment 
V7.1 (USA), 
20 August 2019, 
Amendment #6  
The protocol was amended to update the following as requested by the 
FDA: 
• 
Clarification of the inclusion criteria for subject selection as 
follows: 
- 
to clearly state nonresectable locally advanced disease  
- 
to clearly state that no further suitable treatment options 
are available for subjects eligible for the study 
• 
Revision of the DLT criteria to adequately describe the grading 
as stated in the CTCAE v5.0 dictionary 
• 
Revision of the subject discontinuation rules so if there are 
life-threatening toxicities outside of the DLT period, treatment 
will be discontinued 
 


 
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LIST OF DEFINITIONS AND ABBREVIATIONS 
TERM 
Wording Definition 
Audit 
A systematic and independent examination of the study-related 
activities and documents to determine whether the evaluated 
study-related activities were conducted, and the data were recorded, 
analysed, and accurately reported according to the protocol, 
sponsor’s standard operating procedures, good clinical practices, and 
the applicable regulatory requirement(s). 
Complaint 
A complaint is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, purity, durability, 
reliability, safety or effectiveness, or performance of a drug or drug 
delivery system. 
Compliance 
Adherence to all the study-related requirements, good clinical 
practices requirements and the applicable regulatory requirements. 
End of study 
End of study (EOS) is the date of the last visit or last scheduled 
procedure shown in the Study Schedule for the last active subject in 
the study. 
Enrol/Randomise 
The act of assigning a subject to a treatment. Subjects who are 
enrolled in the study are those who have been assigned to a 
treatment. 
Enter/Consent 
The act of obtaining informed consent for participation in a clinical 
study from subjects deemed or potentially eligible to participate in 
the clinical study. Subjects entered into a study are those who sign 
the informed consent document directly or through their legally 
acceptable representatives. 
Ethics Committee 
A board or committee (institutional, regional, or national) composed 
of medical professionals and non-medical members whose 
responsibility is to verify that the safety, welfare and human rights of 
the subjects participating in a clinical study are protected. 
Investigator 
A physician responsible for the conduct of a clinical study at a study 
site. If a study is conducted by a team of individuals at a study site, 
the investigator is the responsible leader of the team and may be 
called the principal investigator. 
Screen 
The act of determining if an individual meets minimum requirements 
to become part of a pool of potential candidates for participation in a 
clinical study. In this study, screening involves invasive or 
diagnostic procedures and/or tests (for example, diagnostic 
psychological tests, x-rays, blood draws). Informed consent for these 
screening procedures and/or tests shall be obtained; this consent may 
be separate from obtaining consent for the study. 
Subject 
An individual who is or becomes a participant in clinical research, 
either as a recipient of the test article or as a control. A subject may 
be either a healthy human or a patient. 
 


 
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ABBREVIATION 
Wording Definition  
% 
Percent 
βHCG 
Beta human chorionic gonadotrophin 
μL 
Microlitre 
ACE 
Angiotensin-converting enzyme 
ADL 
Activity of daily living 
Ae 
Cumulative amount of unchanged drug excreted into the urine 
AE 
Adverse event 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the (plasma concentration versus time) curve 
AUCinf 
Area under the curve from time zero to infinity 
BOR 
Best overall response 
ceCT/MRI 
Contrast enhanced computed tomography/magnetic resonance 
imaging 
cfDNA 
Cell-free deoxyribonucleic acid 
CL 
Clearance 
CLR 
Renal clearance of the drug from plasma 
Cmax 
Observed maximal (peak) concentration 
CR 
Complete responder 
CRC 
Colorectal cancer 
CRO 
Contract research organisation 
CSR 
Clinical study report 
CT 
Computed tomography 
CYP 
Cytochrome P 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOM 
Dosimetry operational manual 
DOR 
Duration of response 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 


 
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ABBREVIATION 
Wording Definition  
ED 
Early discontinuation 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EGFR 
Epidermal growth factor receptor 
EOAC 
End of additional cycles 
EOCT 
End of core trial 
EOS 
End of study 
ES 
Ewing Sarcoma 
FDA 
Food and Drug Administration 
FIH 
First in human 
FSH 
Follicle stimulating hormone 
GBq 
Gigabecquerel 
GC 
Gastric cancer 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GIST 
Gastrointestinal Stromal Tumours 
GPS 
Global Patient Safety 
Gy 
Gray 
hERG 
Human ether- à-go-go-related gene 
HPLC 
High performance liquid chromatography 
IB 
Investigator’s brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IU/L 
International unit per litre 
i.v. 
Intravenous 
kg 
Kilogram 
MACA 
Maximum administered cumulative activity 
MAD 
Maximum absorbed dose 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Millilitre 


 
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ABBREVIATION 
Wording Definition  
mL/min 
Millilitre per minute  
MS 
Mass spectrometer 
MTCA 
Maximum tolerated cumulative activity 
MTD 
Maximum tolerated dose 
MTSA 
Maximum tolerated single activity 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NOAEL 
No-observed-adverse-effect level 
NSAID 
Nonsteroidal anti-inflammatory drugs 
NTSR1 
Neurotensin receptor 1 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease/progression of disease 
PDAC 
Pancreatic ductal adenocarcinoma 
PERCIST 
PET Response Criteria in Solid Tumours 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial responder 
QTcF 
QT interval Fridericia's correction 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RL 
Radioactivity level 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCCHN 
Squamous-cell carcinoma of head and neck 
SOP 
Standard operating procedure 
SPECT 
Single photon emission computed tomography 
SRC 
Safety review committee 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to maximum observed plasma concentration 
TTP 
Time to progression 


 
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ABBREVIATION 
Wording Definition  
TTR 
Time to response 
ULN 
Upper limit of normal  
Vd 
Volume of distribution 
WHO 
World Health Organization 


 
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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
This phase I/II study will be the first administration of 177Lu-3BP-227 in humans under 
controlled study conditions. The study will generate safety and antitumour activity data and is 
expected to provide a better understanding of the mechanism of action of 177Lu-3BP-227. 
The results observed in terms of antitumour activity during dose escalation, will determine 
whether phase I expansion cohorts will be conducted to further investigate the safety of other 
activity levels and/or other administration schedule (e. g. hyperfractionation) or the 
investigation of efficacy of 177Lu-3BP-227 in the context of indication-specific cohorts or over 
multiple indications. 
1.2 
Name and Description of the Investigational Medicinal Product 
177Lu-3BP-227 is a drug substance consisting of a peptidomimetic neurotensin receptor 1 
(NTSR1) 
targeting 
moiety, 
linked 
to 
a 
chelating 
DOTA 
moiety 
(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which chelates the 
radioactive Lutetium (177Lu); it is applied in a theranostic approach. 
1.3 
Nonclinical Data 
1.3.1 
In Vitro Studies 
natLu-3BP-227 has been extensively tested in vitro. natLu-3BP-227 showed specific and high 
binding affinity (IC50 of 2.05 nM) to NTSR1, natLu-3BP-227 has no agonistic activity in a Ca2+ 
mobilisation assay and prevents the Ca2+ efflux induced by an NTSR1 agonist, therefore, 
characterising the molecule as an NTSR1 antagonist. In the same calcium mobilisation assay, 
3BP-227 displayed weak agonistic activity (EC50 of 95 nM) on the neurotensin receptor 2. 
3BP-227 at 10 μM and natLu-3BP-227 at 1 μM did not show any other potential binding in a 
screening panel (Cerep) of G protein-coupled receptor. 
1.3.2 
Toxicology 
 
 
 
 
 
 
 
 
 
 
1.3.3 
Pharmacokinetic Properties of Unlabelled 3BP-227 
In pharmacokinetics (PK) and metabolism studies, 3BP-227 appeared to be highly bound to 
human plasma proteins (86%), as well as in mouse plasma proteins (95%), with lesser binding 
to rat and dog plasma proteins (71% and 69%, respectively) (Study N° IPS000354). 3BP-227 
was very stable in human and dog plasma in vitro (>24 hours). Metabolic stability assays in 
human and dog liver microsomes showed a long half-life (t1/2>60 minutes) and consequently a 
low intrinsic clearance at a concentration of 0.1 μM of 3BP-227. 
3BP-227 had a poor inhibitory potential towards cytochrome P (CYP) 1A2, 2B6, 2C8, 2C9, 
2C19, 2D6 and 3A4 with a maximum inhibition of 33% towards CYP3A4 (midazolam 
CCI


 
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substrate) at 10 μM. Thus, it is unlikely that these CYPs will be inhibited by 3BP-227 in clinical 
settings. 
The PK of unlabelled 3BP-227 administered as a single i.v. dose has been evaluated in mice. 
Rat and dog toxicokinetics were performed as part of extended single i.v. dose toxicity studies 
in rats and dogs and of a 13-week repeated dose study in rats with the unlabelled 3BP-227.  
After a single i.v. dose in mice, 3BP-227 showed a low plasma clearance (CL of 
64.5 mL/hour/kg) and a moderate terminal elimination t1/2 (1.63 hours). 
After single i.v. administration in rats, the exposure (area under the curve from time zero to 
infinity (AUCinf)) was comparable for males and females. The terminal t1/2 was short and 
approximately two times longer in males than females (0.45 hour and 0.26 hour, respectively). 
The apparent volume of distribution (Vd) was small and approximately two times higher in 
males (402 mL/kg) than in females (221 mL/kg). The systemic CL was low and similar for both 
genders, representing approximately 15% of the hepatic blood flow of in rats. During the 
13-week repeated-dose TK study in rats, a rapid elimination phase was observed. The exposure 
was dose-proportional and no or weak accumulation occurred between Day 1 and Day 85 
(accumulation ratios ranged from 0.9 to 1.7). 
In dogs, the single i.v. bolus PK data indicate that the plasma concentrations of 3BP-227 
decreased in a biphasic manner, with a short elimination t1/2 of 2.15±0.257 hours for the second 
elimination phase and no gender-dependent differences. The apparent Vd was small 
(107±9.8 mL/kg) and the CL very low, representing 2.2% of the dog hepatic blood flow. 
1.3.4 
Biodistribution and Dosimetry of Radiolabelled 3BP-227 
The specificity of 3BP-227 accumulation in NTSR1-expressing tumours in vivo was 
demonstrated in biodistribution studies in mouse xenograft models with both 111In-3BP-227 
and 177Lu-3BP-227. Besides NTSR1-expressing tumours, the uptake of radioactivity in the 
organs was very low, including the kidneys and the liver. It was shown that 3BP-227 did not 
penetrate the blood brain barrier. 177Lu-3BP-227 showed a favourable biodistribution profile 
exhibiting a good tumour uptake associated with a low uptake in normal tissue and a persistent 
tumour uptake leading to favourable tumour-to-kidney activity ratio. 
In rats, the biodistribution profiles and the effective radioactive doses of 111In-3BP-227 and 
177Lu-3BP-227 were comparable. The radioactivity was rapidly cleared from the bloodstream. 
Tissue concentrations were low. Elimination of radioactivity was primarily through the urine 
and to a lesser extent via the faeces. 
In a biodistribution and dosimetry study of 177Lu-3BP-227 in Beagle dogs, the radioactivity was 
rapidly cleared from the blood. 177Lu-3BP-227 was predominantly and rapidly excreted through 
the urinary tract with a secondary elimination route via the liver into the gastrointestinal (GI) 
tract. The main uptake of radioactivity in organs was observed at 2 and 6 hours after injection 
in muscles, intestines, bones and bone marrow, liver, lungs and kidneys. At 72 hours 
post injection, all tissues exhibited less than 1% of the injected dose. The highest absorbed dose 
coefficients were observed in the urinary bladder wall, the large intestinal wall and the kidneys. 
Table 1 below summarises the extrapolation of the organ exposure results from these two 
studies to humans. The extrapolation to humans was performed using a mass-based 
extrapolation in which the concentration in the animal organs was converted to a concentration 
in human organs by multiplying the animal concentration by a ratio of the total body weight of 
the animals and humans [1]. The dosimetry studies in rats and dogs identified as target organs 
of special interest: urinary bladder, large intestinal wall, kidneys and osteogenic cells. 
From the extrapolation of animal data to human, the expected radiation exposure in human 
study is acceptable. 


 
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Table 1 
Radiation Dose Estimates for Adult Humans based on Dosimetry Studies in Rat and Dogs 
Compound 
177Lu-3BP-227 
111In-3BP-227 
177Lu-3BP-227 
Species 
Rat 
Rat 
Dog 
Specific activity 
1.2 to 2.4 mCi/nmol 
1.2 to 2.4 mCi/nmol 
9.9 MBq/μg 
Radioactive dose 
50 or 100 μCi/rat 
50 or 100 μCi/rat 
94.6±5.6 MBq 
API dose 
 
 
2.2 μg/kg 
Main organs 
M - F 
(mSv/MBq) 
M – F 
(mSv/MBq) 
M - F 
(mSv/MBq) 
Kidney 
0.170 - 0.280 
0.160 - 0.250 
0.16 - 0.11 
Liver 
0.094 - 0.140 
0.130 - 0.180 
0.03 -  0.02 
Brain 
0.007 - 0.006 
0.033 - 0.040 
0.00 - 0.00 
Lungs 
0.048 - 0.045 
0.093 - 0.120 
0.02 - 0.01 
Osteogenic cells 
0.650 - 0.540 
0.260 - 0.330 
0.07 - 0.05 
LLI wall 
0.450 - 0.530 
0.190 - 0.230 
0.30 - 0.16 
ULI wall 
0.290 - 0.290 
0.150 - 0.190 
0.27 - 0.15 
Red marrow 
0.160 - 0.110 
0.110 - 0.120 
0.02 - 0.01 
Spleen 
0.046 - 0.065 
0.110 - 0.150 
0.02 - 0.01 
Ovaries 
0.150 
0.180 
0.04 
Testes 
0.200 
0.120 
0.02 
Uterus 
0.150 
0.190 
0.19 
Urinary bladder wall 
0.430 - 0.400 
0.240 - 0.320 
1.19 - 1.27 
Total body 
0.200 - 0.150 
0.110 - 0.140 
0.02 - 0.02 
Effective dose 
0.200 - 0.190  
0.130 - 0.160 
0.03 - 0.10  
API=active pharmaceutical ingredient; LLI=lower large intestine; F=female; M=male; mSv=millisievert; ULI=upper large 
intestine. 
In bold italic, organs with the highest absorbed dose coefficients 
Currently, no data from human use are available under controlled study conditions. Under full 
medical responsibility of Professor Baum (see Section 1.4),
subjects with either pancreatic 
adenocarcinoma (n=6), 
 have been 
administered a low dose of 177Lu-3BP-227 (approximately 1 gigabecquerel (GBq)). Among 
them, five pancreatic ductal adenocarcinoma (PDAC) subjects 
 have shown 
a good tumour uptake after imaging without safety concern. 
subjects had further 
administration of 5.1 to 7.5 GBq with therapeutic intention (see Section 1.4). 
1.3.5 
Pharmacodynamic Effect In Vivo Study 
The potential efficacy of 177Lu-3BP-227 has been investigated in an NTSR1-expressing tumour 
model in mice (HT29 xenograft model in nu/nu mice). 177Lu-3BP-227 was administrated at two 
different doses (100 and 160 MBq) 7 days after tumour cells inoculation in mice (HT29 human 
colon carcinoma xenograft implanted in nude mice) and one control mice group received a 
vehicle. The results showed a dose-dependent tumour growth control for 3 or 5 weeks, without 
any overt signs of toxic effects [2]. 
Please see investigator brochure (IB) for more detailed information. 
1.4 
Clinical Data 
In a preliminary salvage therapeutic administration (compassionate use with non-registered 
medicinal product) , under full medical responsibility of Professor Baum at the Zentralklinik 
Bad Berka in Germany, hereinafter referred to as “individual clinical treatment use”
subjects 
received 177Lu-3BP-227: Six subjects with PDAC, 
 
 [3]. 
Out of the six subjects with PDAC who were imaged with 177Lu-3BP-227, five subjects had a 
good uptake in primary tumours and/or metastases following administration of 1.2 or 1.5 GBq 
CCI
CCI
CCI
CCI
CCI
CCI


 
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177Lu-3BP-227 and one subject imaged with 1.5 GBq 177Lu-3BP-227 had no uptake. These 
results are in line with the 75% of the PDAC expressing NTSR1 as described in the literature 
[4, 5]. Due to the advanced disease stage, most of the subjects did not have the opportunity to 
receive further administration in a range of therapeutic activity; three out of the five subjects 
with NTSR1-expressing tumours had post-imaging administrations. 
Dosimetry calculations are available for three subjects. Subjects received diagnostic doses of 
1.2 to 1.5 GBq. Only Subject 3 received therapeutic activities (of 6.4 GBq, 7.5 GBq and 
5.5 GBq given intra-peritoneally). Kidneys were identified as dose-limiting organs, with 
absorbed doses ranging from 0.48 Gray (Gy)/GBq to 1.42 Gy/GBq. However, none of the 
reported subjects received a dose to the kidney that exceeded 23 Gy (highest absorbed renal 
dose of 22 Gy for a cumulative activity of 20.9 GBq). The specific absorbed doses to the bone 
marrow was low (0.09 to 0.10 Gy/GBq), as well as the absorbed dose in liver, GI tract, thyroid 
and urinary bladder, ranging from 0.06 Gy/GBq to 0.09 Gy/GBq. Moreover, the cumulative 
absorbed doses in these organs were below the organ radiation dose limits of  2 Gy, 35 Gy, 
45 Gy, 45 Gy and 60 Gy respectively (ICRP publication 41).  
Of interest, following initial administration of 1.5 GBq 177Lu-3BP-227 to assess the tumour 
uptake and calculate the organ dosimetry, one of the subjects, Subject 3 who received three 
therapeutic administrations of 6.4, 7.5 and 5.5 GBq of 177Lu-3BP-227 was considered a partial 
responder (per Response Evaluation Criteria in Solid Tumours (RECIST) and positron emission 
tomography (PET) Response Criteria in Solid Tumours (PERCIST) criteria). The administered 
cumulative activity of 20.9 GBq in this subject led to a total organ dose of 22.0 Gy to the 
kidneys. The haemoglobin of this subject remained low during and after treatment, with a short 
and reversible episode of Grade 2 anaemia before the last administration. 
 
 
 
 
 
 
 
 
Overall, no important safety concern was raised during administration during the individual 
clinical treatment use.  
1.5 
Rationale for the Study 
The rationale for this phase I/II study is to use the NTSR1 overexpression as target to deliver 
screening and therapeutic radioactivity to tumour cells. Therefore, tumours with specific 
overexpression of NTSR1 will constitute the target tumour types for 177Lu-3BP-227. 
Previous radiopharmaceutical compounds (e.g. 177Lu-DOTATATE, 177Lu-DOTATOC) have 
been demonstrated as safe and effective in neuroendocrine tumour subjects [3, 7, 8].This 
treatment principle can be applied to 177Lu-3BP-227 for the treatment of cancers with increased 
expression of NTSR1. 177Lu-3BP-227 has been shown to be effective in a NTSR1-expressing 
xenograft model inhibiting tumour growth. Dosimetry data showed a low accumulation of 
radioactivity in the organs and an acceptable tumour to tissue radioactivity uptake. Considering 
the favourable toxicity profile in vitro and in vivo through targeting the NTS/NTSR1 complex 
and the first clinical evidence from an individual clinical treatment use under full medical 
responsibility of Professor Baum (see Section 1.4), radiotherapy with 177Lu-3BP-227 may be 
particularly attractive as it may offer a treatment option, beyond the standard-of-care, for 
cancers such as PDAC, colorectal cancer (CRC), ES, gastric cancer (GC) and cancers of the 
head and neck, where there are still high unmet clinical and therapeutic needs. 
CCI


 
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Even though promising safety data were collected from the individual clinical treatment use 
(compassionate use with non-registered medicinal product), the safety, tolerability and efficacy 
of 177Lu-3BP-227 treatment for cancers expressing NTSR1, needs to be assessed in a 
well-designed prospective clinical study. 
The dose escalation part of the study has been designed to primarily investigate the safety, 
tolerability, dosimetry and preliminary antitumour activity of 177Lu-3BP-227 following 
fractionated i.v. administrations in subjects with unresectable, locally advanced or metastatic 
cancers expressing NTSR1. In radiopharmaceutical studies, this safety assessment also includes 
dosimetry studies to evaluate the radioactive exposure of organs. To optimise the benefit-risk 
ratio, it is essential to identify the proper target population for therapy. In this study, the target 
population will be identified by assessing the tumour uptake following the screening 
administration of 177Lu-3BP-227. Samples will be collected for biomarker exploratory analyses 
to investigate associations between biological and clinical parameters (e.g. better 
characterisation of potential responders, response to treatment, tolerability and safety). 
For phase I (dose escalation), a statistical Bayesian modelling approach [9] may be 
implemented to produce a more precise dose-toxicity response curve and predict subsequent 
activity levels. The objective of the model is to predict activity ranges to be administered that, 
in combination with the dose escalation rules, remain below the maximum tolerated cumulative 
activity (MTCA) level in subjects. 
Upon termination of dose escalation and/or determination of MTCA by the safety review 
committee (SRC), and based on the assessment of the preliminary antitumour activity, cohorts 
of subjects will be studied to further characterise safety and efficacy of 177Lu-3BP-227. 
Antitumour activity of the 177Lu-3BP-227 is expected to be observed from cohort 2 of the dose 
escalation part. In case of a weak antitumour activity across all indications and dose cohorts, it 
is anticipated that further clinical investigations (expansion part) will be needed with optimal 
radioactivity and small molecule mass determination as well as administration schedule 
determination in selected indications. The activity levels will be decided based on the safety 
and preliminary antitumour effect observed in the dose escalation part. The selection of the 
small-molecule/radionuclide ratio will be driven by data from nonclinical studies that will be 
conducted in parallel with the dose escalation part. Finally, the targeted populations might be 
reviewed in light of the tumour uptake, safety, tolerability and preliminary antitumour effects 
observed during dose escalation.  
If a strong antitumour activity signal is observed during phase I, cohorts will be enrolled in the 
phase II part of the protocol immediately after the end of the dose escalation or dose expansion 
parts to assess the efficacy of 177Lu-3BP-227. 
In case of medium objective response rate (ORR), a substantial clinical benefit would be 
observed in selected indications. Based on the actual knowledge built from preclinical studies, 
an individual clinical treatment use (see Section 1.4) and tissue/cancer expression of NTSR1, it 
is planned to rapidly enrol cohorts in PDAC and CRC in a Simon Two-Stage design. Pancreatic 
ductal adenocarcinoma is the most common form of pancreatic cancer and constitutes 90% of 
all cases. It is a highly aggressive tumour with an overall 5-year survival rate of less than 5%, 
[10] and between 1% to 3% after the second stage [11]. Pancreatic ductal adenocarcinoma, the 
worst of all malignancies, is predicted to be the second leading cause of cancer-associated 
mortality within the next 5 to 10 years [12, 13]. This poor overall survival (OS) for subjects 
with pancreatic cancer is mainly due to a lack of biomarkers to enable early diagnosis and a 
lack of prognostic markers that can inform decision making and facilitate personalised 
treatment and an optimal clinical outcome [14]. The overexpression of NTSR1 by PDAC 
tumoural tissue offer a new promise to demonstrate the safety and efficacy of a NTSRI targeted 
radiopharmaceutical such as 177Lu-3BP-227. This hypothesis is well supported by the results of 


 
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preclinical data (see Section 1.7) as well as by clinical data from an individual clinical treatment 
use (see Section 1.4). 
Metastatic CRC (mCRC) constitutes another pressing unmet need, when current available 
treatment options are exhausted. Colorectal cancer is currently the second most commonly diagnosed cancer in Europe and the 
second leading cause of cancer-related death in the United States [15, 16]. Despite significant progress in the treatment of mCRC during the past 
two decades, the prognosis of subjects with mCRC remains poor, with a 5-year survival rate of approximately 13% [17, 18]. Although a subset 
of subjects with liver and/or lung isolated disease is potentially curable with surgery, for other subjects with mCRC, treatment is palliative and 
generally consists of systemic chemotherapy [19, 20]. 177Lu-3BP-227 could be investigated in those subjects who 
have received prior lines of standard-of-care chemotherapy/treatment and have no further 
suitable treatment options and their tumour tissue overexpresses NTSR1, knowing that the 
percentage of CRC tumours expressing NTSR1 is very high, with high degree of expression 
(see Section 1.7). Moreover, the nonclinical data generated from an NTSR1 expressing tumour 
model in mice (HT29 xenograft model in nu/nu mice) are supportive of further investigating 
177Lu-3BP-227 in mCRC (see Section 1.3.5). 
In case of high ORR, it would suggest that the NTSR1 target is the main driver for antitumour 
activity. In this particular situation, a basket single-arm trial will be conducted to further 
characterise the efficacy of 177Lu-3BP-227 in the context of the multiple indications. This 
innovative approach would provide rapid access of the investigational medicinal product (IMP) 
to subjects with great medical need. 
1.6 
Selection of Dosage 
The radioactivity range (5 to 15 GBq) applied in this study is derived mainly from previous 
experiences with 177Lu-DOTATATE [21], although some caution should be applied as it refers 
to other radiolabelled compounds in other indications. In addition, data from an individual 
clinical treatment use (see Section 1.4) of 177Lu-3BP-227 support the dose range selection and 
is endorsed by the dosimetry studies performed with the IMP in rats and dogs. 
In the phase I dose escalation part of this first in human (FIH) study, 5 GBq fractionated into 
two administrations (2×2.5 GBq) will be used as starting radioactivity. In radiotherapy, 
fractionation of the cumulative activity is done for safety and tolerability reasons. Based on the 
biodistribution data obtained in nontumour bearing rats and dogs and consequent allometric 
calculation for human exposure and taking the most conservative approach, administration of 
5 GBq leads to an organ dose of 0.8 Gy for the bone marrow and 1.4 Gy for the kidneys. These 
organ doses are more than 50% below the organs dose limits of 2 Gy and 23 Gy, respectively. 
In an individual clinical treatment use (see Section 1.4), four subjects received single 
administration of 5 GBq without reporting of adverse events (AEs) >Grade 2. 
During dose escalation, it is planned to not exceed the cumulative activity of 15 GBq activity 
(2×7.5 GBq). However, if the MTCA is not reached and if limiting organ dose levels are not 
exceeded, an additional cohort with three administrations at 7.5 GBq may be added, leading to 
a cumulative activity of 22.5 GBq. The dosage used in the dose expansion part will be based 
on the results obtained from the dose escalation part and from the modelling and simulation 
approach. Similarly, results generated during the dose expansion part will drive the dosage that 
will be used in phase II. In any case, subjects will be administered with cumulative activities 
that may be either the MTCA determined in the escalation part or a lower dose with near optimal 
activity. 
In this study, 25 μg (22.1 nmol) of 3BP-227 per 1 GBq 177Lu will be used. This 
radioactivity-small-molecule ratio was used in an individual treatment use (see Section 1.4) and 
yields a specific activity of approximately 45 MBq/nmol, which is routinely achieved 
with -DOTA-conjugated compounds and is considered clinically acceptable [21, 22]. 


 
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In Table 2, the safety margins for each species are presented based on the human equivalent 
dose calculated from body surface area as per Food and Drug Administration (FDA) Guidance 
for Industry “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers” [23]. The small-molecule 3BP-227 has been 
administered within a nonclinical safety program carried out in rats and dogs following a single 
administration. The NOAELs determined in the rats and dogs were 2 mg/kg and 1 mg/kg, 
respectively. Compared to the animal studies, a wide safety margin is observed (based on the 
most sensitive species, a safety factor margin of more than 300 for the starting dose activity and 
more than 100 for the targeted maximum radioactivity). At the dose range of 3BP-227 used in 
this study, no pharmacological effect is expected. 
Table 2 
Estimated Safety Margin in Study/Species based on Human Equivalent Dose Calculated Based 
on Body Surface Area 
Study 
Dose/activity 
HED of 3BP-227 
Estimated safety margin 
for 3BP-227 [a] 
Study phase I/IIa 
Starting dose: 
2.5 GBq of 177Lu-3BP-227 
Corresponding to: 
• 
A total of 62.5 μg of 
3BP-227 (2.5×25μg) per 
administration 
• 
1 μg/kg of 3BP-227 per 
administration 
Maximal dose: 
7.5 GBq of 177Lu-3BP-227 
Corresponding to: 
• 
A total of 187.5 μg of 
3BP-227 (7.5×25 μg) per 
administration 
• 
3.1 μg/kg of 3BP-227 per 
administration 
 
 
Single dose rat 
Study 
763.321.4274 
NOAEL (3BP-227)=2 mg/kg 
0.322 mg/kg 
Starting dose: 
322 times below NOAEL  
Maximal dose:  
104 times below NOAEL 
Single dose dog 
Study 
763.323.5173 
NOAEL (3BP-227)=1 mg/kg [b] 
0.556 mg/kg 
Starting dose: 
556 times below NOAEL 
Maximal dose: 
179 times below NOAEL 
HED=human equivalent dose; NOAEL=no observed adverse events level. 
a 
based on HED and on body surface area (divided by 1.8 for dogs and 6.2 for rats) 
The calculations are based on the following basis: 1 GBq/25 μg 3BP-227 and human body weight of 60 kg 
b 
2 mg/kg 3BP-227 was tested in study 763.323.5173 and was considered within the Maximum Tolerated Dose due to 
slight transient increase in QT interval. A safety pharmacology study tested 1mg/kg 3BP-227 did not show any adverse 
cardiovascular effect. The NOAEL of 1 mg/kg 3BP-227 is derived from the combination of these two studies. 
Rationale for use of 177Lu labelling for Screening Purposes and as a Threshold for 
Radiodiagnosis 
177Lu is a beta (β)- and gamma (γ)-emitting radionuclide. It is a medium-energy β emitter with 
a maximum energy of 0.498 MeV and maximum and mean soft-tissue penetration depths of 
1.7 mm and 0.23 mm, respectively. The t1/2 is 6.7 days (159.5 hours). 177Lu also emits 
low-energy γ-rays at 208 and 113 KeV with 11% and 6% relative abundance, respectively, 
which allows scintigraphy and subsequent dosimetry with the same product. The radiochemical 
physical characteristics of 177Lu are described in Table 3 [21]. 
177Lu presents the advantage of emitting just enough γ radiation for quantitative imaging 
necessary for dosimetry calculation while the β radiation induces the therapeutic effect. 


 
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For imaging purposes, the γ emission of 177Lu is accompanied by the additional radiation burden 
of β emission of 177Lu. Therefore, when radiotherapy is not required, the administration of 177Lu 
may deliver an undesirable radioactivity to the subject. However, the theranostic potential of 
177Lu outweighs the above disadvantage particularly in advanced malignant tumours and avoids 
the uncertainties that may occur from the use of different isotopes with different kinetics that 
could result in less accurate dosimetry planning. 
Table 3 
Radiochemical Physical Characteristics of 177Lutetium 
Physical half-life t½ 
6.65 days 
Decay product 
177Hf 
Maximum β-particle energy 
0.498 MeV  
Mean β-particle energy 
0.133 MeV 
Median tissue penetration 
0.23 mm 
Max. tissue penetration 
1.7 mm 
Main gamma emission lines 
113 keV (6%) 
208 keV (11%) 
The administration of 1.00±0.1 GBq 177Lu-3BP-227 is considered adequate to ensure a good 
uptake at tumour level for dosimetry based on a similar application scheme used by Wild et al. 
[24] for the evaluation of 177Lu-DOTA-JR11 and will thus be used in this study for screening 
purpose, after all other required screening assessments have been completed. 
A lower radioactivity administration would lead to longer acquisition time and a poor diagnostic 
signal (with an increase in signal noise to background ratio) associated with the risk of missing 
subjects who would be eligible for participation in the study and could benefit from the 
treatment. 
1.7 
Population to be Studied 
In this FIH study, the subject population enrolled to receive the IMP will be restricted to PDAC, 
CRC, GC, GIST, squamous-cell carcinoma of head and neck (SCCHN) and ES, which are 
unresectable, locally advanced or metastatic and expressing NTSR1. Due to the late metastatic 
or advanced stage of the disease and progression or failure of response to standard-of-care 
treatments, this subject population is expected to have a reduced life expectancy.  
Tumours/metastases expressing NTSR1 will be identified and documented through the lesion 
uptake of 177Lu-3BP-227 (at low dose) during the screening period. Subjects who participated 
in the imaging study, Study D‑FR‑01087‑002, with 111In-3BP-227 (also called 111In-IPN01087) 
and who have an uptake of 111In-3BP-227 in tumour lesions that is more avid than in the 
nontumoural surrounding tissue based on whole body imaging (planar scintigraphy), as judged 
by the investigator, can also be considered for enrolment in this study, provided that they fulfil 
all other inclusion criteria and do not meet any of the exclusion criteria and were imaged with 
111In-3BP-227 before the first treatment administration (therapeutic dose) of 177Lu-3BP-227. 
 
 
 
 
CCI


 
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In addition, published data also support these NTSR1 expression profiles in the targeted 
indications [4, 5, 25, 26, 27]. In the PDAC population, the NTSR1 was found expressed in 73% 
(8/11) of primary tumours and 63% (14/23) of the metastases. Interestingly, the expression of 
NTSR1 in the membrane compartment was only observed in tumour tissue (85%; 34/40) and 
never in normal tissue. In addition, a strong expression of NTSR1 messenger ribonucleic acid 
(mRNA) was found in 76% (19/25) of the cases of colorectal adenocarcinoma (resection 
material). Protein overexpression has been documented by immunochemistry in 71% (149/210) 
of GC samples. For ES, expression of NTSR1 in the membrane compartment has been found 
in 65% (11/17) of the resection tissue material [6]. 
The five study populations will be enrolled in the phase I dose escalation part. Based on tumour 
uptake, safety and preliminary antitumour effect (ORR), the number of study populations might 
be revised for the potential phase I expansion cohorts and phase II through a protocol 
amendment. 
1.8 
Known and Potential Risks to Human Subjects 
This is the FIH study conducted with 177Lu-3BP-227 under controlled conditions. The study 
will primarily evaluate the safety and tolerability of 177Lu-3BP-227 but also its potential 
antitumour effect in subjects with advanced cancers expressing NTSR1. With the exception of 
an individual clinical treatment use (see Section 1.4), 177Lu-3BP-227 has never been tested in 
humans, but has shown no relevant toxicological effects in the animal studies conducted with 
high safety margins. However, it cannot be ruled out that 177Lu-3BP-227 could have adverse 
effects in the human population, which have not been detected in animal studies. 
As this is the FIH study, the function of organs identified at risk will be checked as part the of 
exclusion criteria. Based on the current level of knowledge, those organs are bone marrow, 
kidney, large intestine, liver and urinary bladder. In conventional fractionated external 
radiotherapy, the experience is that an absorbed dose of 23 Gy to the kidney gives a 5% 
expected risk of nephrotoxicity within 5 years [28, 29, 30]. For the bone marrow, a maximum 
absorbed dose (MAD) of 2 Gy gives approximately a 2% risk of developing leukaemia as a 
long-term toxicity. In this study, the well-established 2 Gy for the bone marrow MAD and the 
more conservative approach with 23 Gy as MAD for the kidney will be applied. 
Safety measures have been taken into consideration to minimise the risk. Each subject recruited 
across the sites may be hospitalised for 24 hours following administration for observation at the 
discretion of the investigator. The level of radioactivity will be monitored until it has fallen to 
safe levels for discharge, to protect medical personnel and relatives. Depending on the local 
CCI


 
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regulation, the subject will be hospitalised either in the nuclear medicine or regular oncology 
ward. 
The participating subjects will be closely monitored during the study and during the long-term 
follow-up period until lost to follow-up, withdrawal of consent, death or a maximum of 5 years, 
whichever occurs first. Subjects may be withdrawn from the study at any time, if judged to be 
in their best interest by the investigator or upon the subject’s wish. The study will be carried 
out in specialised clinical centres with nuclear medicine and medical oncology specialists. 
An SRC will review the safety and dosimetry data on a continuous basis (see Section 4.2.1.4). 
Subject-specific dosimetry will be performed on a regular basis for up to 96 hours after each 
administration to describe the uptake by the tumour and organs identified at risk over the entire 
course of treatment. The cumulative organ doses of kidney, bone marrow and liver will be 
monitored on an ongoing basis as for the other organs identified at risk. If a previous cumulative 
radioactive dose indicates that the organ limit will be exceeded with the next cycle, the activity 
of the next cycle will be reduced. 
Detailed criteria, based on the percentage of subjects experiencing dose limiting toxicities 
(DLTs), have been carefully defined to provide guidance on the next radioactive dose selection. 
The risks associated with this study are considered adequately elucidated and controlled well 
by planned cautionary measures in the study design and the target population as well as with 
the potential benefit of the treatment. 


 
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2 
STUDY HYPOTHESIS 
The present study consists of two parts that aim to test the following hypotheses: 
2.1 
Phase I  
177Lu-3BP-227 is sufficiently well-tolerated to permit clinical investigation in phase II. 
2.2 
Phase II 
177Lu-3BP-227 yields higher objective response rates in subjects who have NTSR1 expressing 
cancers that are unresectable, locally advanced or metastatic based on RECIST version 1.1 by 
central review and as compared with the historical ORR obtained by current standard-of-care 
treatment for each tumour type. 


 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
3.1.1 
Phase I 
To establish the safety and tolerability of fractionated i.v. administrations of 177Lu-3BP-227 in 
subjects with unresectable, locally advanced or metastatic cancers expressing NTSR1. 
3.1.2 
Phase II 
To estimate ORR of fractionated i.v. administrations of 177Lu-3BP-227 in subjects with 
unresectable, locally advanced or metastatic cancers expressing NTSR1. 
3.2 
Secondary Objectives 
3.2.1 
Phase I 
(a) 
To determine the whole-body distribution of 177Lu-3BP-227 and PK of both 
177Lu-3BP-227 and 3BP-227. 
(b) 
To determine the radiation dosimetry of 177Lu-3BP-227 (organ exposure to radiation). 
(c) 
To describe the preliminary antitumour activity of 177Lu-3BP-227. 
3.2.2 
Phase II 
(a) 
To further evaluate the safety profile of 177Lu-3BP-227 at the radioactivity recommended 
by the phase I results. 
(b) 
To further assess the response to treatment with 177Lu-3BP-227 using RECIST 
version 1.1 and/or PERCIST version 1.0 criteria. 
(c) 
To further characterise the whole-body distribution and dosimetry of 177Lu-3BP-227 and 
PK of both 177Lu-3BP-227 and 3BP-227. 
(d) 
To describe the influence of 177Lu-3BP-227 on the health-related quality of life of treated 
subjects. 
3.3 
Exploratory Objectives 
3.3.1 
Phase I/II 
(a) 
To explore the correlation between the tumour uptake of 177Lu-3BP-227 and the NTSR1 
expression on tumours. 
(b) 
To explore renal safety by measuring urinary specific biomarkers. 
(c) 
To evaluate the tumour microenvironment, transcriptomics and other markers of interest 
for the disease through assessment of tumour biopsies. 
(d) 
To explore genomic alterations in circulating cell-free DNA (cfDNA) and in germline 
DNA. 
(e) 
To collect gene mutation status for correlation with clinical outcome. 
(f) 
To collect biobank samples for future analysis of circulating markers (optional; 
additional informed consent required). 
(g) 
To generate a model integrating PK, dosimetry, antitumour activity and safety data. 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a multicentre, open-label phase I/II study of 177Lu-3BP-227 in subjects with 
unresectable, locally advanced or metastatic solid tumours expressing NTSR1 who have 
progressed after their available standard-of-care treatment options and/or are deemed suitable 
for the treatment with 177Lu-3BP-227 as per the investigator’s clinical assessment and/or their 


 
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individual disease state. The study consists of a phase I dose-escalation (and potential expansion 
cohorts) and a phase II assessing the efficacy of 177Lu-3BP-227 in subjects with unresectable, 
locally advanced or metastatic solid tumours expressing NTSR1. 
4.2 
Phase I 
4.2.1 
Dose Escalation 
Phase I will consist of a radioactivity escalation part with the objective of determining the 
MTCA. For phase I, subjects enrolled will have unresectable, locally advanced or metastatic 
tumours expressing NTSR1 originating from either the pancreas (PDAC), colon and rectum 
(CRC), stomach (GC), gastrointestinal stromal tumours (GIST), head and neck region 
(SCCHN) or bone (ES). 
The study screening period includes a screening administration of 177Lu-3BP-227 to assess the 
tumour uptake of each subject by whole body scan (planar scintigraphy, 1 or 2 timepoint(s) at 
the investigator’s discretion) and optional single photon emission computed tomography 
(SPECT)/CT scans (up to 2 at the investigator’s discretion). Only subjects with a tumour uptake 
higher than nontumoural surrounding tissue (based on investigator’s decision) will be deemed 
eligible for treatment. The screening period will last 3 weeks but can be extended by up to 
2 weeks if this is required for logistical reasons. Subjects who participated in the imaging study, 
Study D‑FR‑01087‑002, with 111In-3BP-227 (also called 111In-IPN01087) and who have an 
uptake of 111In-3BP-227 in tumour lesions that is more avid than in the nontumoural 
surrounding tissue based on whole body imaging (planar scintigraphy), as judged by the 
investigator, can also be considered for enrolment in this study, provided that they fulfil all 
other inclusion criteria and do not meet any of the exclusion criteria and were imaged with 
111In-3BP-227 before the first treatment administration (therapeutic dose) of 177Lu-3BP-227. 
During the treatment phase, it is planned that each subject will receive 177Lu-3BP-227 
fractionated into two i.v. administrations separated by 4 to 5 weeks (+4 weeks in case of 
reversible AEs) (Figure 1). The safety evaluation will be done over 4 weeks between Cycle 1 
and Cycle 2 and over 6 weeks between Cycle 2 and end of core trial (EOCT). During this period, 
subjects will have repeated imaging for the calculation of individual dosimetry data and will be 
monitored for signs of toxicity. 
Tumour response will be assessed on CT or MRI, as well as with 18F-FDG-PET scans at the 
EOCT visit, (corresponding to 6 weeks after the second administration). 
Subjects may receive up to four additional administrations of 177Lu-3BP-227 after the EOCT, 
if they have clinical benefit and an acceptable tolerability profile and if the organ dose limits 
are not exceeded. The safety data evaluation will be conducted by the sponsor. The decision to 
administer additional cycles is based on the investigator’s judgement and subject’s discretion 
and must be discussed with and agreed upon by the sponsor. The clinical benefit will be defined 
as complete responder (CR), partial responder (PR) or stable disease or based on their 
biochemical response. 
A long-term follow-up period will start after the EOCT, early discontinuation (ED) or end of 
additional cycles (EOAC) visit and subjects will be followed up every 3 months (±2 weeks) 
until lost to follow-up, withdrawal of consent, death or a maximum of 5 years, whichever occurs 
first. 


 
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Figure 1 Phase I Study Design Scheme 
 
Note: Population screened includes subjects with unresectable disease. 
1Additional cycles are optional depending on the clinical benefit observed in the subjects during the core trial, as well as on the 
toxicities and organ absorbed doses. 
4.2.1.1 
Definition of the MTCA 
Several radioactivity amounts of 177Lu-3BP-227 are planned to be tested according to an 
adaptive radioactivity escalation plan. Each subject will only participate in one part of the 
protocol. The purpose of the radioactivity escalation part is to determine the MTCA. If not 
feasible, the maximum tolerated single activity (MTSA) or the maximum administered 
cumulative activity (MACA) will be determined according to the situation below: 
• 
The MTCA is defined as the maximum tolerated cumulative activity that may be 
administered following fractionated i.v. administrations of at least 4 weeks apart, so that:  
- 
No more than 33% of the subjects experience a DLT during Cycles 1 and/or 2 (see 
DLT definition in Section 4.7.1.1), and 
- 
The cumulative radiation in each target organ does not exceed the acceptability 
limits (see Section 4.7.1). 
• 
The MTSA is defined as the highest single radioactivity that can be given so that no more 
than 33% of the subjects experience a DLT during Cycle 1. The MTSA will be 
determined in case of unacceptable toxicity seen after Cycle 1. 
• 
The MACA will be determined if the MTCA is not reached during the dose escalation 
part. 
4.2.1.2 
Cohorts Description 
The dose escalation part will be conducted over five cohorts from a starting cumulative activity 
of 5 GBq up to a maximum cumulative activity of 15 GBq, fractionated into two 
administrations of 2.5 GBq and 7.5 GBq respectively. 
The size of the cohorts will be three to five treated subjects, to secure a minimum of three 
evaluable subjects per cohort who completed 2 cycles of treatment. A cohort will be considered 
as completed once three subjects of the cohort complete Cycle 2 or early discontinue during 
Cycle 2 (except for cohort 1, see Proceeding to the Next Cohort described in Section 4.2.1.4). 
If a subject replacement is needed to complete the cohort enrolment, see Section 4.7.1.3 for 
replacement rules. 


 
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For safety reasons, the first three subjects of a cohort will be administered sequentially, one 
week apart to allow a sufficient observation period for any adverse reaction. 
4.2.1.3 
Dose Escalation Mode 
Dose escalation is planned to proceed in two steps, with two different increments for the 
radioactivity escalation. In the first step, in order to minimise the number of subjects receiving 
subtherapeutic activity, the inter-cohort radioactivity escalation will be performed by increment 
of 3 GBq (1.5 GBq per administration), up to the first study drug related treatment-emergent 
AE (TEAE) (Grade 2 or higher, except hair loss) or until a DLT occurs. Afterwards, the 
maximum increment will be reduced to 2 GBq (1 GBq per cycle) for all subsequent cohorts if 
dose escalation is allowed. However, even if no Grade 2 or higher AE are observed up to a 
cumulative activity of 11 GBq, radioactivity will be increased by 2 GBq (1 GBq per cycle). 
Table 5 illustrates the escalation plan based on the escalation scheme defined above. However, 
if DLTs are reported, a statistical Bayesian modelling approach will be implemented to produce 
a more precise dose-DLT curve to guide the dose selection (see details in Attachment 5, 
Section 19.5) and predict an activity not exceeding the MTCA/MTSA that could be tested in 
the next cohort. 
Table 5 
Cohorts and Radioactivity Escalation Plan 
Planned 
radioactivity 
escalation 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Cumulative 
5 GBq 
8 GBq 
11 GBq 
13 GBq 
15 GBq 
Per cycle 
2.5 GBq/C 
4 GBq/C 
5.5 GBq/C 
6.5 GBq/C 
7.5 GBq/C 
C=cycle; GBq=gigabecquerel. 
Once the dose escalation has been completed, the MTCA level may be repeated in a last cohort 
(see Section 4.2.1.4 for stopping rules and Section 4.2.1.1 for MTCA definition). If the MTCA 
is not reached and if limiting organ dose levels are not exceeded at the highest planned activity 
(2×7.5 GBq) and if no individual withdrawal criteria are met, an additional cohort (Cohort 6) 
with three administrations at the highest single administration level may be added (3×7.5 GBq). 
4.2.1.4 
Safety Review Committee 
The SRC will review the safety and radiation exposure data and jointly decide with the sponsor 
whether to proceed with the enrolment of the next cohort dose level and the second dosing cycle 
within a cohort. For this purpose, the SRC will be composed of all phase I investigators, who 
have treated at least one subject in the study cohort with study medication, one independent 
expert, a dosimetry expert evaluating the dosimetry data of the study (from a centralised 
dosimetry centre) and at least one sponsor representative. Regular meetings will be held. A 
specific charter will be developed to define roles and responsibilities, as well as the dataset to 
be reviewed by the SRC and the review timepoints. 


 
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Figure 2 Flow of Dose Escalation Cohorts and SRC Meetings 
 
A=administration of study compound; EOCT=end of core trial; SRC=Safety Review Committee. 
SRC1=Decision on start of next cohort 
SRC2=Confirmation or adjustment of A2 in next cohort 
 
Proceeding to the Next Cohort 
At the time of radioactivity escalation, the available clinical safety and radiation exposure 
information will be reviewed and discussed by the SRC to jointly decide with the sponsor  if 
the escalation can proceed as planned. 
For each cohort, an SRC meeting will be held after the end of the third subject’s Cycle 1. If 
during that observation period (after the first administration) no DLT occurs and all three 
subjects can receive the full radioactivity level (RL) as planned for the respective cohort (i.e. all 
three subjects can receive the second administration), the next cohort can be started with the 
first administration of the first subject at the earliest 3 weeks after the third subject of the 
previous cohort has received the second administration. No more than two dose-escalation 
cohorts will be conducted in parallel (Figure 2). If a DLT occurs after the first administration 
in cohort n, cohort n+1 will only be started after the second SRC (2nd administration) of the 
cohort n. 
Due to the possible subtherapeutic activity of the lowest dose, the escalation decision to the 
planned dose of 4 GBq/cycle in Cohort 2 will be taken if only one subject from Cohort 1 has 
received the second administration without any safety problems at the end of the second cycle 
(i.e. at Cycle 2 Day 29, see Figure 2). 
Proceeding to the Second Administration in a Cohort 
For each cohort, a SRC meeting will be held after the end of the third subject’s Cycle 2 of the 
preceding cohort and before the second administration of the first subject in a cohort, (Figure 2) 
to review all available safety data and radiation exposure from previous cohort(s). The second 
radioactivity administration will be confirmed based on the rules described in Attachment 5, 
Section 19.5. 
Stopping Rules for Dose Escalation  
The MTCA is defined in Section 4.2.1.1. 
The radioactivity escalation will be stopped as soon as:  
• 
The MTCA and/or MTSA have been defined with good precision; or  
• 
The maximum planned radioactivity of 15 GBq, fractionated into two administrations 
separated by 4 weeks, is administered without safety concerns. 
Transition from Dose Escalation to Other Study Parts 


 
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Upon completion of the phase I dose escalation or upon reaching the MTCA and confirmed 
jointly by the SRC and the sponsor, and in consideration of the accumulated subject data, 
cohorts of subjects will be studied to further characterise the safety and efficacy of 
177Lu-3BP-227. In the case of acceptable tolerability and evident antitumour activity across all 
enrolled subjects in phase I, a phase II basket trial design will be utilised to study the antitumour 
activity of 177Lu-3BP-227 in subjects with NTSR1 expressing tumours. However, if the 
antitumour activity is driven by a certain type of tumour, tumour-specific phase II cohort(s) will 
be initiated utilising an Optimal Simon’s Two Stage design (see Section 4.3). 
4.2.2 
Dose Expansion 
If safety evaluation and dose schedules of 177Lu-3BP-227 cannot be fully explored during the 
phase I dose escalation part, a phase I expansion part will serve to accomplish this objective 
including, but not limited to, schedules of high loading doses followed by fractionated lower 
doses or evaluation of 177Lu-3BP-227 in combination with other antitumoral treatments (to be 
defined). The expansion part will also serve to clarify any uncertainties of antitumour responses. 
The number of cohorts and subjects will be determined based on emerging data from the dose 
escalation part and the modelling and simulation approach, and will be documented as part of 
a protocol amendment.  
4.3 
Phase II 
Phase II study will be conducted either with a basket design trial or indication-specific cohorts 
with an Optimal Simon’s Two Stage design, according to the scenarios described above. 
 
 
 
One, two or three further cohorts may be initiated (subject to results emerging 
from ongoing preclinical studies and antitumour efficacy seen during dose escalation and 
amending the current protocol) likely to enrol subjects with GC, ES and/or SCCHN. 
x The PDAC cohort will enrol approximately 55 subjects and will investigate whether 
177Lu-3BP-227 attains an ORR superior to a clinically accepted historical threshold of 
current standard-of-care treatment for subjects with unresectable, locally advanced or 
metastatic disease.  
x The CRC cohort will enrol approximately 70 subjects and will investigate whether 
177Lu-3BP-227 attains an ORR superior to a clinically accepted historical threshold of 
current standard-of-care for subjects with unresectable, locally advanced or metastatic 
disease.  
The current protocol will be amended at the end of the phase I to document the rationale of the 
phase II design. In any case, the cumulative activity administered during phase II will not 
exceed the MTCA determined during phase I. 
Sample size calculation for cohorts other than PDAC and CRC will be documented as part of a 
protocol amendment. 
4.4 
Study Endpoints 
4.4.1 
Primary Endpoint 
4.4.1.1 
Phase I 
For the dose escalation, the primary endpoint is MTCA or MACA, if the MTCA is not identified 
during the dose escalation part. The primary variables used for the MTCA determination will 
be the incidence of DLTs (as defined in Section 4.7.1.1) and the organ exposure to radiation 
during two cycles of treatment. The DLT period for the determination of the primary endpoint 
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starts at the first administration of 177Lu-3BP-227 to EOCT/ED. Safety evaluation will 
encompass DLTs, frequency and nature of AEs, abnormal findings from physical examination, 
vital signs, 12-lead electrocardiogram (ECG), 3-lead ECG Holter, Eastern Cooperative 
Oncology Group (ECOG) performance status deterioration, clinical laboratory tests (including 
haematology, blood biochemistry, hormone analysis, urinalysis and pregnancy test) and 
changes in specific renal safety biomarkers. 
In case the phase I dose expansion cohorts are implemented, the primary endpoint will be safety 
and tolerability measured by the type, severity, expectedness and frequency of AEs. 
4.4.1.2 
Phase II 
The primary endpoint is ORR measured by CT or MRI using RECIST version 1.1. Tumour 
response assessments are performed every 8 weeks or at the time of occurrence of first signs of 
clinical progression as determined by the investigator. 
4.4.2 
Secondary Endpoints 
4.4.2.1 
Phase I 
For biodistribution and dosimetry of 177Lu-3BP-227, the secondary endpoints are:  
• 
Maximal uptake (%), maximal concentration achieved (Cmax); time post injection to 
achieve maximal concentration (Tmax); AUC at the target lesions, discernible organs and 
blood; t1/2 of activity concentrations in blood; 
• 
Highest absorbed dose, specific absorbed dose to the target lesions (Gy/GBq), specific 
absorbed dose per organ (Gy/GBq) and cumulative absorbed organ doses (Gy). 
For PK of 3BP-227, the secondary endpoints are:  
• 
PK parameters including, but not limited to, Cmax, AUC, t1/2, CL, Vd, cumulative amount 
of unchanged drug excreted into the urine (Ae), renal clearance of the drug from plasma 
(CLR), as measured in plasma and urine at defined timepoints. 
For pharmacodynamics, the secondary endpoints are: 
• 
Objective response rate and DCR, as determined by RECIST version 1.1 in subjects who 
received IMP; 
• 
Progression-free survival (PFS) and OS rates as determined from start of study treatment 
until occurrence of event and/or end of observation period; 
• 
Evaluation of metabolic tumour response using PERCIST (version 1.0) or practical 
PERCIST; 
• 
Changes in serum tumour markers relevant and specific to the underlying tumour disease 
from baseline to EOCT, which is planned 6 weeks after the second 177Lu-3BP-227 dose 
administration. 
4.4.2.2 
Phase II 
The secondary endpoints are: 
• 
Disease control rate, time to progression (TTP), time to response (TTR), duration of 
response (DOR) as per RECIST version 1.1; 
• 
Qualitative and quantitative changes in tumour-to-background uptake using PERCIST 
version 1.0; 
• 
Progression-free survival (PFS) and OS as determined from start of study treatment until 
occurrence of event and/or 6 and 12 months after start of study treatment; 
• 
Changes in serum tumour markers relevant and specific to the underlying tumour disease 
from baseline to EOCT; 


 
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• 
Changes in health-related quality of life scores from baseline to EOCT measured by 
validated and disease-specific questionnaires; 
• 
Safety and tolerability measured by the type, severity, expectedness and frequency of 
AEs;  
• 
For PK, biodistribution and dosimetry, the endpoints will be similar as for phase I. 
4.4.3 
Exploratory Endpoints 
Exploratory endpoints are the same for phase I and II: 
• 
Tumour uptake of 177Lu-3BP-227 and the correlation with NTSR1 expression on tumour 
biopsies; 
• 
Tumour microenvironment and other markers of interest (such as NTSR1 expression, 
Ki67, gene expression and DNA damage) in tumour biopsies taken at baseline, at EOCT 
visit or at disease progression, whichever occurs earlier; 
• 
Genomic profiling in circulating cfDNA and in germline DNA;  
• 
Gene mutation status in correlation with clinical outcome; 
• 
Specific renal safety biomarkers specific for proximal tubulus toxicity. 
4.5 
Study Duration 
For phase I, the maximum duration of subject participation in the core trial is 21 weeks. 
However, if, according to the investigator, a subject has clinical benefit, the subject may receive 
up to four additional cycles after the EOCT, provided they have an acceptable tolerability 
profile and the organ dose limits are not exceeded. This is at the subject’s discretion and must 
be discussed and agreed upon with the sponsor. The clinical benefit will be defined as CR, PR 
or stable disease (SD) as per RECIST criteria version 1.1 or based on biochemical responses. 
For phase I dose expansion and phase II, the study duration will be refined in light of phase I 
results and recommended treatment regimen (doses and intervals). 
In all cases, a long-term follow-up period will start after the EOCT, ED or EOAC visit and 
subjects will be followed up every three months (±2 weeks) until lost to follow-up, withdrawal 
of consent, death or a maximum of 5 years, whichever occurs first. 
4.6 
Randomisation and Blinding 
4.6.1 
Method of Randomisation 
4.6.1.1 
Subject Unique Identifier 
At screening, potential subjects will be allocated an 11-digit subject number consisting of: 
• 
The country code (three digits); 
• 
The centre number (three digits); 
• 
The sequential order of entry of the subject at the centre (five digits). 
4.6.1.2 
Randomisation Number 
Not applicable for phase I, as this is not a randomised study. 
For the phase II, the protocol could be amended to include randomisation.  
4.6.2 
Blinding 
Not applicable, this is an open-label study. 
4.6.3 
Code-break 
Not applicable, this is not a blinded study. 


 
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4.7 
Discontinuation Rules 
4.7.1 
Individual Discontinuation Rules 
In accordance with the Declaration of Helsinki and the applicable country’s regulations, each 
subject is free to withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator at the institution. 
The investigator will be responsible for monitoring subject compliance. A subject can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 
The investigator has the right to withdraw a subject from the study in the event of concurrent 
illness, AEs, or other reasons concerning the health or well-being of the subject, or in the case 
of lack of cooperation. 
If any of the following occur, no further treatment will be administered: 
• 
life-threatening toxicities outside of the DLT reporting period 
• 
subject withdraws their consent to further treatment; 
• 
cumulative kidney dose exceeds 23 Gy; 
• 
cumulative bone marrow dose exceeds 2 Gy, as determined by dosimetry of peripheral 
blood samples and imaging; 
• 
cumulative liver dose exceeds 30 Gy; 
• 
occurrence of a DLT for phase I dose escalation only (see Section 4.7.1.1). 
All cases of discontinuation will be discussed between the investigator and the sponsor. 
4.7.1.1 
Definition of Dose Limiting Toxicity (Dose Escalation) 
The DLTs are defined for any of the following IMP-related AEs according to National Cancer 
Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale version 5.0 
[31], that occur during the defined DLT assessment period (from the first administration of 
177Lu-3BP-227 to EOCT/ED): 
• 
Grade 4 neutropenia for seven or more consecutive days; 
• 
Febrile neutropenia or neutropenic infection (defined as a documented infection with 
neutrophil count decreased Grade 3 or 4); 
• 
Grade 3 or 4 thrombocytopenia (platelet count decreased) with clinically meaningful 
bleeding (i.e. requiring urgent hospitalisation or transfusion to manage the bleeding); 
• 
Grade 4 thrombocytopenia for seven or more consecutive days; 
• 
Any Grade 3 anaemia (Hb<8.0 g/dL; transfusion indicated) or Grade 4 anaemia 
(life-threatening consequences; urgent intervention indicated); 
• 
Any Grade 3 or higher laboratory abnormalities on aspartate aminotransferase/alanine 
aminotransferase (AST/ALT) with accompanying Grade 2 or higher bilirubin (Hy’s law); 
• 
any Grade 3 or higher renal injury/toxicity (estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73 m2); 
• 
Any Grade 3 or higher GI AE, not resolved to Grade ≤2 within 48 hours despite optimal 
adequate medical management, with the following specifications: 
- 
Grade 3 nausea, vomiting (inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalisation indicated) 
- 
Grade 3 diarrhoea (increase of ≥7 stools per day over baseline; hospitalisation 
indicated; severe increase in ostomy output compared to baseline; limiting 
self-care activities of daily living (ADL)) or Grade 4 diarrhoea (life-threatening 
consequences; urgent intervention indicated) 


 
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- 
Grade 3 constipation (obstipation with manual evacuation indicated; limiting 
self-care ADL) or Grade 4 constipation (life-threatening consequences; urgent 
intervention indicated); 
• 
Any toxicity related to 177Lu-3BP-227 resulting in a treatment delay of more than four 
weeks due to either delayed recovery to baseline or resolution of any AE to Grade ≤2 
(with the exception of alopecia and lymphopenia). 
• 
Grade 5 toxicity (death) 
4.7.1.2 
Procedures for Subject Discontinuation 
For subjects who discontinue participation in the study before the planned completion of 
therapy, it is intended that full end of study (EOS) assessments (see Section ) will be performed 
and the subjects will be followed-up for AEs until the event or its sequelae resolve or stabilise 
at a level acceptable to the investigator and the sponsor’s clinical monitor or his/her designated 
representative (see Section 8). If a subject drops out or is discontinued from the study after IMP 
administration and before planned study completion (either during the Core Trial period or if 
the subject is receiving additional treatment cycles), an ED visit will take place within 14 days 
after ED. The investigator determines this timepoint taking into account the expected safety 
profile and the current clinical status of the subject. This visit will correspond to an EOCT visit 
(or EOAC visit if the subject dropout during additional cycles). Thereafter, follow-up for 
survival information will take place every three months. For those subjects with ED, every 
effort should be made to perform a safety follow-up at the latest 5 weeks after the last IMP 
administration.  
The reason for and date of withdrawal from the study must be recorded in the electronic case 
report form (eCRF).  
If the discontinuation is based on subject decision, every attempt will be made to determine: 
• 
The reason for discontinuation; 
• 
Whether the subjects also decided to withdraw consent for the sponsor to collect and use 
the data collected up to the discontinuation point. 
Data collected prior to subject discontinuation may be kept in study records and shared with the 
sponsor for study analyses (see Section 13), unless a subject formally specifies their decision 
to withdraw consent for the use of data collected before discontinuation. 
Subjects withdrawn from the study for unacceptable AE(s) will be followed until resolution or 
stabilisation of the AEs. 
4.7.1.3 
Replacement Rules 
In phase I, a cohort will be considered as completed once three subjects of the cohort complete 
Cycle 2 or discontinue early during Cycle 2 (except for Cohort 1). Except for Cohort 1, if 
subjects discontinue for any reason other than a DLT (e.g. disease progression) before end of 
Cycle 2, they may be replaced. 
4.7.2 
Discontinuation of a Cohort or a Site or Study Termination 
A specific site or a given cohort can be discontinued or the complete study terminated 
prematurely at any time, if the sponsor judges it necessary for any reason. In that case, all 
scheduled procedures and assessments for subjects who are still in the study will be performed. 
Some possible reasons for the closure of a study site may include: 
• 
failure of the investigator staff to comply with the protocol or with the GCP guidelines. 
• 
safety concerns 
• 
inadequate subject recruitment. 


 
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In case of premature discontinuation of a site or complete study termination, the sponsor will 
notify the impacted investigator(s) in writing, depending on the reason(s) for discontinuation, 
whether the ongoing subjects should undergo the remaining IMP dose administration(s). 


 
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5 
SELECTION OF SUBJECTS 
5.1 
Inclusion Criteria 
5.1.1 
Phase I 
Eligible subjects must fulfil all the following inclusion criteria: 
(1) 
Signed informed consent form prior to all study procedures. 
(2) 
Aged 18 years or older. 
(3) 
Histologically or cytologically confirmed unresectable, locally advanced or metastatic 
disease and has received prior lines of standard-of-care chemotherapy/treatment and has 
no further suitable treatment options and a documented decision by a multidisciplinary 
oncology board including a specialist of the concerned pathology. 
(4) 
Subjects have: 
(a) 
PDAC, or 
(b) 
CRC (colorectal adenocarcinoma), or 
(c) 
GC (gastric adenocarcinoma), or  
(d) 
Gastrointestinal stromal tumours (GIST), or 
(e) 
SCCHN, or 
(f) 
ES. 
(5) 
Tumours showing: 
(a) 
uptake of 177Lu-3BP-227 (screening formulation) in known primary or metastatic 
sites as judged by the investigator to be greater than background; or 
(b) 
uptake of 111In-3BP-227 in known primary or metastatic sites (for subjects who 
participated in Study D-FR-01087-002) as judged by the investigator to be greater 
than background. 
(6) 
Measurable disease (based on RECIST version 1.1).  
(7) 
Criterion 7 is removed by protocol amendment. 
(8) 
Documentation of progressive disease in the 6 months prior to study start (treatment). 
(9) 
Eastern Cooperative Oncology Group performance status of 0 or 1 (unless disability is 
related to surgery in ES and agreed by the sponsor). 
(10) Adequate organ function as evidenced by: 
(a) 
Leukocytes ≥3000/μL 
(b) 
Absolute neutrophil count ≥1500/μL 
(c) 
Platelets ≥75,000/μL 
(d) 
Hb >9 g/dL or >10 g/dL (if history of cardiac disease) 
(e) 
Total serum bilirubin ≤2 times upper normal institutional limits (ULN) 
(f) 
AST/ALT ≤2.5×ULN (or ≤5×ULN, if subject has liver metastases) 
(g) 
eGFR ≥55 mL/min. 
(11) Estimated life expectancy of >3 months. 
(12) Female subjects must not be pregnant or lactating at study entry and during the course of 
the study and must not become pregnant for at least 6 months following the last study 
treatment. Women of childbearing potential must agree to use a highly effective method 
of contraception (see note below).  
(13) Male subjects must not father children during the study and for at least 6 months after 
the last study treatment and in addition must agree to use a condom for this period to 


 
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protect his partner from contamination with the IMP. For males with partners who are of 
child bearing potential, effective contraception is a combination of male condom with 
either cap, diaphragm or sponge with spermicide (double barrier methods), but these are 
not considered to be highly effective. A man is considered to be infertile if he has had 
bilateral orchidectomy or successful vasectomy. Effective contraception includes a 
female partner of childbearing potential if she is using highly efficacious contraception 
(see note below), but the male subject must agree to use a condom to protect his partner 
as described above. 
(14) Must be willing and able to comply with study restrictions and to remain at the clinic for 
the required time during the study period and willing to return to the clinic for the 
follow-up evaluation, as specified in the protocol. 
Note: Highly effective methods of contraception that result in a low failure rate (i.e., <1% per 
year) when used consistently and correctly include combined (oestrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, 
or transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation 
(oral, 
injectable, 
or 
implantable), 
intrauterine 
device, 
intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner (the vasectomised 
partner has received medical assessment of the surgical success at least 6 months prior to the 
first study treatment and provided that partner is the sole sexual partner of the female subject 
of childbearing potential trial participant), or sexual abstinence; 
True abstinence, when in line with the preferred and usual lifestyle of the subject, is considered 
a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of study treatment and for 6 months after the last dose of 177Lu-3BP-227. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, and post-ovulation method) and withdrawal are not acceptable 
methods of contraception; 
Female subject is considered of childbearing potential i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 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. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
For male subjects, acceptable methods of effective contraception include sexual abstinence, 
successful vasectomy, bilateral orchidectomy and barrier methods (i.e. condom). In addition, 
male subjects should not donate sperm and female subjects should not donate eggs for at least 
2 years after the last study treatment). 
5.1.2 
Phase II  
The inclusion criteria for phase II will be revised based on the scenario adopted and 
indication(s) selected for investigation in phase II. This will be documented as part of a protocol 
amendment. 
5.2 
Exclusion Criteria (Phase I/II) 
Eligible subjects must not have any of the following: 
(1) 
Prior treatment received: 
(a) 
Any antitumour treatment since last documented disease progression 


 
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(b) 
Any chemotherapy within 3 weeks or nitrosourea within 6 weeks prior to first 
treatment IMP administration  
(c) 
Any curative radiotherapy within 4 weeks, or palliative radiotherapy within 7 days 
prior to first treatment IMP administration 
(d) 
Any monoclonal antibodies within 4 weeks or tyrosine kinases inhibitors within 
2 weeks prior to the first treatment IMP administration 
(e) 
Any other IMP within 2 weeks prior to first treatment IMP administration, if the 
previous compound is a mechanism-based molecularly targeted agent whose t1/2 
is not well-characterised. 
(2) 
Brain metastases. 
(3) 
Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject 
at high risk of renal toxicity during the study. 
(4) 
Only nonmeasurable metastatic bone lesions. 
(5) 
Existing or planned colostomy during study participation. 
(6) 
Any history of inflammatory bowel disease. 
(7) 
Any uncontrolled significant medical, psychiatric or surgical condition or laboratory 
finding, that would pose a risk to subject safety or interfere with study participation or 
interpretation of individual subject results. 
(8) 
Clinically significant abnormalities on ECG at screening including corrected QT 
interval (Fridericia's formula) >450 msec for males or 470 msec for females at 
screening. 
(9) 
Previously received external beam irradiation to a field that includes more than 30% of 
the bone marrow or kidneys. 
(10) Criterion 10 is removed by protocol amendment. 
(11) Any unresolved NCI-CTCAE Grade 2 or higher toxicity (except alopecia) from 
previous antitumour treatment and/or medical/surgical procedures/interventions. 
(12) Known allergy to IMP or its excipients administered in this study, including imaging 
contrast media. 
(13) Positive pregnancy test (female subjects). 
(14) Likely to be uncompliant or uncooperative during the study, in the judgment of the 
investigator. 
(15) Unable to understand the nature, scope and possible consequences of the study, in the 
judgment of the investigator. 
(16) Sponsor employees or investigator site personnel directly affiliated with this study, and 
their immediate families. Immediate family is defined as a spouse, parent, child or 
sibling, whether biological or legally adopted. 
Eligibility criteria for phase II will be reviewed as soon as phase I results are available. 
5.3 
Rationale for Specific Inclusion/Exclusion Criteria 
Not applicable 


 
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6 
STUDY CONDUCT 
6.1 
Study Schedule of Assessments 
The schedule of procedures and assessments is summarised and presented in Attachment 1 
Section 19.1, related to the dose escalation part of the phase I. The total volume of blood to be 
drawn for each subject is detailed in Attachment 2, Section 19.2. 
In the eventuality of phase I expansion cohorts and for phase II, the schedule of assessment will 
be adapted based on phase I results and documented through a protocol amendment. 
6.2 
Study Visits and Procedures 
All screened subjects must be identifiable throughout the study. The investigator will maintain 
a list of all subjects screened, with subject numbers and names, to enable records to be found at 
a later date, if required. Records should be completed up to the time of premature termination 
or normal study completion. In the event that a subject is a screen failure or does not receive 
study treatment, the primary reason will be recorded. Subjects may be re-screened after 
discussion and agreement with the sponsor. The conditions for re-screening include 
re-assessment of inclusion criteria (6) and (10) at a later time point. 
If the COVID-19 pandemic prevents subjects from coming to the site, subjects can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor before being implemented. In such a case, the investigator will 
perform a telemedicine visit and will make every effort, where applicable, to contact the 
subject’s general practitioner or specialist physician to ensure all important medical information 
and safety event(s) occurring since the last visit are collected. Guidance on how to collect 
protocol-planned assessments will be provided to the investigator in a separate document. This 
document will be filed in the electronic trial master file. Independent ethics committees 
(IECs)/institutional review boards (IRBs) will be notified of the changes as applicable locally. 
Of note, as the adapted visit deviates from the regular protocol plan, the changes will be 
recorded as protocol deviations related to COVID-19. 
6.2.1 
Screening 
Subjects will attend the clinical unit for an outpatient visit following which they will enter a 
screening period of 3 weeks prior to the first treatment administration. The screening period 
can be extended by up to two weeks if this is required for logistical reasons and agreed with the 
sponsor. 
The screening IMP will be administered minimum 1 week prior to Day 1 after all other required 
screening assessments have been completed. 
Subjects may be hospitalised for 24 hours following the screening IMP administration at the 
discretion of the investigator.  
6.2.1.1 
Informed Consent 
After a subject has received explanations and response(s) to their potential questions about the 
study by the investigator (or designee) and has been given reasonable time to consider study 
participation, a signed and dated informed consent form will be obtained prior to any study 
procedures. 
Subjects will be offered to participate to an optional research biobanking program. Subjects 
who agree to participate will be requested to sign a separate informed consent form. 
6.2.1.2 
Screening Procedures 
After informed consent is obtained, screened subjects will be allocated a study-specific subject 
number, which must comply with formatting specifications provided by the sponsor (see 
Section 4.6.1.1). 


 
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During this initial screening visit, and subsequent ones, screening tests and assessments will be 
performed to check compliance with inclusion/exclusion criteria and study requirements in 
order to confirm subjects’ eligibility prior to enrolment. 
The screening procedures/evaluations detailed in Attachment 1, Section 19.1 will be performed 
during one or several outpatient visits. 
The baseline assessment is the assessment done closest to Day 1 of the treatment administration 
(e.g. haematology and biochemistry, see Attachment 1 Section 19.1).  
Evaluations obtained as part of routine medical care or previous assessments performed during 
(or before) the screening period may be used in place of the study specific evaluations. Subjects 
will acknowledge and agree to the possible use of this information for the study by giving 
informed consent. 
For subjects who received the screening IMP administration and found ineligible to participate 
in the study, a physical examination, vital sign monitoring and clinical laboratory test 
assessment (as described in Attachment 3 Section 19.3) will be performed before discharge. 
Additionally, a safety follow-up visit or contact, whichever is feasible, will be performed within 
5 weeks (+2 weeks) after the IMP screening administration to assess the safety (see Table 7). 
At least, clinical laboratory tests (e.g. haematology and biochemistry, as described in 
Attachment 3 Section 19.3), AEs and concomitant medication/therapy will be collected. If an 
on-site visit is not feasible, the visit may be performed by phone call. The clinical laboratory 
tests may be done locally. 
6.2.2 
Treatment Period and Additional Cycles for Phase I Dose Escalation 
The visit descriptions in this section are relative to the phase I dose escalation part of the study. 
In case of phase I dose expansion and for phase II, these visits and timepoints will be amended 
in light of the phase I results. 
After each administration of IMP/177Lu-3BP-227, subjects may be hospitalised for at least 
24 hours for observation at the investigator’s discretion. Afterwards, subjects can be discharged 
when the radioactivity reaches an acceptable level as per local regulation. The subjects must 
return to the study centre for further evaluations per the schedule of assessment.  All other visits 
will be outpatient. Subjects are to be observed on study and if the disease comes under control 
are to be kept on study; if the disease does not appear to come under control, the subject is to 
be removed from study and treated as clinically indicated. 
6.2.2.1 
Early Discontinuation or End of Core Trial Visit 
Subjects who complete the core trial, i.e. subjects who receive two treatment administrations 
and who continue the study until 6 weeks after the second dose administration, will be 
considered as having completed the study. 
Subjects who discontinue the study prior to the EOCT visit are considered as early discontinued 
subjects. The assessments required at the ED visit are the same as the assessments required at 
the EOCT visit.  
Subjects with ongoing AEs or clinically significant laboratory test abnormalities (as determined 
by the investigator) will be monitored by the investigator as described in Section 4.7.1. 
6.2.2.2 
End of Additional Cycles 
If, according to the investigator, a subject has clinical benefit, the subject may receive up to 
four additional cycles after the EOCT, provided they have an acceptable tolerability profile and 
the organ dose limits are not exceeded. This is at the subject’s discretion and must be discussed 
and agreed upon with the sponsor. For these subjects, an EOAC visit will be done 6 weeks after 
last dose administration. 


 
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6.2.2.3 
End of Study 
End of study (EOS) is defined as the last visit or last scheduled procedure shown in the Schedule 
of Assessment for the last active subject in the study. 
6.2.3 
Long-term Follow-up 
For both phase I and phase II, a long-term follow-up period will start after the EOCT, ED or 
EOAC visit and subjects will be followed up every 3 months (±2 weeks) until lost to follow-up, 
withdrawal of consent, death or a maximum of 5 years, whichever occurs first. During this 
period, if subjects do not receive any other chemotherapy or radiotherapy, they will be followed 
for the antitumour effect and long-term safety of the IMP. Otherwise, subjects will be followed 
for antitumour effect up to the administration of any other chemotherapy or radiotherapy and 
for the safety aspects (in particular for haematological and renal safety) for the remainder of the 
long-term follow-up period. 
Five Years After the EOCT, ED or EOAC Visit  
In the long-term follow-up period, subjects will be followed up every 3 months (±2 weeks) until 
lost to follow-up, withdrawal of consent, death or a maximum of 5 years, whichever occurs 
first. The following safety assessments will be performed by the site: these assessments can be 
performed on-site or by remote visit: 
• 
Survival status 
• 
Haematology and biochemistry tests (haemoglobin, platelet count, white blood cell count 
(absolute counts), AST, ALT, total bilirubin (with conjugated bilirubin if total bilirubin 
is abnormal i.e. outside the laboratory normal range), creatinine and urea) performed 
until the start of new antitumour treatment or up to 2 years after the EOCT, ED or EOAC 
visit, whichever comes first. Laboratory tests can be performed locally; results should be 
collected from the local laboratory. 
• 
All AEs and serious adverse events (SAEs) are to be reported up to 6 months after the 
EOCT, ED or EOAC visit or until new antitumour treatment starts, whichever comes 
first. Thereafter, only AEs and SAEs related to the IMP or study procedure should be 
reported for the remainder of the safety follow-up period. 
• 
Subsequent antitumour treatment  
All collected data will be recorded in the eCRF. 
6.2.4 
Unscheduled Visits 
Unscheduled visits or assessments may be necessary at any point during the treatment period 
to assess individual safety or tolerability. For example, laboratory assessments should be 
performed as clinically indicated during the study, tumour assessment could be performed 
whenever disease progression is suspected. Should an unscheduled visit or procedure listed in 
the schedule of assessment be performed during the study, the data will be recorded in the 
eCRF. 
6.3 
Study Restrictions 
6.3.1 
Concomitant Medications 
The IMP excretion is partially hepatic; it is at the investigator’s discretion to treat subjects with 
laxatives to accelerate excretion from the intestine. 
Any antitumour treatment other than the IMP is prohibited from screening to 6 weeks after the 
last dose administration. All antitumour treatments given prior the first IMP dosing should be 
recorded in the eCRF. Dose, trade name, number of cycle and duration of treatment will be 
recorded as well. 


 
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Any prior or concomitant medication or therapy given to a subject either 30 days prior to dosing 
either within five half-lives of the previous product (if longer than 30 days) and during the study 
will be indicated in the eCRF. Dose, trade name and duration of treatment will be recorded. 
Hormone substitution or therapies impacting one of the respective pituitary axis should be listed 
in the concomitant medications. 
The potential of 177Lu-3BP-227 to be associated with drug-drug interactions has not been 
established. It is anticipated that the major route of excretion will be via the kidneys and so 
medications which might affect renal function should be avoided or used with due caution as 
assessed by the investigator. These medications include but are not limited to the following. 
Drugs causing prerenal damage: 
• 
Drugs that cause excessive gastrointestinal losses, either through diarrhoea or vomiting, 
also cause volume depletion and may precipitate acute kidney injury (AKI). 
• 
Nonsteroidal anti-inflammatory drugs (NSAIDs), even in short courses, can cause AKI 
as a result of renal underperfusion. 
• 
Angiotensin-converting enzyme (ACE) inhibitors can also cause a deterioration in renal 
function. However, this is a problem only in patients with compromised renal perfusion, 
particularly those with renal artery stenosis. 
• 
Care should be taken when an ACE inhibitor and NSAID are prescribed together, as this 
combination may precipitate an acute deterioration in renal function. 
Drugs causing intrarenal damage: 
• 
Intrarenal damage may result in a direct toxic effect on the kidneys or hypersensitivity 
reactions. 
• 
Most drugs that cause damage within the kidneys do so as a result of hypersensitivity 
reactions, which involve either glomerular or interstitial damage. 
• 
Drugs that have been reported to cause glomerulonephritis include penicillamine, gold, 
captopril, phenytoin and some antibiotics, including penicillins, sulfonamides and 
rifampicin. 
• 
Drugs that may cause interstitial nephritis include penicillins, cephalosporins, 
sulfonamides, thiazide diuretics, furosemide, NSAIDs and rifampicin. 
• 
There are a number of drugs that cause direct toxicity to the renal tubules (acute tubular 
necrosis) – e.g. aminoglycosides, amphotericin and ciclosporin. 
Drugs causing postrenal damage (urinary tract obstruction): 
• 
High-dose sulfonamides, acetazolamide or methotrexate may cause crystalluria and 
could therefore cause urinary tract obstruction. 
• 
Anticholinergics (e.g. tricyclic antidepressants), and alcohol may cause urinary tract 
obstruction due to retention of urine in the bladder. 
Other nephrotoxic drugs: 
• 
Cephalosporins: cephaloridine, one of the first cephalosporins introduced, has been 
associated with direct renal toxicity and is no longer in clinical use. Other cephalosporins 
are much less likely to produce renal damage but third-generation cephalosporins (e.g. 
cefixime) have (very rarely) been reported to cause nephrotoxicity. 
• 
Analgesics:  
- 
NSAIDs may cause AKI due to hypoperfusion and interstitial nephritis, as well as 
analgesic nephropathy (chronic interstitial nephritis and papillary necrosis). 
- 
Analgesic nephropathy has been most commonly seen with combination analgesic 
products that contain aspirin and/or paracetamol. 


 
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- 
Analgesic nephropathy is one of the few preventable causes of chronic kidney 
disease. Discontinuation of the drugs often results in stabilisation or even 
improvement in renal function, but continued use leads to further renal damage. 
• 
Lithium: serum levels of lithium consistently above the therapeutic range have been 
associated with development of nephrogenic diabetes insipidus. 
Any further antitumour treatment for the disease under study that may have been taken during 
the long-term follow-up period should be reported on the prior and concomitant medications 
page of the eCRF. 


 
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7 
STUDY TREATMENT 
7.1 
Investigational Medicinal Product 
7.1.1 
Dosage Form and Strength 
3BP-227 (also called IPN01087) is a DOTA-conjugate of a NTSR1 antagonist, with a 
 
 
The radiolabelled IMP, 177Lu-3BP-227, is intended to be manufactured in two ways either 
decentralized at local radiopharmacies or centralized by a central manufacturing organisation. 
For all screening and treatment formulations of the IMP, the specific activity of 177Lu-3BP-227 
stays constant at 25 Pg 3BP-227 per 1 GBq 177Lu at time of infusion. 
One vial can contain up to 17.5 GBq of 177Lu-3BP-227 at the end of manufacturing, this amount 
takes into account decay to ensure the administration of the highest planned activity of 7.5 GBq 
of 177Lu-3BP-227 from the vial. 
7.1.1.1 
Decentralized Supply Dosage Form and Strength 
The 3BP-227 is radiolabelled with 177Lu at a specific ratio, time and temperature. The screening 
and treatment IMP are in a solution of ethanol and normal saline containing 
DiethyleneTriaminePentaAcetate (DTPA) and ascorbic acid to complex free 177Lu and to 
protect the drug product from radiolysis, respectively. The IMP consists of a sterile clear 
solution, free from visible particles, filled in 27-mL Type I borosilicate glass vials closed with 
a chlorobutyl rubber stopper and crimped with aluminium seal. 
7.1.1.2 
Centralized Supply Dosage Form and Strength 
The 3BP-227 is radiolabelled with 177Lu at a specific ratio, time and temperature. The screening 
and treatment IMP are formulated in a solution of sterile water for injection containing 
DiethyleneTriaminePentaAcetate (DTPA) to complex free 177Lu and ascorbate buffer to protect 
the drug product from radiolysis and to extend the shelf life. The IMP consists of a sterile clear 
to slightly yellow solution, free of suspended particles, filled in 25 mL Type I borosilicate glass 
vials, closed with a chlorobutyl rubber stopper and crimped with aluminium seal. 
7.1.2 
Supplies, Packaging and Labelling 
For some qualified sites, the IMP will be produced and supplied by the local radiopharmacy 
with a batch number, a date and time of expiry and a certificate of analysis. 
For the other sites, the IMP will be produced and supplied by a central manufacturing 
organisation with batch number, expiry date and time and certificate of analysis. 
The IMP will be packaged in a primary Type I borosilicate glass vial and a secondary 
lead/tungsten containment for shielding, labelled according to applicable regulations, 
requirements and national laws in force. 
7.1.3 
Storage 
The investigator, or an approved representative (e.g. pharmacist), will ensure that the IMP is 
maintained all the time in a dedicated, adequate shielding container and stored in a secured area, 
under recommended temperature monitored storage conditions. 
In case of decentralized manufacturing by the local radiopharmacy, the IMP should be stored 
at ambient temperatures. 
In case of manufacturing by the central manufacturing organisation, the IMP should be stored 
between +2°C and +8°C. 
Since the IMP shelf life will vary depending on the mode of manufacturing (decentralised or 
centralised) and potentially on supporting data generated during the conduct of the study, the 
exact shelf life is indicated on the IMP label. 
CCI


 
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7.1.4 
Preparation, Dispensing and Administration Procedures 
All IMP provided to the site pharmacist will be allocated and dispensed by appropriately trained 
staff. IMP will be administered under medical supervision. 
Specific preparation/reconstitution instructions, if applicable, will be specified in a separate 
document. 
7.1.4.1 
Route of Administration 
The screening IMP formulation consists of 1 GBq of 177 Lu-3BP-227 in a total volume of 10 mL 
that will be administered by i.v. infusion over 10 minutes. 
The treatment IMP formulation consists of a 2.5 to 10 GBq of 177 Lu-3BP-227 in a total volume 
of 20 mL that will be administered by i.v. infusion over 20 minutes. 
If infusion reactions are observed, the infusion rate should be slowed to around 30 minutes or 
stopped if the reaction is severe. 
In both cases, a 100 mL saline solution will be administered concomitantly, over a period of 
30 minutes and starting at the same time as the IMP administration. The same venous access 
will be used for IMP and saline solution. Infusion should be done in the contralateral arm of the 
PK sampling. 
7.1.4.2 
Dosing Regimen in Phase I 
The total radioactivity amount per cohort will be fractionated into two administrations separated 
by 4 weeks. Each separate dose will be instantly prepared prior to infusion. 
The absorbed organ doses, especially the doses to kidney, bone marrow and liver as a limiting 
organ, will be analysed after each treatment cycle so that the following administrations can be 
adapted and to not exceed cumulative absorbed organ dose limits. 
The subject will be instructed to drink water (at least 1.5 L/24 hours) on the days following 
each IMP administration. 
7.1.4.3 
Dosing Regimen in Phase II 
The dose regimen in phase II will determined based on the data collected from the dose 
escalation part and will not exceed the MTCA. 
7.1.5 
Accountability 
The investigator should ensure adequate records (allocation, disposition, shipment, dispensing 
and returned drugs) are maintained in an IMP accountability log. 
Unused IMP will be destroyed on site per local destruction procedure after approval of the 
sponsor. 
7.1.6 
Spillage 
All due precautions and site procedures should be implemented to prevent spillage or leakage 
of radiodiagnostics or radiotherapeutics. Infusion bags, i.v. lines and venous access should all 
be secured, and the connections thoroughly checked. The infusion line should be taped in a loop 
and taped to the subject to prevent direct tension between the line and the venous access. 
Despite precautions, if spillage or leakage should occur, then the site procedures must be 
implemented to protect the subject, staff and members of the public from radiation exposure. 
The subject should be moved from the area of the spillage or leakage while the area is 
decontaminated. Details of the spillage or leakage should be recorded (including how the 
incident happened, the time of the incident, an estimate (if possible) of the amount of substance 
lost) and the measures taken. In addition, the incident is to be reported in the same manner as 
an adverse event using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
Preferred Term ‘Product Leakage’ and as appropriate Preferred Term ‘Occupational exposure 


 
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to radiation’ (if there is exposure to staff) and Preferred Term ‘Exposure to radiation’ (if there 
is exposure to the subject or members of the public). 
7.2 
Product Complaints 
The sponsor collects product complaints on study drugs used in clinical trials to ensure the 
safety of study participants, monitor quality and facilitate process and product improvements. 
The investigator is responsible for handling the following aspects of the product complaint 
process in accordance with the instructions provided for this study: 
• 
Recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose. 
• 
Faxing the completed product complaint form within 24 hours to the sponsor or designee. 
If the investigator is asked to return the product for investigation, they should return a copy of 
the product complaint form with the product. 


 
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8 
SAFETY ASSESSMENTS 
The following safety parameters will be collected and reviewed:  
• 
DLTS (phase I dose escalation only, for definition see Section 4.7.1.1) 
• 
AEs 
• 
physical examination  
• 
vital signs 
• 
12-lead ECG 
• 
24-hour 3-lead Holter ECG (phase I dose escalation only) 
• 
ECOG performance status 
• 
clinical laboratory tests including haematology, blood biochemistry, hormone analysis,  
urinalysis and pregnancy test 
• 
specific renal safety biomarker. 
The timepoints referenced in the study schedule of assessments in Attachment 1, Section 19.1 
refer to the phase I dose escalation part of the study. In case of dose expansion cohorts and for 
phase II, these timepoints will be revised based on the dose escalation safety data and 
documented through a protocol amendment. 
Further routine medical assessments or any additional safety procedures may be performed 
during the study, if warranted and after mutual agreement by the sponsor and the investigator, 
or when clinically indicated. 
Any clinically significant finding that results in a diagnosis should be recorded as an AE from 
the time informed consent is given. 
The investigator will be responsible for a clinical assessment of the study participants during 
the whole participation of the subjects in the study, from informed consent up to discharge from 
the study, and for the set-up of a discharge plan if needed. 
Every effort should be made to ensure that all safety evaluations are completed by the same 
individual who made the initial baseline determination. 
The sponsor’s medical monitor and the Global Patient Safety (GPS) physician will monitor 
safety data throughout the course of the study. 
8.1 
Adverse Events 
Monitoring of AEs will be done from the time that a subject gives informed consent and 
throughout the study and will be elicited by direct, nonleading questioning or by spontaneous 
reports. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g. nausea, chest pain), signs 
(e.g. tachycardia, enlarged liver) or the abnormal results of an investigation (e.g. laboratory 
findings, ECG). 
An AE can include an undesirable medical condition occurring at any time, even if no IMP has 
been administered. All AEs, irrespective of causality, are to be reported to the sponsor up to 
6 months after the EOCT, ED or EOAC visit or until new antitumour treatment starts, 
whichever comes first. After this timepoint, up to the end of the 5-year follow-up period, AEs 
should only be reported if the event is evaluated as related to the IMP or study procedure by the 
investigator. 


 
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This definition includes events occurring from the time of the subject giving informed consent 
until the EOS (last visit in the long term follow-up period)/ED. 
Natural disease progression or deterioration of the malignancy treated in the study will be 
recorded as part of the efficacy evaluation. The signs and symptoms of disease progression will 
be documented as part of the radiological or clinical progression. Events that cannot be 
differentiated from progressive disease (PD) should be captured as AE/SAEs. Death due to 
disease progression should be reported as an SAE irrespective of causality if reported during 
the study period and up to 6 months after the end of the cycle of the last dose of study drug. 
Serious adverse events including death/fatal outcome will be reported to sponsor if evaluated 
as related to study treatment or procedure up to the protocol defined follow-up period and EOS.  
8.1.2 
Adverse Events Categorisation, Recording, and Follow-up 
For all AEs, sufficient information should be obtained by the investigator to determine the 
causality of the AE (i.e. IMP administration, study procedure or other illness). The investigator 
is required to assess causality and record that assessment in the eCRF. 
All AEs, including SAEs, are to be accurately recorded on the AE page of the subject’s eCRF.  
Each event will be graded for severity using the classifications of NCI-CTCAE version 5.0 [31]. 
For events not addressed in the NCI-CTCAE version 5.0 classifications, the following grading 
will apply: 
• 
Mild (Grade 1): Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• 
Moderate (Grade 2): Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL. 
• 
Severe (Grade 3): Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting selfcare 
ADL. 
• 
Life-threatening (Grade 4): Life-threatening consequences; urgent intervention 
indicated. 
• 
Death (Grade 5): Death related to AE. 
The relationship of an AE to IMP administration will be classified by the investigator according 
to the following: 
• 
Related: Reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose-response relationship, pharmacology) to assume a causal relationship 
with IMP administration in the sense that it is plausible, conceivable or likely. 
• 
Not related: Reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with IMP administration. 
8.1.2.1 
Assessment of Expectedness 
The expectedness of an AE shall be determined by the sponsor according to the current 
approved version of the IB. 
8.1.2.2 
Follow-up of Adverse Events 
Any AEs already recorded and designated as “continuing” should be reviewed at each 
subsequent assessment. 
If an AE is still present at the end of the study, reasonable follow-up clinical monitoring should 
be managed by the investigator or any appropriate physician until the event or its sequelae 
resolves or stabilises at an acceptable level, as judged by the investigator and the sponsor’s 


 
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medical monitor or his/her designated representative. The frequency of follow-up evaluation is 
left to the investigator’s discretion. 
8.1.2.3 
Reporting of Adverse Events 
Any AEs/SAEs, irrespective of causality, are to be reported to the sponsor up to 6 months after 
the EOCT, ED or EOAC visit or until new antitumour treatment starts, whichever comes first. 
After this timepoint, up to the end of the 5-year follow-up period, AEs/SAEs should only be 
reported if the event is evaluated as related to the IMP or study procedure by the investigator.  
Any AE considered related to IMP administration that the investigator becomes aware of after 
completion of the EOS/ED visit must be reported to the sponsor and will be recorded in the 
eCRF. EOS for AE reporting is defined as the end of the 5-year follow-up or death. 
8.1.3 
Serious Adverse Event Assessment and Reporting to Sponsor 
The investigator must pursue and obtain information adequate both to determine the outcome 
of the AE and to assess whether it meets criteria for classification as an SAE requiring 
immediate notification to the GPS department of the sponsor. 
An SAE is any AE that: 
• 
Results in death; 
• 
Is life-threatening; that is, any event that places the subject at immediate risk of death 
from the event as it occurs. It does not include an event that, had it occurred in a more 
severe form, might have caused death; 
• 
Results in inpatient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons: 
- 
Hospitalisation is defined as any inpatient admission (even if less than 24 hours). 
For chronic or long-term inpatients, inpatient admission also includes transfer 
within the hospital to an acute/intensive care inpatient unit. 
- 
Prolongation of hospitalisation is defined as any extension of an inpatient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for the initial admission, as determined by the investigator or treating 
physician. For protocol-specified hospitalisation in clinical studies, prolongation 
is defined as any extension beyond the length of stay described in the protocol. 
Prolongation in the absence of a precipitating, treatment emergent, clinical AE 
(i.e. not associated with the development of a new AE or worsening of a 
pre-existing condition) may meet criteria for “seriousness” but is not an adverse 
experience and thus is not subject to immediate reporting to the sponsor. 
- 
Preplanned or elective treatments/surgical procedures should be noted in the 
subject’s screening documentation. Hospitalisation for a preplanned or elective 
treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae which meet the criteria for seriousness described above. 
• 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions; 
• 
Results in a congenital anomaly/birth defect in the offspring of a subject who received 
the IMP; 
• 
Is an important medical event that may not result in death, be life-threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 


 
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convulsions that do not result in inpatient hospitalisation, or the development of drug 
dependency or drug abuse. 
In addition to the above criteria, any additional AE that the sponsor or an investigator considers 
serious should be immediately reported to the sponsor. This includes any suspected or 
confirmed coronavirus COVID-19 (SARS-CoV-2) infection (seriousness criteria should be 
“other medically significant” if no other seriousness criteria are present (e.g. hospitalisation)). 
In case of suspected or confirmed COVID-19 infection, the IMP administration may be 
temporarily discontinued depending on the subject’s clinical presentation. In some cases, the 
investigator may request a subject be retested before the IMP administration is resumed. 
All SAEs, regardless of treatment group or suspected relationship to IMP, must be reported 
immediately (within 24 hours of the investigator’s knowledge of the event) to the sponsor’s 
pharmacovigilance contact using the contact details specified on the front page of the current 
document. 
Email is the preferred method of SAE notification. If email is not available, facsimile 
transmission is the alternative method. In rare circumstances and in the absence of facsimile 
equipment, notification by telephone is acceptable. If the immediate report is submitted by 
telephone, this must be followed by a detailed written report using the SAE report form. 
The following information is the minimum that must be provided to the sponsor’s 
pharmacovigilance contact: 
• 
study number 
• 
investigational site identification 
• 
subject number 
• 
AE 
• 
investigator’s name and contact details. 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. Upon receipt of the initial report, the sponsor 
will ask for the investigator’s causality assessment, if it was not provided with the initial report. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to distinguish a primary AE considered the foremost 
untoward medical occurrence, from secondary AEs that occurred as complications. 
8.1.4 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the current approved IB and that the investigator identifies as related to the IMP or procedure. 
8.1.5 
Pregnancy 
Information regarding pregnancies occurring during the study must be collected and reported 
to the sponsor as SAEs. The sponsor will request further information from the investigator 
regarding the course and outcome of the pregnancy. 
The investigator must instruct all female subjects to inform him immediately should they 
become pregnant. The investigator should counsel the subject, discuss the risks of continuing 
with the pregnancy and the possible effects on the foetus. Monitoring of the subject should 
continue until conclusion of the pregnancy. 
Investigators must instruct all male subjects to inform them immediately, should their sexual 
partner become pregnant during the study. The investigator is to report to the sponsor if they 
become aware of a pregnancy occurring in the partner of a subject participating in the study. If 


 
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the female partner gives her consent, the pregnancy outcome should be followed up and 
reported.  
If there is an abnormal pregnancy outcome or an AE reporting in the foetus/neonate/child 
following exposure to the IMP during an Ipsen-sponsored clinical study, the information will 
be collected in two clinical study SAE report forms, one for the mother and one for the 
foetus/neonate/child. 
Pregnancies (in female subjects and partners of male subjects) with a conception date within 
90 days after subject’s dosing must also be reported to the investigator for onward reporting to 
the sponsor. 
8.1.6 
Adverse Events of Special Interest 
Not applicable. 
8.1.7 
Deaths 
All AEs resulting in death during the study period must be reported as SAEs. 
The convention for recording deaths is as follows: 
• 
adverse event term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction); 
• 
outcome: fatal. 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be reported as “death” or “sudden death”. 
8.1.8 
Reporting to Competent Authorities, IECs/IRBs and other Investigators 
The sponsor will ensure that processes are in place for submission of reports of SUSARs 
occurring during the study to the competent authorities, IECs/IRBs and other investigators 
concerned. 
Reporting will be done in accordance with the applicable regulatory requirements. 
The sponsor must report all SUSARs to the European Medicines Agency’s EudraVigilance 
database within 15 days. Fatal and life-threatening SUSARs should be reported within 
7 calendar days, with another 8 days for completion of the report. 
The sponsor may prepare additional reports for other authorities (e.g. FDA). 
8.2 
Specific Safety Assessments 
The investigator is responsible for monitoring subjects’ safety at all times during the study. 
For each assessment performed, the investigator must document their review of the result(s) in 
the source document(s) and, in case of an abnormal result or value(s) falling outside of 
predefined normal ranges, he/she should evaluate the finding according to NCI-CTCAE. 
An abnormal finding may lead to a retest at the discretion of the investigator. 
8.2.1 
Physical Examinations 
Complete physical examinations will be conducted as timepoints presented in the schedule of 
assessments in Attachment 1, Section 19.1. 
This complete physical examination should include an evaluation of the general health, head, 
eyes, ears, nose, neck and throat (HEENT), heart, chest, abdomen, extremities, skin, lymph 
nodes, cardiovascular status and neurological status. 
Limited physical examination should be directed at the evaluation of symptoms or specific 
potential safety issues (in particular in case of haematological or renal toxicity). 
Any changes from baseline (prior to the first treatment IMP administration) or new 
abnormalities in physical examination findings judged to be clinically significant by the 


 
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investigator will be recorded as AEs. Any physical examination findings (abnormalities) 
persisting at the end of the study will be followed by the investigator until resolution or until 
reaching a clinically stable endpoint. 
8.2.2 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate and body temperature) will be 
assessed as presented in the schedule of assessments in Attachment 1, Section 19.1. 
Systolic and diastolic blood pressure and heart rate assessments will be performed with an 
automated device so that measurements are independent of the observer. These parameters will 
be recorded after at least 5 minutes rest in supine position for supine assessment. 
8.2.3 
Height and Weight 
Height and weight will be assessed as presented in the schedule of assessments in Attachment 1, 
Section 19.1. 
8.2.4 
Electrocardiograms 
12-lead computerised standard ECGs, with paper printout, will be recorded and assessed 
locally. 
Recordings should be performed in supine position after at least 5 minutes of rest. 
During the screening period, a triplicate 12-lead ECG will be recorded to check eligibility 
criteria by measuring the ECG parameters, in particular the QTc (Fridericia's correction, QTcF) 
interval in order to exclude subjects with high/abnormal QT values before the screening 
administration (minus 15 minutes). Afterwards, single 12-lead ECG recordings will be 
performed at the end of 177Lu-3BP-227 screening infusion (±15 minutes) and 4 hours after the 
end of 177Lu-3BP-227 infusion (±30 minutes). 
At each treatment administration, a triplicate 12-lead ECG will be recorded on Day 1 before 
the infusion (baseline) (minus 15 minutes).  
Afterwards, single 12-lead ECGs, will be recorded on Day 1 just after 177Lu-3BP-227 infusion 
(±15 minutes), at 4 hours (±30 minutes) after the end of 177Lu-3BP-227 infusion and on Day 2 
at 24 hours (±4 hours) after the end of 177Lu-3BP-227 infusion as well as at EOCT and EOAC 
visits. 
The timepoints of postdose assessments and the number of replicates may be modified, or 
additional timepoints may be added, based on data collected during the study. 
Table 7 summarizes the ECG assessments to be performed for QTc monitoring during screening 
and treatment administration at each cycle. 


 
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Table 6 
Timepoints and Replicates of 12-lead ECG Recordings 
 
Timepoint 
Replicate 
Screening 
administration 
Before infusion (minus 15 minutes) 
Triplicate 
End of infusion (±15 minutes) 
Single 
4 hours (±30 minutes) after the end of 
infusion 
Single 
Treatment 
administration 
(at each cycle) 
Before infusion (minus 15 minutes) 
Triplicate 
End of infusion (±15 minutes) 
Single 
4 hours (±30 minutes) after the end of 
infusion 
Single 
24 hours (±4 hours) after the end of 
infusion 
Single 
For each timepoint, computerised standard ECGs will be recorded so that the following 
parameter can be calculated and reported on the ECG paper printout: 
• 
sinus rhythm 
• 
duration of RR interval or heart rate 
• 
duration of PR interval 
• 
duration of QRS interval 
• 
duration of QT interval 
• 
QT interval corrected by the Fridericia’s methodology. 
Automated ECG interval data will be interpreted by a qualified physician at the site as soon as 
possible after the time of ECG collection, and ideally while the subject is still present, for 
immediate subject management. The qualified physician will document their review and 
interpretation (including evaluation of clinical significance in case of abnormality) on every 
ECG printout. 
The paper printouts will be kept in the source documents at site. The QTcF intervals, ECG 
interpretation and abnormalities will be reported in the eCRF for integration with other clinical 
study data. 
In the phase I dose escalation part, starting before each administration of the study drug, a 24-
hour 3-lead continuous ECG Holter will be recorded to monitor cardiac safety during the 
treatment. Holter assessments will be reviewed centrally. Results will be provided to the site in 
a timely manner and retained as source data. 
8.2.5 
Performance Status 
The performance status of the subjects will be defined by the ECOG scoring and assessed as 
presented in the schedule of assessments in Attachment 1, Section 19.1. For ES subjects, ECOG 
assessment should take into account disabilities related to surgery (see inclusion criterion 9). 
8.2.6 
Clinical Laboratory Tests 
Blood and urine samples collection will be performed for standard clinical laboratory tests, 
including biochemistry, haematology, hormone analysis and urinalysis panels, as well as 
specific tests and pregnancy tests for women of childbearing potential, at timepoints indicated 
in the schedule of assessments in Attachment 1, Section 19.1.  
Clinical laboratory tests will be analysed by local laboratory.  


 
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The results of laboratory tests performed during the screening phase must be obtained before 
dosing on Day 1 (within 48 hours before Cycle 1 Day 1 visit). 
The investigator will review each safety laboratory test result, document the review, and if 
applicable, record any AEs according to NCI-CTCAE. 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply: 
• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered clinically significant by the investigator, or the laboratory test 
abnormality suggests a disease and/or organ toxicity that is new or has worsened from 
baseline based on sponsor review. 
All clinically significant out of normal range laboratory tests occurring during the study may 
be repeated at appropriate intervals until they return to baseline or to a level deemed acceptable 
by the investigator or until the abnormality is explained by an appropriate diagnosis that does 
not require further follow-up. 
NOTE: it is to be borne in mind that all the biological samples will contain the radioactive 
substance 177Lu-3BP-227 and appropriate measures must be taken during handling, storage and 
shipment. 
8.2.6.1 
Blood Analyses 
Venous blood samples will be taken at the timepoints described in the schedule of assessment 
(Attachment 1, Section 19.1). Samples collected at Day 1 are to be taken predose, samples 
collected at Day 2 are to be collected at 24 hours ±2 hours. 
An estimation of the amount of blood required is provided in Attachment 2, Section 19.2. 
The parameters to be assessed are listed in Attachment 3, Section 19.3. 
For the determination of renal function, eGFR will be calculated by using the MDRD formula 
preferably; other methods to estimate renal function are acceptable if they are validated 
measures such as creatinine clearance by Cockcroft & Gault. Hormone analyses will only be 
performed for subjects who do not have substitution or therapy impacting one of the respective 
pituitary axis (e.g. no cortisol sampling in subjects who receive corticosteroids, no 
thyroid-stimulating hormone and free thyroxine sampling in subjects who have thyroxine 
substitution. 
8.2.6.2 
Urinalysis 
Freshly voided urine samples (at least 10 mL) will be collected at the timepoints described in 
the schedule of assessment (Attachment 1, Section 19.1). 
A dipstick assessment of the parameters listed in Attachment 3, Section 19.3 will be performed. 
In case of positivity and in the absence of common causes for proteinuria, a proteinuria 
determination in a 24 hours urine collection sample will be performed, according to the 
investigator's discretion and within a timeframe compatible with sufficient radioactivity 
excretion from the subject. 
In case of abnormal result on the dipstick, a request for a confirmatory analysis or additional 
assessments might be sent to the local laboratory, at the discretion of the investigator. 
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the investigator there are any clinically significant abnormalities in microscopy, 
they will be recorded as AEs in the eCRF. 


 
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8.2.6.3 
Pregnancy Test 
Serum and urine pregnancy tests will be performed as per the schedule of assessments 
(Attachment 1, Section 19.1). 
8.2.7 
Specific Renal Safety Biomarkers 
CCI


 
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9 
PHARMACOKINETIC ASSESSMENTS 
The PK of 177Lu-3BP-227 and 3BP-227, as well as the dosimetry assessments and timepoints 
described below are related to the phase I part of the study. The PK and dosimetry assessments 
will also be included in phase II. However, the timepoints might be revised based on the phase I 
results and documented as part of a protocol amendment. 
9.1 
Pharmacokinetics of 177Lu-3BP-227 
9.1.1 
Blood Sample Collection 
Total activity concentration in whole blood will be determined using a gamma counter 
calibrated for 177Lu, according to the dosimetry operational manual (DOM).  
For each subject, total activity concentration in whole blood will be measured. Each subject 
will have 18 blood samples (2 mL each) collected at Cycle 1 and Cycle 2 on the following 
timepoints after the end of 177Lu-3BP-227 infusion: 
• 
Day 1: before the infusion (baseline), at the end of infusion (0), 5 minutes ± 1 minute, 
30 minutes ± 5 minutes, 90 minutes ± 15 minutes and 4 hours ± 30 minutes post infusion 
• 
Day 2: 24 hours ± 2 hours 
• 
Day 3: 48 hours ± 2 hours 
• 
Day 4 to Day 5: 72 to 96 hours. 
For subjects receiving additional administrations (up to four additional cycles), blood samples 
will be taken during first and third additional cycles according to the timepoints described 
above. After the second and fourth additional administrations, a single blood collection will be 
performed at 24 hours (as close as possible to the SPECT/CT) for the radioactive assessment 
of 177Lu-3BP-227. 
Blood samples should be collected from the arm opposite to that of the study drug infusion, or 
from another site. 
The accurate time of sample collection and the duration for measuring the activity concentration 
must be recorded. Any issues associated with sample collection or processing should be 
reported to the sponsor’s monitor. 
Complete instructions for sample collection, processing and handling will be provided in a 
DOM. 
Note that nominal sample collection times may be changed during the study based on available 
data. These changes will be decided by the sponsor. In any case, the total number of assessments 
may be decreased but it will not be increased. 
9.1.2 
Urine Sample Collection 
To determine the renal excretion of 177Lu, total activity concentration in urine will be 
determined using a gamma counter calibrated for 177Lu, according to the DOM.  
The samples for urine total activity concentration analysis will be taken from urine collected 
during four different periods at Cycle 1 only: from the start of the 177Lu-3BP-227 infusion to 
6 hours, 6 to 12 hours, 12 to 24 hours and 24 to 48 hours after the end of infusion (from the 
start of the 177Lu-3BP-227 infusion to 6 hours after the end of the infusion only for US sites). 
Subjects should void shortly before the 177Lu-3BP-227 infusion (not to be collected) and shortly 
before the end of the last collection period. 
The accurate time of urine collection and the total urine volume for each collection interval 
must be recorded. All problems associated with sample collection or processing should be 
reported to the sponsor’s monitor. 


 
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Complete instructions for urine collection, processing and handling will be provided in the 
DOM. 
9.2 
Nuclear Medicine Imaging for Dosimetry  
Imaging of the tumour uptake of 177Lu-3BP-227 will be performed locally by the site 
investigator. All images will be centralized and analysed by independent readers for dosimetry 
analysis of the dose limiting organs and tumour lesions. For screening, the uptake of 
177Lu-3BP-227 at tumour lesions will be assessed locally and will take precedence to central 
assessment. 
During the treatment period, to improve the determination of the biokinetics of 177Lu-3BP-227 
and perform an absolute quantification of radioactivity in target organs, whole body scans 
(planar scintigraphy) and SPECT/CT will be performed at Cycles 1 and 2 at the following 
timepoints just after the end of 177Lu-3BP-227 infusion: 
• 
Day 1: 4 (±2) hours 
• 
Day 2: 24 (±6) hours 
• 
Day 3: 48 (±6) hours 
• 
Day 4: 72 to 96 hours 
• 
Days 7 to 8: 138 to 168 hours 
Within each cycle, a single SPECT/standard dose CT will be performed. For all other time 
points, SPECT/low dose CT will be performed. Details of the procedures will be provided in 
the Image Acquisition Guidelines. 
For subjects receiving additional administrations (up to four additional cycles), dosimetry 
assessments will be performed after the first and third additional administrations with nuclear 
medicine imaging as described above. After the second and fourth additional administrations, 
a single whole body scan and SPECT/standard dose CT at 48 (±6) hours will be performed.  
Details on the procedures will be given in a separate DOM. 
NOTE: The optimal schedule of the whole body scans (planar scintigraphy) and SPECT/CT 
has not been established. Some adaptations in timepoints or number of assessments might be 
required during the study and will be decided by the dosimetry expert and the sponsor. In any 
case, the number of whole-body scans (planar scintigraphy) and SPECT/CT will not increase 
and corresponds to the maximum number of assessments. The schedule adaptation can only 
lead to a decreased number of assessments. 
9.3 
Pharmacokinetics of 3BP-227 
9.3.1 
Blood Sample Collection 
Blood will be sampled for the purpose of determining plasma levels of 3BP-227 using 
high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) 
detection, according to a separate protocol established with the dedicated analytical laboratory. 
For each subject, 3BP-227 plasma concentration will be measured. Each subject will have 
10 blood samples (2 mL each) collected at Cycle 1 only at the following time points: 
• 
Day 1: before the infusion (baseline), at the end of infusion of 177Lu-3BP-227 (0), 
5 minutes ±1 minute, 30 minutes ±5 minutes, 90 minutes ± 15 minutes and 4 hours 
±30 minutes, 6 hours ±30 minutes and 8 hours ±1 hour after the end of infusion. 
• 
Day 2: 24 hours ±2 hours after the end of infusion of 177Lu-3BP-227. 
• 
Day 3: 48 hours ±2 hours after the end of infusion of 177Lu-3BP-227. 
Blood samples should be collected from the arm opposite to that of the study drug infusion, or 
from another site. 


 
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The accurate time of sample collection must be recorded. Any issues associated with sample 
collection or processing should be reported to the sponsor’s monitor. 
Complete instructions for sample collection, processing, handling and shipment will be 
provided in the laboratory manual. 
Residual plasma used for 3BP-227 PK analysis may also be used for exploratory analysis. This 
could include using leftover plasma for protein binding analysis, metabolite profiling or  
analysis of excipients. Plasma samples remaining from the analysis may be retained by the 
sponsor for additional investigations (i.e. long term stability, reproducibility). 
Note that nominal sample collection times may be changed during the study based on available 
data. These changes will be decided by the sponsor. In any case, the total number of assessments 
may be decreased but it will not be increased. 
9.3.2 
Urine Sample Collection 
To determine the renal excretion of 3BP-227, the concentration of 3BP-227 in urine will be 
determined using HPLC with MS/MS detection, according to a separate protocol established 
with the dedicated analytical laboratory. 
The samples for urine 3BP-227 concentration analysis will be taken from urine collected during 
four different periods at Cycle 1 only: from the start of the infusion to 6 hours, 6 to 12 hours, 
12 to 24 hours and 24 to 48 hours after the start of infusion (from the start of the infusion to 
6 hours after the end of the infusion only in US sites). Subjects should void shortly before the 
177Lu-3BP-227 infusion (not to be collected) and shortly before the end of the last collection. 
The accurate time of urine collection and the total urine volume for each collection interval 
must be recorded. Any issues associated with sample collection or processing should be 
reported to the sponsor’s monitor. 
Complete instructions for urine collection, processing, handling and shipment will be provided 
in the laboratory manual. 


 
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10 
PHARMACODYNAMIC/EFFICACY ASSESSMENTS 
The study schedule of assessments in Attachment 1, Section 19.1 is applicable for the phase I 
parts of the study. The need and timepoints for phase II will be assessed based on the phase I 
results. Eventual changes will be described in a protocol amendment. 
10.1 
Imaging Assessments 
Tumour response assessments will be performed by the site investigator (local) for the phase I 
dose escalation part and by independent reader (central) for the phase II. All contrast enhanced 
computed tomography/magnetic resonance imaging (ceCT/MRI) scans will be obtained and 
used for the tumour response assessments as described in RECIST version 1.1 (Attachment 4, 
Section 19.4) by the investigator and/or independent readers. Either ceCT or MRI images can 
be used for tumour assessment. However, the same method should be used throughout the 
study. 
All 18F-FDG-PET images will be obtained and used for the metabolic tumour response 
assessments as described in PERCIST version 1.0 [38,] (see Table 7 in Section 19.6) by the 
investigator and/or independent readers. 
During phase I, even if analysed locally, all images will be transferred to the central imaging 
laboratory for storage and potential central analysis upon sponsor request, e. g for the analysis 
of the homogeneity of the tumour uptake by 177Lu-3BP-227, using PERCIST version 1.0 or 
practical PERCIST. During phase II, the independent panel’s assessment will take precedence 
in case of a discrepancy between the local and central reviews using PERCIST version 1.0. 
10.1.1 
Screening Imaging Assessments 
The screening tumour assessments will be performed within 3 weeks before screening IMP 
infusion. If a historic ceCT/MRI scan is present that is not older than 1 month at the time of 
informed consent signature, this scan can be used. However, the site should ensure that all 
required anatomies (including brain) are covered and perform scanning for missing anatomies. 
Imaging parameters and approach used at screening should remain consistent throughout the 
study and follow-up. This examination will serve as inclusion criteria check and baseline 
assessment for RECIST v1.1 tumour response evaluation. 
As bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions, these lesions are difficult to assess through RECIST version 1.1. These 
techniques can be used to confirm the presence or disappearance of bone lesions. Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
in RECIST version 1.1. Blastic bone lesions are nonmeasurable. As a consequence, subjects 
with only bone lesions are not eligible for the study. 
10.1.2 
Phase I Imaging Assessments 
Radiological assessments for tumour response will be performed as per schedule of assessment 
(Attachment 1, Section 19.1.) as well as when clinically indicated. Additionally, in the event of 
biological or clinical signs of disease progression further radiological assessments can be done 
based upon the investigator’s judgment. 
For PDAC, CRC, GC and GIST, chest/abdomen/pelvis scans are required and can be performed 
in two images if required; from chest to abdomen and from abdomen to pelvis. The scans should 
extend from the lateral ends of the clavicles (to ensure complete coverage of lung apices) down 
to the lesser trochanters or caudally thereof (to ensure complete coverage of inguinal lymph 
nodes). For abdominal/pelvic scans, the scan should begin cranially at the right dome of the 


 
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diaphragm and extend down to the lesser trochanters or caudally thereof (to ensure complete 
coverage of inguinal lymph nodes). 
For SCCHN, scans from head to pelvis are required and can be performed in three images if 
required; from head to chest, from chest to abdomen and from abdomen to pelvis). 
For ES subject, whole body scans will be performed at screening to assess the localization of 
the targeted lesions. In case of lesions outside of the usual acquisition areas (chest to pelvis), 
the number of bed positions will be adapted  accordingly for further assessment. 
18F-FDG-PET  images will be assessed locally and the results for screening and EOCT visit 
will be collected in the eCRF. 
After the EOCT, ED or EOAC visit, subjects will be followed up every 3 months (±2 weeks) 
to further evaluate the efficacy (by CT or MRI) until disease progression, administration of any 
other chemotherapy or radiotherapy, lost to follow-up, withdrawal of consent, death or a 
maximum of 2 years, whichever occurs first (see Section 6.2.3). After disease progression is 
confirmed, no further CT/MRI scans will be required for tumour/disease assessment. The 
survival status and safety of the subjects will continue to be monitored as indicated in 
Section 8.1.2.3 until lost to follow-up, withdrawal of consent, death or a maximum of 5 years, 
whichever occurs first. 
10.1.3 
Phase II Imaging Assessments 
For phase II, serial radiologic assessments of tumours by CT or MRI will be performed by 
investigators at Baseline and every 8 weeks (anticipated duration of two cycles), until either 
disease progression, start of a new antitumour treatment, withdrawal of consent, or maximum 
cumulative radioactivity is reached. For each subject, the same method of assessment must be 
used throughout the study. 
Tumour assessments should be completed until it has been determined that the subject has 
progressive disease (in accordance with RECIST version 1.1). In the event of the subject 
discontinuing study treatment for reasons other than disease progression, a tumour assessment 
should be completed as soon as possible relative to the date of study termination, to assess 
overall disease status. 
18F-FDG-PET scans images will be assessed to measure metabolic tumour response using 
PERCIST version 1.0. 
Complete instructions from acquisition to central review will be provided by the contract 
research organisation (CRO) in charge of the central review and assessment. 
After the EOCT, ED or EOAC visit, subjects will be followed up every 3 months (±2 weeks)  to 
further evaluate the efficacy (by CT or MRI) until disease progression, administration of any 
other chemotherapy or radiotherapy, lost to follow-up, withdrawal of consent, death or a 
maximum of 2 years, whichever occurs first (see Section 6.2.3). 
10.2 
Quality of Life Questionnaire 
Quality of Life questionnaires will be completed by the subjects during phase II. The 
questionnaire types and the timepoints for assessment will be described as part of a protocol 
amendment at the end of phase I, based on the selected phase II study design and the selected 
indications for investigation. 
It is important that the quality of life questionnaires are completed prior to the other required 
assessments and that the investigator does not influence the subject’s responses to the 
questionnaires in any way. 


 
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10.3 
Tumour Markers 
Tumour markers will be measured in serum at specific timepoints as described in the study 
schedule of assessments in Attachment 1, Section 19.1. 
According to the type of tumour, the following tumour markers will be analysed: 
• 
Serum carcinoembryonic antigen (CEA) will be analysed in all subjects. 
• 
Serum cancer antigen 19-9 (CA 19-9) will be analysed in all subjects except in subjects 
with SCCHN. 
• 
Serum LDH and bone specific alkaline phosphatase will be analysed only in subjects 
with ES. 
All measurements will be done by the local laboratory. 
10.4 
Genomic Profiling in Circulating Cell-free DNA and Germline DNA 
 
 
 
 
 
10.5 
Gene Mutation Status 
10.6 
Tumour Biopsy 
CCI
CCI
CCI


 
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CCI


 
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11 
BIOBANKING 
Analysis of biobank samples will be performed outside the scope of the main study and will be 
reported separately. Therefore, this analysis is optional. 
CCI


 
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12 
STATISTICAL ANALYSES 
An interim analysis of the data will be performed between phase I and phase II. 
12.1 
Analysis Sets 
For dose escalation only, all subjects who complete Cycle 2 or discontinue during Cycle 1 or 
Cycle 2 due to a DLT will be included in the MTCA and MTSA evaluations.  
For the overall study, all subjects who received at least one dose of the IMP will be included in 
the safety evaluation. All subjects who receive at least one dose of IMP and who have 
postbaseline efficacy data will be included in the efficacy evaluations. All subjects with 
evaluable 3BP-227 PK data and no major protocol deviation with an impact on PK analysis will 
be included in the evaluation of 3BP-227 PK. All subjects with evaluable dosimetry images and 
no major protocol deviation with an impact on dosimetry analysis will be included in the 
evaluation of dosimetry. All subjects with evaluable blood or urine dosimetry data and no major 
protocol deviation with an impact on 177Lu-3BP-227 PK analysis will be included in the 
evaluation of 177Lu-3BP-227 PK. Major deviations will be described in a specific document. 
12.2 
Statistical Methodology for Phase I 
12.2.1 
Sample Size Calculation 
12.2.1.1  Dose Escalation 
As this is primarily a descriptive safety and tolerability study, the total number of subjects is 
not based on a formal statistical sample size calculation.  
For the dose escalation part, the actual sample size required to adequately determine the 
MTCA/MTSA during dose escalation depends on the initial dose, rate of dose escalation and 
the observed dose-toxicity and dose/radiation exposure relationships. Simulation studies have 
been performed to quantify the operational characteristics (i.e. precision of the MTCA/MTSA, 
sample size, number of subjects being over/under dosed) of the adaptive dose-escalation design 
under a number of plausible dose-DLT relationship scenarios. Results are provided in 
Attachment 5, Section 19.5. Based on experience, the chosen sample size of three to five 
subjects per cohort is considered sufficient to fulfil the objectives of the study. It is anticipated 
that approximately 30 subjects will be required to establish the MTCA or MACA. 
12.2.1.2 Dose Expansion 
If safety evaluation of 177Lu-3BP-227 and dose schedules cannot be fully explored during the 
phase I dose escalation part, a phase I expansion part enrolling up to 45 subjects will serve to 
accomplish this objective including, but not limited to, schedules of high loading doses 
followed by fractionated lower doses or evaluation of 177Lu-3BP-227 in combination with other 
antitumoral treatments (to be defined). The expansion part will also serve to clarify any 
uncertainties of antitumour responses. The sample size will be specified in a protocol 
amendment. 
12.2.2 
Statistical Methods 
Details of the statistical analysis will be specified in the statistical analysis plan (SAP). The 
statistical analyses will be conducted using Statistical Analysis System. Summary descriptive 
tables, by RL, will be provided.  
Continuous data will be summarised with the following items: frequency, median, range, mean 
and coefficient of variation (CV) if relevant. 
Categorical data will be presented in contingency tables with frequencies and percentages of 
each modality (including missing data modality). The 95% confidence interval will be 
calculated following the exact method. 


 
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To describe time dependent parameters (PFS, OS), Kaplan-Meier curves and life tables will be 
provided. The 95% confidence interval of the median will be given. 
An overview of the main analysis strategy is provided in the following sections. 
12.2.3 
Demographic and Other Baseline Characteristics 
Summary statistics will be presented for the total study population and by cohort. Frequency 
tables for qualitative data will be provided. Medical and surgical history findings will be 
summarised using MedDRA terms. 
12.2.4 
Maximum Tolerated Single and Cumulative Activity 
Individual listings and treatment summaries of DLTs with NCI-CTCAE code and grade will be 
presented. 
The incidence of subjects with DLTs during Cycles 1 or 2 will be summarised by treatment 
and, if possible, modelled as a function of the fractional doses for Cycles 1 and 2 using Bayesian 
logistic regression. The moderately-informative independent priors used during the interim 
analysis (see Attachment 5, Section 19.5 for details) as well as noninformative priors will be 
used for this analysis in order to assess sensitivity of the estimates. Parameter estimates and 
model predictions will be reported with 90% credibility sets. The MTCA and MTSA will be 
computed as a derived function of model parameters. 
The posterior distribution of the MTCA and MTSA will be summarised in tabular and graphical 
formats. 
The number of subjects with at least one DLT or NCI-CTCAE Grade t2 (excluding hair loss) 
will be tabulated by RL by cycle and overall. The type of DLT and NCI-CTCAE Grade t2 will 
also be presented. 
12.2.5 
Safety Evaluation 
For the overall study, descriptive statistics will be calculated on the safety parameters. No 
formal statistical analyses of safety data are planned. 
Summaries will be prepared by treatment group and, as needed, by timepoint. 
All AEs will be coded according to the latest version of the MedDRA and NCI-CTCAE.  
Study drug TEAE summaries will include the overall incidence (by system organ class (SOC) 
and preferred term (PT)), events by maximum intensity, events by relationship to study drug, 
events leading to discontinuation of study drug and SAEs. 
Physical examination findings, vital signs, ECG 3-lead 24h Holter recordings and clinical 
laboratory parameters will be summarised descriptively at each timepoint. Actual and change 
from baseline data will be calculated and summarised where data are available. The 
investigator’s interpretation of 12-lead ECGs will be listed. 
Concomitant medications will be coded using the latest version of the World Health 
Organization (WHO) drug dictionary and will be summarised by treatment group and overall 
with the number and percentage of subjects receiving concomitant medication by drug class 
and preferred drug name. 
The NCI-CTCAE version 5.0 classification [31] will be used to classify all TEAEs and 
laboratory abnormalities. 
Maximum grade or severity will be tabulated by subject for each MedDRA SOC and PT. 
Analyses of AEs and SAEs will be performed in two different ways: regardless of the 
relationship to the study treatment and related to the study treatment. Moreover, all AEs without 
SAEs and SAEs only will be tabulated. 


 
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For haematological and biochemical toxicities, the worst NCI-CTCAE grade by subject and by 
cycle will be tabulated and listed. For white blood cells, neutrophils, platelets and haemoglobin, 
with associated Grade 3 or 4 toxicities, nadir and day to nadir will be calculated. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
It was not present prior to receiving the first dose of 177Lu-3B-227; or  
• 
It was present prior to receiving the first dose of 177Lu-3B-227 but the intensity increased 
during the active phase of the study; or  
• 
It was present prior to receiving the first dose of 177Lu-3B-227, the intensity is the same 
but the drug relationship became related during the active phase of the study. 
12.2.6 
Pharmacokinetics, Biodistribution and Dosimetry 
12.2.6.1 Biodistribution and Pharmacokinetic Analysis of 177Lu-3BP-227 
The biodistribution and PK analyses of the radiopharmaceutical 177Lu-3BP-227 will be 
performed under the responsibility of the sponsor’s Clinical Pharmacokinetics and 
Pharmacometrics department. 
The following biodistribution (i.e. organ PK) parameters will be evaluated: 
• 
maximal uptake (%) at the target lesion 
• 
maximal uptake (%) in discernible organs and blood 
• 
the Cmax of 177Lu-3BP-227 in discernible thoracic and abdominal organs, target lesion 
and blood 
• 
the Tmax of 177Lu-3BP-227 in discernible thoracic and abdominal organs, target lesion 
and blood 
• 
the AUC of 177Lu-3BP-227 in discernible thoracic and abdominal organs, target lesion 
and blood 
• 
terminal t1/2 of activity concentrations of 177Lu-3BP-227 in blood. 
Data analysis and all biodistribution parameters will be further described in a SAP. 
Biodistribution data for target lesion and all abdominal and thoracic organs analysed will be 
listed for each study subject and each sampling timepoint. In addition, arithmetic mean, 
arithmetic standard deviation, CV and number of data points will be provided per sampling 
point. The biodistribution parameters will be estimated for each subject. Total radioactivity 
cumulatively excreted in the urine in the interval 0 to 6 hours, 6 to 12 hours, 12 to 24 hours and 
24 to 48 hours postinfusion will be determined for each subject. 
Measured total 177Lu-3BP-227 radioactivity concentrations in whole blood and urine will be 
listed for each study subject and each sampling time point. In addition, means, standard 
deviation, CV and number of data points will be provided per sampling point. Based on the 
individual 177Lu-3BP-227 blood time-activity curves, the concentration-time profiles of 
177Lu-3BP-227 and the AUC in blood, will be estimated for each subject. 
12.2.6.2 Radiation Dosimetry Analysis of 177Lu-3BP-227 
The radiation dosimetry analysis of the radiopharmaceutical 177Lu-3BP-227 will be performed 
by an independent expert under the responsibility of the sponsor’s Clinical Pharmacokinetics 
and Pharmacometrics department. 
Further details on dosimetric assessments and on dosimetric parameters will be provided in a 
Dosimetry Assessment Plan. 
The dosimetric assessments will be performed and reported according to the criteria set out by 
the European Association of Nuclear Medicine Dosimetry Committee guidance document: 
good practice of clinical dosimetry reporting [32]. 


 
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Calculations will be conducted for the following parameters (only in organs showing uptake): 
• 
organs receiving the highest absorbed dose 
• 
specific absorbed dose to the target lesion (Gy/GBq) 
• 
specific absorbed dose per organ (Gy/GBq) 
• 
cumulative absorbed organ doses (Gy). 
Cumulative absorbed organ doses (Gy) and organs of highest radioactivity uptake will be 
identified visually. Regions of interest will be placed over these organs to determine the relative 
activity in the respective organs. Time activity curves (describing % IA/ROI of the activity 
amount injected versus time, considering renal excretion activity) will be derived. The absorbed 
doses of the dose-limiting organs (kidney, bone marrow and liver) will be evaluated and 
reported to the investigator before the next administration of 177Lu-3BP-227 can be initiated to 
enable activity adaptations in the event the next dose may exceed the organ limits of 23 Gy 
(kidney), 2 Gy (bone marrow) and 30 Gy (liver). The dosimetry results for all other organs will 
be finalized for the final study report with the restriction that the dosimetry data must be 
available for the SRC meeting. These data can be reviewed at any time if a major safety issue 
occurs. 
The proportion of renally excreted radioactivity, whole blood radioactivity, and dosimetric 
whole body images will be used to calculate the dosimetry of 177Lu-3BP-227. 
12.2.6.3 Pharmacokinetic Analysis of 3BP-227 
The PK analysis of 3BP-227 will be performed under the responsibility of the sponsor’s Clinical 
Pharmacokinetics and Pharmacometrics department. 
Analysis of PK data by a noncompartmental approach will be documented in a separate SAP. 
Individual plasma and urine concentrations of 3BP-227 will be listed and summarised by time 
points using descriptive statistics for continuous variables (number of available observations, 
mean, median, standard deviation, minimum, maximum, geometric mean, and geometric 
coefficient of variation assuming lognormally distributed data). Linear and semilogarithmic 
plots of individual and mean plasma concentration-time profiles as well as spaghetti plots will 
be reported. 
Any suspicious concentration will be investigated and kept in the PK analysis if possible. All 
excluded concentrations will be justified in the report. 
If 3BP-227 levels are measurable in plasma and urine, PK parameters of 3BP-227 (including, 
but not limited to, Cmax, AUC, t1/2, Cl, Vd, Ae, CLR) will be derived using the noncompartmental 
approach on the individual plasma concentration-time profiles of 3BP-227 and on the individual 
urine concentrations. 
An attempt to build an integrated model taking into account PK, dosimetry as well as efficacy 
and safety data will be made if warranted by the data. The exploratory analysis will be captured 
in a separate data analysis plan and reported in a standalone report. 
12.2.7 
Pharmacodynamic/Efficacy Evaluation 
For phase I, tumour response will be evaluated only by the site investigator, using the revised 
RECIST guideline version 1.1 (see Attachment 4, Section 19.4). Only subjects with measurable 
disease at baseline, who have received at least two administrations of 177Lu-3BP-227 and 
reached the end of Cycle 2 or EOCT visit would be considered evaluable for response. 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs and permit reproducible repeated 
measurements. On occasion, if the largest lesion does not permit reproducible measurement, 


 
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the next largest lesion which can be measured reproducibly will be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. If lymph nodes are included in the 
sum, then only the short axis will be added into the sum. The baseline sum of diameters will be 
used as reference to further characterise any objective tumour regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including any measurable lesions over and above the five 
target lesions should be identified as nontarget lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or unequivocal 
progression of each should be noted throughout follow-up. 
Subjects will be evaluated as CR, PR, SD, PD, or inevaluable according to RECIST version 1.1. 
Based on this classification, the following endpoint will be calculated as defined by 
RECIST version 1.1 and below. 
• 
Objective Response Rates (ORR): proportion of subjects with a best overall response 
(BOR) characterised as either a Complete Response (CR) or Partial Response (PR) 
relative to the total number of evaluable subjects 
• 
Disease control rate (DCR): proportion of subjects with a BOR characterised as CR, PR 
or SD relative to the total number of evaluable subjects 
The PFS and OS will also be evaluated as defined per RECIST version 1.1. 
Details of the response evaluation will be given in a separate image review charter. Details of 
the analysis will be specified in the SAP. 
Efficacy data will be summarised using descriptive statistics and will be graphically displayed, 
if appropriate. The correlation between pharmacodynamic parameters and selected safety, 
efficacy, or PK parameters may be graphically displayed. Further statistical analyses may be 
conducted. Details of the response evaluation will be given in a separate image review charter. 
Details of the analysis will be specified in the SAP. 
An attempt to build an integrated model taking into account PK, dosimetry as well as efficacy 
and safety data will be made, if warranted by the data. The exploratory analysis will be captured 
in a separate data analysis plan and reported in a standalone report. 
12.2.8 
Interim Analysis/Safety Review Committee  
During the dose escalation part and before each decision on further dose escalation, safety and 
dose limit organ exposure data will be summarised and presented to the SRC. This SRC will be 
set-up for the dose escalation decisions (after the end of the third subject’s Cycle 1) and second 
dosing cycle (after the end of the third subject’s Cycle 2).  
At the time of SRC meeting, all cumulative available information will be reviewed.  
A continual reassessment method (CRM) in conjunction with a Bayesian approach modelling 
of DLT rates and radiation exposure to target organs may be performed during the planned 
review meetings to generate additional relevant information for the adaptive dose selection 
decisions. PK and pharmacodynamic data may be also incorporated in the model. The SRC will 
review all available data and make the final decision as to dose escalation, de-escalation, or 
cohort expansion during the adaptive dose-escalation phase. This group will also determine 
when to implement predefined stopping rules. 
An interim analysis of the escalation cohort data may be done when the MTCA or MACA have 
been determined. 
A specific charter will be developed to define roles and responsibilities, as well as the data set 
to be reviewed by the SRC. 


 
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Full analysis will be performed on the entire dataset at the EOCT and at the end of the long-term 
follow-up.  
12.2.9 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the International Council for 
Harmonisation (ICH) guideline on structure and contents of CSRs. A final CSR will be prepared 
where any subject has signed informed consent, regardless of whether the study is completed 
or prematurely terminated. Where appropriate an abbreviated report may be prepared. The CSR 
will comply with any applicable regulatory requirements, national laws in force and will be in 
English. 
As indicated in Section 12.2.8, a full analysis based on all data recorded until the last  subject 
completed their EOCT visit will be performed. This analysis will be included in a CSR. An 
addendum to the report will be prepared, including all data recorded from the follow-up period 
and additional cycles that occurred after the first data cut-off. 
12.3 
Statistical Methodology for Phase II 
12.3.1 
Sample Size Calculation 
In case the antitumour activity is driven by a type of tumour, tumour-specific phase II cohort(s) 
will be initiated utilising an Optimal Simon Two-Stage design [33] to further evaluate the 
antitumour activity of 177Lu-3BP-227. This approach tends to minimise the average number of 
subjects exposed to a new drug while addressing the scientific question.  
The corresponding hypotheses (H) to be tested are: H0: ORR ≤ORR0 versus H1: ORR>ORR0 
where ORR is the true objective response rate following 177Lu-3BP-227 treatment and ORR0 is 
the minimum objective response rate that would be considered to further clinical development. 
For the purpose of the a priori sample size calculation, the following values are used for the 
PDAC cohort: ORR0 is 17% and ORR is 35%. These values reflect the results from PDAC 
therapy [34] currently registered and are considered standard-of-care, and the level of 
expectation for the IMP prior to phase I.  
Similarly, for the CRC cohort (blended population with regard to somatic mutations in BRAF 
and RAS genes), ORR0 is 15% and ORR is 30% [35;36]. The value for ORR0 reflects an 
estimated average result from different clinical studies that investigated CRC therapies in 
different populations [35, 36]; it is anticipated that based on lack of available and effective 
therapies an enrichment of poor-prognosis subjects with metastatic and recurrent CRC and 
prevalent mutations in BRAF and RAS will occur in the study population, while it is anticipated 
that it is unlikely for subjects with wild-type disease for which effective therapies exist over 
multiple lines of treatment to be enrolled. Subjects with somatic BRAF and RAS mutations are 
anticipated to have less exposure to prior treatment for metastatic disease compared with 
subjects with prevalent wild type BRAF or RAS tumours. 
The assumptions forming the understanding of the expected efficacy of standard-of-care 
treatment and leading to sample size estimations may be updated based on results emerging 
from phase I and evolving scientific knowledge. 
In the first stage of the design, for the PDAC cohort, 16 subjects will be treated and evaluated 
for the ORR. If there are three or fewer responders in these 16 subjects, the cohort will be 
stopped for futility. Otherwise, 28 additional subjects will be treated and evaluated for a total 
of 44 subjects. The null hypothesis will be rejected if 12 or more responders are observed in the 
44 subjects. This design yields a nominal one-sided type I error rate of 5% and a power of 80%, 
if the true response rate is 35%.  
Similarly, in the first stage of the design, for the CRC cohort 19 subjects will be treated and 
evaluated for the ORR. If there are three or fewer responders in these 19 subjects, the cohort 


 
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will be stopped for futility. Otherwise, 36 additional subjects will be treated and evaluated for 
a total of 55 subjects. The null hypothesis will be rejected if 13 or more responders are observed 
in the 55 subjects. This design yields a nominal one-sided type I error rate of 5% and a power 
of 80%, if the true response rate is 30%.  
Nonevaluable subjects will be replaced to meet the above numbers of evaluable subjects. A 
subject will be considered as nonevaluable and therefore replaced, if no evaluation post 
treatment is available or in case of drop-out before the 4-month visit for PDAC cohort and 
8-month visit for CRC cohort with an insufficient follow-up duration (i.e. status being still 
“Stable Disease” as per RECIST version 1.1). In case of overenrollment, the first 16 evaluable 
subjects in the PDAC cohort and 19 subjects in the CRC cohort will be analysed at Stage 1 to 
make the decision about starting Stage 2. Assuming a non-evaluability rate of 20% for the 
PDAC cohort [34] and the CRC cohort [36], the number of subjects to be enrolled is expected 
to be approximately 55 and 70, respectively. 
One, two or three further cohorts may be initiated (subject to results emerging from ongoing 
preclinical studies and antitumour efficacy seen during dose escalation and amending the 
current protocol) likely to enrol approximately 120 subjects with GC, SCCHN and/or ES.  
In the case of acceptable tolerability and evident antitumour activity across all enrolled subjects 
in phase I, a phase II basket trial design will be utilised to study the antitumour activity of 
177Lu-3BP-227 in subjects with NTSR1 expressing tumours. The sample size will be described 
as part of a protocol amendment.  
Subjects in each phase of the study will have a 5-year safety follow-up after the EOCT, ED or 
EOAC visit. The dose, the number and length of cycles in phase II will be refined according to 
phase I results. 
However, if the antitumour activity is driven by a type of tumour, tumour-specific phase II 
cohort(s) will be initiated utilising an Optimal Simon’s Two Stage design (see Phase II). 
12.3.2 
Analysis Sets 
All subjects who receive at least one dose of the study drug will be included in the safety 
evaluation. All subjects who receive at least one dose of study drug and who have postbaseline 
efficacy data for the ORR will be included in the efficacy evaluations of the primary endpoint. 
All subjects who receive at least one dose of study drug and who have any postbaseline 
secondary efficacy data will be included in the efficacy evaluations of the secondary endpoints. 
12.3.3 
Demographic and Other Baseline Characteristics 
Summary statistics will be presented for all treated subjects. Frequency tables for qualitative 
data will be provided. Medical and surgical history findings will be summarised using MedDRA 
terms. 
12.3.4 
Efficacy Evaluation  
Tumour response will be assessed in imaging studies of CT or MRI scans after cycle 2 and 
subsequently every 8 weeks for the first 6 months and every 12 weeks thereafter. 
The primary endpoint is ORR and will be calculated as defined in RECIST version1.1 and in 
Section 12.2.7. As part of secondary efficacy endpoints, DCR, TTP, Time to response (TTR), 
DOR, PFS and OS will also be determined as defined by RECIST version 1.1, metabolic 
response will also be determined as defined by PERCIST version 1.0.  
In the particular context of the Simon Two-Stage approach, ORR will be analysed at the end of 
Stage 1 (and no later than after the 16-week visit of the last evaluable subject of the Stage 1 
cohort for each PDAC and CRC cohorts). If the observed number of responders is below a 
predefined threshold, this part of the study will be stopped for futility. Otherwise, additional 
subjects will be treated to complete the planned enrolment. At the end of Stage 2, the null 


 
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hypothesis will be rejected depending on the total observed number of responders based on a 
predefined threshold. 
At the end of the phase II, descriptive summaries will be provided for all primary and secondary 
efficacy endpoints. For the primary endpoint, final analysis will take into account the sequential 
sampling procedure of the design and the underlying binomial distribution assumed by the 
Simon Two-Stage design. 
12.3.5 
Safety Evaluation 
Safety analyses similar to phase I (see Section 12.2.5) will be performed for phase II, except 
for DLT assessments and 24-hour 3-lead ECG Holter measurements. 


 
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13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Collection 
In compliance with Good Clinical Practice (GCP), the source data, i.e. medical records/medical 
notes, etc. should be clearly marked and permit easy identification of a subject’s participation 
in the specified clinical study. 
Source data identification and location, whether standalone documents or direct eCRF records, 
will be specified in a standalone document signed by the investigator(s). 
The investigator must record all data relating to protocol procedures, study drug administration, 
laboratory data, safety, PK and pharmacodynamic data on the source documents and report 
requested data on eCRFs provided for the study (see Section 13.2).  
To ensure accurate, complete and reliable data, the sponsor or its representative will provide 
instructional material to the study site(s), as appropriate. Training will be given during a 
start-up/initiation meeting for instructions on the completion/data entry of any source data 
documents and eCRFs. 
The investigators or their designees must verify that all data entries in the eCRF are accurate 
and consistent with source data records . If certain information is not available for a particular 
timepoint and/or subject, specific instructions should be followed, e.g. to document that the 
procedure was either not done or not applicable. 
For all subjects who received any administration of 177Lu-3BP-227 the full obtained data set 
needs to be recorded in the eCRF. 
For all screening failures who did not receive the screening IMP administration, a minimum of 
data including the primary reason for screening failure will be recorded in the eCRF. 
13.2 
Data Reporting 
Electronic data capture (EDC) will be utilised for collecting subject data. The study site is 
required to have a computer and internet connection available for study site entry of clinical 
data. All entries in the eCRF will be made under the electronic signature of the person 
performing the action. This electronic signature consists of an individual and confidential 
username and password combination. It is declared to be the legally binding equivalent of the 
handwritten signature. Only sponsor authorised users will have access to the eCRF as 
appropriate to their study responsibilities. Users must have successfully undergone software 
application training prior to entering data into the eCRF. 
13.3 
Data Management 
Details of all data management procedures, from the initial planning to the archiving of final 
data sets/documents following database freeze/lock will be documented in appropriate 
standalone data management and validation plan(s).  
Data management will be conducted by a CRO approved by the sponsor. All data management 
procedures will be completed in accordance with the contracted CRO’s standard operating 
procedures. Prior to data becoming available for processing at the assigned data management 
CRO, they will be monitored.  
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately 
and that suitable queries are raised to resolve any missing or inconsistent data. The investigator 
will receive the data from the clinical study in an electronic format (PDF files), which will be 
an exact copy of the eCRF and will include the full audit trail, for archiving purposes and future 
reference. 


 
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Any queries generated during the data management process will also be tracked by the 
contracted data management CRO. It is the central study monitor’s responsibility to ensure that 
all queries are resolved by the relevant parties. 
The CRO will also ensure, via SAE reconciliation, that SAE data collected in the eCRF are 
consistent with SAE data held in the sponsor’s GPS department (and vice versa). 
The coding of AE, medical history and prior/concomitant medication/nondrug therapy terms 
will be performed by the sponsor’s Central Group. Prior/Concomitant medications will be 
coded using the latest version of the WHO drug dictionary and AEs/medical history/nondrug 
therapy terms will be coded using the latest version of MedDRA. 
13.4 
Record Keeping 
The investigator will keep records of all original source data. This might include laboratory 
tests, medical records and clinical notes. 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed. 
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed 
by the monitor when closing out the study site. The sponsor will inform the investigator, in 
writing, as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws responsibility for 
maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


 
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14 
REGULATORY AND ETHICAL CONSIDERATIONS 
14.1 
Regulatory Considerations 
The study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH Guidelines related to GCP. Any episode of noncompliance 
will be documented. The EDC system will comply with the FDA, 21 Code of Federal 
Regulations Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for 
Industry: Computerized Systems Used in Clinical Trials. 
In addition, the study will adhere to all applicable international and local regulatory 
requirements.  
All or some of the obligations of the sponsor will be assigned to a CRO.  
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data (see 
Section 4.6.1.1). 
14.2 
Ethical Review Considerations 
The following documents should be submitted to the relevant ethics committee(s) (EC) for 
review and approval to conduct the study (this list may not be exhaustive): 
• 
protocol/amendment(s) approved by the sponsor 
• 
currently applicable IB or package labelling 
• 
relevant investigator’s curriculum vitae 
• 
subject information and informed consent document(s) and form(s) 
• 
subject emergency study contact cards 
• 
recruitment procedures/materials (advertisements), if any. 
The EC(s) will review all submission documents as required, and a written favourable opinion 
for the conduct of the study should be made available to the investigator before initiating the 
study. This document must be dated and clearly identify the version number(s) and date(s) of 
the documents submitted/reviewed and should include a statement from the EC that they 
comply with GCP requirements. 
The study may begin at the investigative site(s) only after receiving this dated and signed 
documentation of the EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC either for 
information, or for review and approval, depending on how substantial the modifications are: 
(1) the IB; (2) reports of SAEs; (3) all protocol amendments and revised informed consent(s), 
if any. 
At the end of the study, the EC will be notified about the study completion. 
14.3 
Subject Information Sheet and Consent 
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering, orally and/or in writing, to any 
questions the subject may have throughout the study and sharing any new information that may 
be relevant to the subject’s willingness to continue his or her participation in the study in a 
timely manner. 
The subject information sheet and consent document will be used to explain the potential risks 
and benefits of study participation to the subject in simple terms before the subject is entered 
into the study and to document that the subject is satisfied with his or her understanding of the 
study and desires to participate.   


 
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The investigator is ultimately responsible for ensuring the EC-approved informed consent is 
appropriately signed and dated by each subject prior to the performance of any study 
procedures. Informed consent obtained under special circumstances may occur only if allowed 
by local laws and regulations. 
The study has the option for subjects to consent to the collection of serum and whole blood 
samples for biobanking for future exploratory analysis and storage for up to 15 years (where 
local regulations allow). A specific informed consent is required for the collection of these 
samples and will be explained after the subject has given written informed consent for the main 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.4 
Final Report Signature 
The coordinating investigator or designee will be proposed to review and sign the clinical study 
report for this study, indicating agreement with the analyses, results, and conclusion of the 
report. 
CCI


 
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15 
INSURANCE AND FINANCE 
15.1 
Insurance 
The sponsor declares that it has taken out a product liability insurance covering all subjects 
screened and enrolled in this study in respect to risks involved in the study. 
15.2 
Financial Agreement 
Since this study is to be performed in partnership with a CRO, separate financial agreements 
between the sponsor and the CRO on one side, and the CRO and the investigator site on the 
other side, will be signed prior to initiating the study, outlining overall sponsor and investigator 
responsibilities in relation to the study. 


 
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16 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A startup training session will be done 
prior to screening start to instruct the investigators and study coordinators. This session will 
give instruction on the protocol, the completion of the eCRF and all study procedures. 
16.1 
Protocol Amendments and Protocol Deviations and Exceptions 
16.1.1 
Protocol Amendments 
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• 
nonsubstantial amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the IECs or 
regulatory authorities for information purposes; 
• 
substantial amendments are those considered ‘substantial’ to the conduct of the clinical 
study where they are likely to have a significant impact on the: 
- 
Safety or physical or mental integrity of the subjects; 
- 
Scientific value of the study; 
- 
Conduct or management of the study, or 
- 
Quality or safety of the study drug used in the study. 
Substantial amendments must be submitted to and approved by the IECs and relevant 
regulatory authorities, according to local regulations, prior to implementing changes. 
• 
urgent amendments are those that require urgent safety measures to protect the study 
subjects from immediate hazard and as such may be implemented immediately by the 
sponsor with subsequent IECs and regulatory authority notification, forthwith. 
The principal investigator and the sponsor will sign the protocol amendment. 
16.1.2 
Protocol Deviations and Exceptions 
Protocol deviations are defined and classified as either major or minor for a given study. Major 
deviations (or a combination of minor becoming major) may or may not impact the analysis 
population. All minor and major protocol deviations will be identified and recorded by the 
investigator site personnel and should be traceable. 
Major protocol deviation definition: 
Any changes in the study design, study conduct and/or procedures that are not in accordance 
with the protocol and any study materials originally approved by the IEC and which may affect 
the subject’s rights, safety or wellbeing, or the completeness, accuracy and reliability of the 
study data. A major protocol deviation is any significant divergence from the protocol, i.e. 
nonadherence on the part of the subject, the investigator, or the sponsor to protocol specific 
inclusion/exclusion criteria, primary objective evaluation criteria and/or GCP guidelines. 
Generally, a protocol deviation qualifies as major if: 
(1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject. 
(2) 
The deviation compromises the scientific integrity of the data collected for the study. 
(3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s). 
(4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures. 


 
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(5) 
The deviation is inconsistent with Ipsen’s research, medical and ethical principles. 
Minor protocol deviation definition: 
Any changes in the study design, study conduct and/or procedures that are not in accordance 
with the protocol and any study materials originally approved by the IEC but that do not have 
an important impact on the subject’s rights, safety or well-being, or the completeness, accuracy 
and reliability of the study data. A minor protocol deviation is any significant divergence from 
the protocol that does not impact the study results. 
As a matter of policy, the sponsor will not grant exceptions to protocol-specific entry criteria to 
allow subjects to enter a study. If under extraordinary circumstances such action is considered 
ethically, medically and scientifically justified for a particular subject, prior approval from the 
sponsor and the responsible IRB/IEC, in accordance with the standard operating procedure 
(SOP), is required before the subject is allowed to enter the study. 
If investigative centre personnel learn that a subject who did not meet the protocol eligibility 
criteria was entered in a study (a protocol deviation), they must immediately inform the sponsor. 
Such subjects will be discontinued from the study, except in exceptional instance, following 
review and written approval by the sponsor and the responsible IRB/IEC, according to the 
applicable SOP. Retention of these subjects in the study will be discussed between sponsor and 
investigator, taking into account subject safety and data reliability. The IRB/IEC will be 
informed if subject safety/protection is ignorantly impacted. 
16.1.3 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (e.g. when new staff become involved). 
The investigator must assure that all study staff members are qualified by education, experience, 
and training to perform their specific responsibilities. These study staff members must be listed 
on the clinical unit authorisation form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
16.2 
Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
subjects are protected, study data are accurate (complete and verifiable to source data), and that 
the study is conducted in compliance with the protocol, GCP, and regulatory requirements. 
Before the study initiation visit, the sponsor-assigned study monitor will write a monitoring 
plan indicating the monitoring procedures and at which occasions during the study monitoring 
visits will be performed. 
Periodic visits will be made to the study site throughout the study at mutually agreeable times. 
Any appropriate communication tools will be set-up to ensure the sponsor and/or its 
representative is/are available for consultation, so they can stay in contact with the study site 
personnel. 
Adequate time and space for monitoring visits should be made available by the investigator. 


 
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The investigator will allow direct access to all relevant files (for all subjects) and clinical study 
supplies (dispensing and storage areas), for the purpose of verifying entries made in the eCRF, 
and assist with the monitor’s activities, if requested. 
Quality of the paper-based or electronic data will be reviewed to detect errors in data collection 
and, if necessary, to verify the quality of the data. 
The eCRF is expected to be completed on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The study monitor will use 
functions of the EDC system to address any queries raised while reviewing the data entered by 
the study site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the date of 
birth visible and annotated with the subject number as identification. 
16.3 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules.  This includes 
that the study may be audited at any time by quality assurance personnel designated by the 
sponsor, or by regulatory bodies. The investigator must adhere to the GCP principles in addition 
to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies, and 
applicable EC with direct access to any original source documents. 
The investigator(s) should demonstrate due diligence in recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with the 
sponsor. The sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
16.3.1 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised quality assurance 
personnel may carry out inspections and audits. 
16.3.2 
Data Quality Assurance 
Monitored eCRF, transferred from the investigator site to the assigned data management group, 
will be reviewed (secondary monitoring) for completeness, consistency and protocol 
compliance. 
Reasons should be given in the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator for clarification/correction. The 
investigator must ensure that queries are dealt with promptly. All data changes and clarifications 
can be viewed in the audit trail function of the eCRF. 


 
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17 
PUBLICATION POLICY 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the consent 
of each individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study. For multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by the study investigators or a 
steering committee. The sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is submitted 
for publication or communicated. This condition also applies to any amendments that are 
subsequently requested by referees or journal editors. The sponsor will undertake to comment 
on the draft documents within the time period agreed in the contractual arrangements, including 
clinical trial agreements, governing the relationship between the sponsor and authors (or the 
author’s institution). Requested amendments will be incorporated by the author, provided they 
do not alter the scientific value of the material. 
If patentability could be adversely affected by publication, this will be delayed until (i) a patent 
application is filed for the content of the publication in accordance with applicable provisions 
of the clinical trial agreement concerned, (ii) the sponsor consents to the publication, or (iii) the 
time period as may be agreed in the contractual arrangements, including clinical trial 
agreements, governing the relationship between the sponsor and authors (or authors’ institution) 
after receipt of the proposed publication by the sponsor, whichever of (i), (ii) or (iii) occurs 
first. 
The author undertakes to reasonably consider the sponsor's request for delay to the proposed 
publication should the sponsor reasonably deem premature to publish the results obtained at 
that particular stage of the study. 


 
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18 
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Guédé D, Reigner B, Vandenhende F et al. Bayesian adaptive designs in single ascending 
dose trials in healthy volunteers. Br J Clin Pharmacol 2014;78(2):393–400. 
10. 
D'Onofrio M, Ciaravino V, De Robertis R et al. Percutaneous ablation of pancreatic 
cancer. World J Gastroenterol 2016;22(44):9661-73. 
11. 
American Cancer Society. Pancreatic Cancer Survival Rates, by Stage. Last updated May 
2016, 
[available 
at: 
https://www.cancer.org/content/cancer/en/cancer/pancreatic-
cancer/detection-diagnosis-staging/survival-rates.html, accessed on 2017 June 26]. 
12. 
Rahib L, Smith BD, Aizenberg R et al. Projecting cancer incidence and deaths to 2030: 
the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer 
Res 2014;74(11):2913–21. 
13. 
Kleeff J, Michl P. Targeted therapy of pancreatic cancer: biomarkers are needed. Lancet 
Oncol 2017;18(4):421-2. 
14. 
Previdi MC, Carotenuto P, Zito D et al. Noncoding RNAs as novel biomarkers in 
pancreatic cancer: what do we know? Future Oncol 2017;13(5):443-53. 
15. 
Van Cutsem E, Cervantes A, Adam R et al. ESMO consensus guidelines for the 
management of patients with metastatic colorectal cancer. Ann Oncol 2016;27(8):1386-
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16. 
Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol 
2015;33(16):1809-24. 
17. 
King GT, Lieu CH, Messersmith WA. Frontline Strategies for Metastatic Colorectal 
Cancer: New Sides to the Story. AJHO 2016;12(10):4-11. 
18. 
Howlader N, AM N, M K, et al. SEER Cancer Statistics Review, 1975-2012, National 
Cancer 
Institute, 
Bethesda, 
MD. 
 
[available 
at: 
https://seer.cancer.gov/archive/csr/1975_2013/, accessed on 2017 June 26].  


 
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Khatri VP, Petrelli NJ, Belghiti J. Extending the frontiers of surgical therapy for hepatic 
colorectal metastases: is there a limit? J Clin Oncol 2005;23(33):8490-9. 
20. 
Clark JW, Grothey A. Systemic chemotherapy for metastatic colorectal cancer: 
Completed 
clinical 
trials. 
Last 
updated 
May 
2017, 
[available 
at: 
http://www.uptodate.com/contents/systemic-chemotherapy-for-metastatic-colorectal-
cancer-completed-clinical-trials, accessed 2017 June 26]. 
21. 
Bodei L, Mueller-Brand J Baum RP et al. The joint IAEA, EANM, and SNMMI practical 
guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. 
Eur J Nucl Med Mol Imaging 2013;40(5):800-16. 
22. 
Breeman W, de Blois E, Bakker W et al. Radiolabeling DOTA-Peptides with 90Y and 
177Lu to a high specific activity. In: Radionucleide Peptide Cancer Therapy 1st edition. 
Michigan, USA: Taylor and Francis; 2006:119-25. 
23. 
Food and Drug Administration, Center for Drug Evaluation and Research (CDER). 
Guidance for Industry. Estimating the maximum safe starting dose in initial clinical trials 
for 
therapeutics 
in 
adult 
healthy 
volunteers. 
July 
2005 
[available 
at: 
https://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf, accessed 2017 Jul 
04]. 
24. 
Wild D, Fani M, Fischer R et al. Comparison of somatostatin receptor agonist and 
antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med 
2014;55(8):1248–52. 
25. 
Gui X, Guzman G, Dobner PR et al. Increased neurotensin receptor-1 expression during 
progression of colonic adenocarcinoma. Peptides 2007;29(9):1609-15. 
26. 
Shimizu S, Tsukada J, Sugimoto T et al. Identification of a novel therapeutic target for 
head and neck squamous cell carcinomas: a role for the neurotensin-neurotensin receptor 
1 oncogenic signaling pathway. Int J Cancer 2008;123(8):1816-23. 
27. 
Zhou Z, Xie J, Cai Y et al. The significance of NTR1 expression and its correlation with 
β-catenin and EGFR in gastric cancer. Diagn Pathol 2015;10:128. 
28. 
Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 
1995;31(5):1249-56. 
29. 
Emami B, Lyman J, Brown A et al. Tolerance of normal tissue to therapeutic irradiation. 
Int J Radiat Oncol Biol Phys 1991;21(1):109–22. 
30. 
National Council on Radiation Protection and measurements. Misadministration of 
radioactive material in medicine – Scientific background, 1991, [available at: 
http://public.eblib.com/choice/publicfullrecord.aspx?p=3382330, accessed: 2017 Jul 04]. 
31. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0, 2018 [available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/ 
accessed 28 February 2018] 
32. 
Lassmann M, Chiesa C, Flux G et al. EANM Dosimetry Committee guidance document: 
good practice of clinical dosimetry reporting. Eur J Nucl Med Mol Imaging 
2011;38(1):192-200. 
33. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
1989;10(1):1-10. 
34. 
Wang-Gillam A, Li CP, Bodoky G et al. Nanoliposomal irinotecan with fluorouracil and 
folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy 
(NAPOLI-1): 
a 
global, 
randomised, 
open-label, 
phase 3 
trial. 
Lancet 
2016;387(10018):545-57. 


 
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35. 
Mayer RJ, Van Cutsem E, Falcone A et al. Randomized trial of TAS-102 for refractory 
metastatic colorectal cancer. N Engl J Med 2015;372(20):190919. 
36. 
Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus 
irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 
2004;351(4):337-45. 
37. 
Tibaldi FS, Beck BHL, Bedding AW et al. Implementation of a Phase 1 adaptive clinical 
trial in a treatment of type 2 diabetes. Drug Inf J 2008;42:455-65. 
38. 
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving 
Considerations for PET response criteria in solid tumors. J Nucl Med 2009;50(1):122-50. 
 


 
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19 
ATTACHMENTS 
19.1 
Attachment 1 – Study Schedule of Assessments for Phase I Dose Escalation 
 


 
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Table 7 
Schedule of Assessments for Phase I – For Subjects who are Screen Failures after IMP 
Screening Administration 
Procedures and assessments 
IMP Screening 
Discharge Visit [a] 
IMP Screening Follow-
up Visit [b] 
AEs 
x 
x 
Physical examination 
x 
x 
Vital signs  
x 
x 
Haematology and biochemistry [c] 
x 
x 
Urinalysis 
x 
x 
Prior/concomitant medication/therapy 
x 
x 
177Lu-3BP-227 screening administration 
x 
 
a 
before site discharge 
b 
5 weeks after the IMP Screening Discharge Visit +2 weeks. If the subject is not able to come 
for an onsite visit, the visit may be performed by phone call. The clinical laboratory tests may 
be done locally. If the subject is not available for a visit or a call, the investigator can contact 
his oncologist/general practitioner to get the data requested in protocol. 
c 
additional safety assessments including haematology and biochemistry can be done if 
clinically indicated 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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Table 8 
Schedule of Assessments for Phase I – Dose Escalation 
Procedures and 
assessments 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
Screening 
Treatment Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 
[d] 
D2 
D3 
D4 
D5 
D7 
D 15 D 22 
D29 
D1 
[e] 
D2 D3 D4 D5 D7 
D15 
D22 
D29 
D43 
Visit window 
(days) 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+7 
±14 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics and 
height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
x 
 
 
 
 
 
 
 
 
 
ECOG performance status 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
ceCT/MRI  
x [f] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
18F-FDG-PET 
 
x [g] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
177Lu-3BP-227 screening 
administration [h] 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour biopsy 
x [i] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
AE=adverse event; ceCT/MRI=contrast enhanced computed tomography/magnetic resonance imaging; cfDNA=cell-free deoxyribonucleic acid; D=Day; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; ED=early discontinuation; EOCT=end of core trial; IMP=investigational medicinal product; NTSR1=neurotensin receptor 1; PET=positron emission tomography; 
PK=pharmacokinetic; SPECT=single photon emission computed tomography. 
a 
the ED visit will take place within 14 days after ED from the study and at the latest 5 weeks after the last IMP administration, the visit will correspond to an EOCT visit. For subjects who 
received the screening IMP administration and found ineligible to participate to the study, an ED visit will be performed within 5 weeks (+ 2 weeks) after the IMP screening administration 
to assess the safety. At least, clinical laboratory tests (e.g. haematology and biochemistry), AEs and concomitant medication/therapy will be collected. If the subject is not able to come for an 
on-site visit, the visit may be performed by phone call. The clinical laboratory tests may be done locally.  
b 
follow-up visits will take place every 3 months (±2 weeks) and will start after the EOCT, ED or EOAC visit. Efficacy will be assessed until disease progression, administration of any other 
chemotherapy or radiotherapy, lost to follow-up, withdrawal of consent, death or a maximum of 2 years, whichever occurs first (see Section 6.2.3). After disease progression is confirmed, no 
further CT/MRI scans will be required for tumour/disease assessment. The survival status and safety of the subjects will continue to be monitored as indicated in Section 8.1.2.3 until lost to 
follow-up, withdrawal of consent, death or a maximum of 5 years, whichever occurs first.  
c 
the screening period can be extended by two weeks if this is required for logistical reasons. 
d 
Day 1 of Cycle 1 is the day of the first treatment administration. Day 1 of Cycle 2 and each potential subsequent cycle may coincide with Day 29 of the previous cycle if all safety assessments 
are performed and allow for the next administration. 
e 
in case of toxicity requiring a delay, the next treatment administration will be delayed by up to 4 weeks. 
f 
whole body ceCT or ceMRI including brain unless a similar exam has already been performed within 1 month prior to Day -21.  
g 
Cycle 1 Day 1 18FDG-PET between Day -21 and Day 1. 
h 
screening administration will be done after confirmation of eligibility (i.e. after all other screening assessments have been performed), minimum 1 week before the first treatment 
administration. 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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Procedures and 
assessments 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
Screening 
Treatment Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1  
[d] 
D2 
D3 
D4 
D5 
D7 
D 15 D 22 D29 
D1 
[d] 
D2 D3 D4 D5 D7 D15 D22 
D29 
D43 
Visit window 
(days) 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+7 
±14 
177Lu-3BP-227 treatment 
administration 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
177Lu-3BP-227 PK [j] 
 
x 
x 
x 
x 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
Planar scintigraphy [k] 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x  
 
 
 
 
 
SPECT/CT scan [k] 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x  
 
 
 
 
 
Blood sampling for 
3BP-227 PK [l] 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sampling for 
177Lu-3BP-227 PK [m] and 
3BP-227 PK [t] 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
i 
in case subject consents to have a  biopsy and in case it can be accomplished with reasonable safety, a tumour biopsy will be taken during screening from the primary or metastatic lesion, 
whichever is accessible, ideally on lesions which are positive for NTSR1 on 177Lu 3BP-227 SPECT/CT following IMP screening administration, as soon as 177Lu uptake has been confirmed. 
If not, archival tissue from a previous tumour biopsy can be used for exploratory analysis (tumour microenvironment analysis and transcriptomics). 
j 
eighteen blood samples will be collected during the treatment period. Blood samplings will be performed just before the 177Lu-3BP-227 infusion (baseline), at the end of infusion (0), 5 minutes 
±1 minute, 30 minutes ±5 minutes, 90 minutes ±15 minutes and 4 hours ±30 minutes, 24 hours ±2 hours, 48 hours ±2 hours and 72 to 96 hours post infusion. 
k eleven whole body scans (planar scintigraphy) and SPECT/CT acquisitions will be performed during the treatment period. Whole body scans (planar scintigraphy) and SPECT/CT scan will 
be performed at the following timepoints just after the end of 177Lu-3BP-227 infusion: Day 1: 4 (±2) hours, Day 2: 24 (±6) hours, Day 3: 48 (±6) hours, Day 4: 72 to 96 hours, and Days 7 to 
8: 138 to 168 hours. Within each cycle, a single SPECT/standard dose CT will be performed. A SPECT/low dose CT will be performed at all other timepoints. Details of the procedures will 
be provided in the Image Acquisition Guidelines. At screening, planar scintigraphy (1 or 2 timepoint(s) at the investigator’s discretion) and optional SPECT/CT scans (up to 2 at the 
investigator’s discretion) will be performed after screening administration of 177Lu-3BP-227. 
l 
ten blood samples will be collected at cycle 1. Blood samplings will be performed just before 177Lu-3BP-227 infusion (baseline), at the end of infusion of 177Lu-3BP-227 (0), 5 minutes 
±1 minute, 30 minutes ±5 minutes, 90 minutes ±15 minutes and 4 hours ±30 minutes, 6 hours ±30 minutes, 8 hours ±1 hour, 24 hours ±2 hours and 48 hours ±2 hours after the end of infusion 
of 177Lu-3BP-227. 
m four urine samples will be collected during the treatment period at the following time periods and only for Cycle 1: from the start of the IMP infusion to 6 hours, 6 to 12 hours, 12 to 24 hours, 
and 24 to 48 hours (from the start of the IMP infusion to 6 hours after the end of the infusion only for US sites) after the end of 177Lu-3BP-227 infusion. 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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Procedures and 
assessments 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
Screening 
Treatment Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 [d] 
D2 
D3 
D4 
D5 
D7 
D 15 D 22 D29 D1[d] D2 D3 D4 D5 D7 D15 D22 
D29 
D43 
Visit window 
(days) 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+7 
±14 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x [z] 
Physical examination 
x 
x [y] 
 
 
 
 
 
x 
 
x 
x 
 
 
 
 
 
x 
 
x 
x 
 
Vital signs  
x [n] 
x [n] 
x 
x 
 
 
x 
x 
x 
x 
x [n] 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Body weight 
x 
x [y] 
 
 
 
 
 
x 
 
x 
x 
 
 
 
 
 
x 
 
x 
x 
 
ECG (12-lead) [o] 
x 
x 
x 
 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
x 
 
24-hour 3-lead Holter ECG 
[p] 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Haematology  and 
biochemistry [w] 
x 
x [y] 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x [y] 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
x 
x 
 
Prior/concomitant 
medication/therapy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
n 
prior to and at the end of 177Lu-3BP-227 infusion (0) as well as 30±5 minutes, 90±15 minutes, 4 hours±30 minutes after the end of 177Lu-3BP-227 infusion. 
o 
during the screening period, a triplicate 12-lead ECG will be recorded before the screening administration (minus 15 minutes), and a single 12-lead ECG will be recorded at the end of 
177Lu-3BP-227 infusion (±15 minutes) and 4 hours (±30 minutes) after the end of infusion. At each treatment administration, a triplicate 12-lead ECG will be recorded on Day 1 before the 
infusion (baseline) (minus 15 minutes) and a single 12-lead ECG recordings at the end of 177Lu-3BP-227 infusion (±15 minutes), at 4 hours after the end of 177Lu-3BP-227 infusion 
(±30 minutes) and on Day 2 at 24 hours after the end of 177Lu-3BP-227 infusion (±4 hours) as well as at EOCT. All 12-lead computerised standard ECGs will be recorded in the supine 
position after at least 5 minutes of rest. 
p 
starting before 177Lu-3BP-227 infusion, a 24-hour 3-lead continuous ECG Holter will be recorded. 
 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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Procedures and 
assessments 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
Screening 
Treatment Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 [d] 
D2 
D3 
D4 
D5 
D7 
D 15 D 22 D29 D1[d] D2 D3 D4 D5 D7 D15 D22 
D29 
D43 
Visit window 
(days) 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+7 
±14 
Pregnancy test [q] 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Hormone analysis [r] 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Tumour markers in serum 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
q 
serum pregnancy test will be performed at the screening visit. A urine pregnancy test will be performed on Day1 prior to IMP administration and at EOCT/ED. 
r 
sample for hormone analysis (NTSR1 organ expressing) should be taken at the closest to 08:00. 
s 
  
t 
four urine samples will be collected during the treatment period at the following time periods and only for Cycle 1: from the start of the IMP infusion to 6 hours, 6 to 12 hours, 12 to 24 
hours, and 24 to 48 hours after the start of 177Lu-3BP-227 infusion (from the start of the infusion to 6 hours after the end of the infusion only for US sites). 
u 
 
v 
if an additional cohort of subjects is recruited to receive 3 cycles of therapy as described in the Study Design (dose escalation part Phase I), the schedule of assessments for the third cycle of 
therapy is to be the same as the schedule of assessments for Cycle 2. 
w additional safety assessments including haematology and biochemistry can be done if clinically indicated. 
x 
urine samples will be collected (and frozen) at the following timepoints: Cycle 1: Day 1: early morning, before the infusion (baseline), Day 3: early morning (48 hours after the end of 
177Lu-3BP-227 infusion at the latest) and EOCT/ED: early morning. 
y 
on Day 1, assessments to be done predose and up to 48 hours before IMP infusion. 
z 
Any AEs/SAEs, irrespective of causality, are to be reported to the sponsor up to 6 months after the EOCT, ED or EOAC visit or until new antitumour treatment starts, whichever comes 
first. After this timepoint, up to the end of the 5-year follow-up period, AEs/SAEs should only be reported if the event is evaluated as related to the IMP or study procedure by the 
investigator. 
 
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Table 9 
Schedule of Assessments for Additional Cycles in Case of Clinical Benefit and Good Tolerability 
Procedures and assessments 
Additional cycles 
EOAC or ED [g] 
D1 
D2 
D3 
D4 
D5 
D7 
D15 
D22 
D29 
D43 
Visit window (days) 
 
 
+1 
 
 
+1 
±1 
±1 
+7 
(+28) 
+7 
ECOG performance status 
x 
 
 
 
 
 
 
 
 
x 
ceCT/MRI [a] 
 
 
 
 
 
 
 
 
x 
x 
18F-FDG-PET 
 
 
 
 
 
 
 
 
 
x 
177Lu-3BP-227 treatment administration 
x 
 
 
 
 
 
 
 
 
 
Planar scintigraphy [b] 
x 
x 
x 
x 
x 
 
 
 
 
SPECT/CT scan [b] 
x 
x 
x 
x 
x 
 
 
 
 
Blood sampling for 177Lu 3BP-227 PK [c] 
x 
x 
x 
x 
 
 
 
 
 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
 
 
 
 
x 
x 
Vital signs  
x [d] 
x 
x 
 
 
x 
x 
x 
x 
x 
Body weight 
x 
 
 
 
 
 
x 
 
x 
x 
ECG (12-lead) [e] 
x 
 
 
 
 
 
 
 
 
x 
Haematology and biochemistry 
x 
x 
 
 
 
x 
x 
x 
x 
x 
Urinalysis  
x 
 
 
 
 
 
 
 
x 
x 
Prior/concomitant medication/therapy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test [f] 
x 
 
 
 
 
 
 
 
 
x 
Tumour markers in serum 
x 
 
 
 
 
 
 
 
 
x 
AE=adverse event; ceCT/MRI=contrast enhanced computed tomography/magnetic resonance imaging; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOAC=end of additional cycles; IMP=investigational medicinal product; PET=positron emission tomography; PK=pharmacokinetic; SPECT=single photon emission computed tomography. 
a 
ceCT/MRI will be done every 2 cycles during additional administrations, to confirm the clinical benefit after 2 additional administrations (i.e. at Cycle 4 and EOAC). In case of early 
discontinuation, the ceCT/MRI should be performed at the ED visit, to confirm any disease progression. 
b 
full dosimetry assessment will be performed after the first and third additional administrations as described for Cycles 1 and 2. After the second and fourth additional administrations, only a 
single SPECT/standard dose CT at 48 (±6) hours will be performed 
c 
After  the first and the third additional administration, blood samplings will be performed just before 177Lu-3BP-227 infusion (baseline), at the end of infusion of 177Lu-3BP-227 (0), 
5 minutes ±1 minute, 30 minutes ±5 minutes, 90 minutes ±15 minutes and 4 hours ±30 minutes, 24 hours ±2 hours and 48 hours ±2 hours, and 72 to 96 hours ±2 hours. After the second and 
fourth additional administrations a single blood collection will be performed at 24 hours only (as close as possible to the SPECT/CT).  
d 
prior to and at the end of 177Lu-3BP-227 infusion (0) as well as 30±5 minutes, 90±15 minutes, 4 hours±30 minutes after the end of 177Lu-3BP-227 infusion. 
e 
at each cycle, a triplicate 12-lead ECG will be recorded on Day 1 before the infusion (baseline) (minus 15 minutes). A single 12-lead  computerised standard ECG, with paper printout, will 
be recorded in supine position after at least 5 minutes of rest during each cycle on Day 1 at the end of 177Lu-3BP-227 infusion (±15 minutes) and at 4 hours (±30 minutes) after the end of 
177Lu-3BP-227 infusion as well as at EOAC. 
f 
a urine pregnancy test will be performed on Day 1 prior to IMP administration. 
g the ED visit will take place within 14 days after ED from the study and at the latest 5 weeks after the last IMP administration. 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
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19.2 
Attachment 2 – Blood Sampling Summary 
This table gives an indication of the number of (veni) punctures and blood volumes for all blood 
sampling (screening, safety laboratories and bioanalytical assays) during the study. Since this 
is a multicentre study using local labs, blood volumes for some assessments may vary between 
labs depending on their internal processes.  
Fewer venipunctures and blood draws may actually occur if needed for safety purposes, but this 
will not require a protocol amendment. 
Purpose 
Maximum  
blood volume per 
sample (mL) 
Maximum 
number of 
blood samples 
Maximum total 
volume (mL) 
Screening 
Clinical laboratory tests [a] 
25 
1 
25 
Core trial 
Clinical laboratory tests [a] 
25 
10 
250 
Radiopharmaceutical PK blood 
2 
18 
36 
3BP-227 PK 
2 
11 
22 
Tumour markers in serum 
3 
2 
6 
EOCT/ED 
Clinical laboratory tests [a] 
25 
1 
25 
Tumour markers in serum 
2 
1 
2 
Additional cycles (number per cycle) 
Clinical laboratory tests [a] 
25 
6 
150 
Radiopharmaceutical PK blood 
2 
9 
18 
Tumour markers in serum 
2 
1 
2 
EOAC 
Clinical laboratory tests [a] 
25 
1 
25 
Tumour markers in serum 
2 
1 
2 
LTFU 
Clinical laboratory tests [a] 
25 
8 
200 
Total volume over study period 
 
Approximately 820 mL 
βHCG=beta human chorionic gonadotrophin; ED=early discontinuation; EOCT=end of core trial; LTFU=long-term 
follow-up; PK=pharmacokinetic. 
a 
clinical laboratory tests include blood samples for the analysis of haematology, biochemistry, serum βHCG 
(pregnancy test) and hormone analysis as applicable according to the schedule of assessments. 
b 
 
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19.3 
Attachment 3 – Clinical Laboratory Tests 
Haematology 
Screening 
Core 
trial 
EOCT/ 
ED 
Additional 
cycles 
EOAC 
LTFU 
RBC count  
x 
x 
x 
x 
x 
 
Haematocrit 
x 
x 
x 
x 
x 
 
Hb 
x 
x 
x 
x 
x 
x 
MCV 
x 
x 
x 
x 
x 
 
WBC count  
x 
x 
x 
x 
x 
x 
Absolute counts of: 
x 
x 
x 
x 
x 
x 
• 
Neutrophils 
 
 
 
 
 
 
• 
Lymphocytes 
 
 
 
 
 
 
• 
Monocytes 
 
 
 
 
 
 
• 
Eosinophils 
 
 
 
 
 
 
• 
Basophils 
 
 
 
 
 
 
Platelets count 
x 
x 
x 
x 
x 
x 
ED=early discontinuation; EOAC=end of additional cycles; EOCT=end of core trial; Hb= haemoglobin; LTFU=long-term 
follow-up; MCV=mean corpuscular volume; RBC=red blood cell; WBC=white blood cell. 
 
Clinical chemistry 
Screening 
Core 
trial 
EOCT/ 
ED 
Additional 
cycles 
EOAC 
LTFU 
ALT 
x 
x 
x 
x 
x 
x 
Albumin 
x 
x 
x 
x 
x 
 
ALP 
x 
x 
x 
x 
x 
 
AST 
x 
x 
x 
x 
x 
x 
Calcium 
x 
x 
x 
x 
x 
 
Chloride 
x 
x 
x 
x 
x 
 
Conjugated bilirubin (direct) [a] 
x 
x 
x 
x 
x 
x 
Creatinine 
x 
x 
x 
x 
x 
x 
CRP 
x 
x 
x 
x 
x 
 
eGFR 
x 
x 
x 
x 
x 
 
Glucose  
x 
x 
x 
x 
x 
 
Potassium 
x 
x 
x 
x 
x 
 
Sodium 
x 
x 
x 
x 
x 
 
Total bilirubin 
x 
x 
x 
x 
x 
x 
Total cholesterol 
x 
x 
x 
x 
x 
 
Total protein 
x 
x 
x 
x 
x 
 
TG 
x 
x 
x 
x 
x 
 
Urea 
x 
x 
x 
x 
x 
x 
Uric acid 
x 
x 
x 
x 
x 
 
Serum tumour markers:  
• 
CEA - all subjects 
• 
CA 19-9 – all subjects except 
SCCHN 
• 
Serum LDH and BSAP for ES 
 
x 
x 
x 
x 
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BSAP=Bone Specific 
Alkaline Phosphatase; CA 19-9=cancer antigen 19-9; CEA=carcinoembryonic antigen; eGFR=estimated glomerular 
filtration rate; ED=early discontinuation; EOAC=end of additional cycles; EOCT=end of core trial; ES=Ewing Sarcoma;  
LDH=Lactate dehydrogenase; LTFU=long-term follow-up; SCCHN=squamous-cell carcinoma of head and neck; 
TG=triglycerides. 
a 
only to be performed if the total bilirubin is abnormal i.e. outside the laboratory normal range 
 


 
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Urinalysis 
Screening 
Core 
trial 
EOCT/ 
ED 
Additional 
cycles 
EOAC 
LTFU 
Urinalysis (dipstick) 
 
 
 
 
 
 
Bilirubin 
x 
x 
x 
x 
x 
 
Blood 
x 
x 
x 
x 
x 
 
Glucose 
x 
x 
x 
x 
x 
 
Ketones 
x 
x 
x 
x 
x 
 
Leucocytes 
x 
x 
x 
x 
x 
 
Nitrite 
x 
x 
x 
x 
x 
 
pH 
x 
x 
x 
x 
x 
 
Protein 
x 
x 
x 
x 
x 
 
Proteinuria 
x 
x 
x 
x 
x 
 
Specific gravity 
x 
x 
x 
x 
x 
 
Urobilinogen 
x 
x 
x 
x 
x 
 
Urine collection 
 
 
 
 
 
 
Proteinuria (only in case dipstick 
is positive, according to 
investigator’s discretion and 
sufficient radioactivity excretion 
from the subject) 
x 
x 
x 
x 
x 
 
ED=early discontinuation; EOAC=end of additional cycles; EOCT=end of core trial; LTFU=long-term follow-up. 
 
Hormone analysis 
Screening 
Core 
trial 
EOCT/ 
ED 
Additional 
cycles 
EOAC 
LTFU 
Cortisol 
x 
 
x 
 
 
 
fT4 and TSH 
x 
 
x 
 
 
 
IGF-1 
x 
 
x 
 
 
 
PTH 
x 
 
x 
 
 
 
ED=early discontinuation; EOAC=end of additional cycles; EOCT=end of core trial; fT4=free thyroxine; 
IGF1=insulin-like growth factor 1; LTFU=long-term follow-up; PTH=parathyroid hormone; TSH=thyroid-stimulating 
hormone. 
 
Pregnancy test 
Screening 
Core 
trial 
EOCT/ 
ED 
Additional 
cycles 
EOAC 
LTFU 
 
urine/serum 
urine 
urine 
urine 
urine 
 
ED=early discontinuation; EOAC=end of additional cycles; EOCT=end of core trial; LTFU=long-term follow-up. 


 
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19.4 
Attachment 4 – RECIST Version 1.1 Guidelines 
 


 
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19.5 
Attachment 5 – Statistical Details and Simulation Results for Implementation of 
Adaptive Bayesian Dose Escalation Design 
19.5.1 
Statistical Model 
After study screening procedures, eligible subjects will receive up to 2 i.v. administrations of 
177Lu-3BP-227 in two consecutive treatment cycles 4 weeks apart. A range of doses will be 
tested, including possibly 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 and 7.5 GBq per cycle. Additional 
or alternative dose levels may be chosen. These possible dose levels are labelled as d=1, …, N, 
where N is the maximum number of dose levels for the study. 
The analysis is based on a method reported by Guede et al.[9] and Tibaldi et al. [37]. 
If, during Cycle 1, a subject receives dose d1 and in Cycle 2 dose d2, the probability, p, of 
observing a subject with DLTs up to 4 weeks after the two cycles of dosing is modelled as a 
function of dose as: 
 
where p0, MTSA and β are the model parameters having the following interpretation: 
• 
p0 is the probability of observing DLTs under placebo (d1=d2=0),  
• 
MTSA is the maximum tolerated single activity, being defined as the dose d1 at which 
the predicted probability of DLTs is 33% for dosing Cycle 1 (single dose), and 
• 
β is a slope coefficient indicating the impact of a second dose d2 on DLT probability. 
The prior distribution on p0, MTSA and β determine the prior distribution on the probability of 
DLT as a function of up to two doses. For cycle 1 data analysis, the dose d2 is set to zero. So, 
only parameters p0 and MTSA are involved. β is involved when subjects undergo their second 
cycle. A positive β indicates an increase in DLT probability with second dose. 
The MTCA is defined as the maximum tolerated cumulative activity (d=d1+d2, where d1=d2) 
that may be administered following fractionated i.v. administrations of the same dose d1 at least 
4 weeks apart so that no more than 33% of the subjects experience a DLT during Cycles 1 
and/or 2. 
The MTCA can be presented as a derived parameter from the logistic regression model. It is 
expressed as: 
 
The MTCA will be equal to twice the MTSA when β equals 0 (i.e. the DLT probability is not 
changed after a second dose). When the DLT probability is increased (β>0), the MTCA will be 
decreased (and vice versa).  
During the study, the target organ exposure will be monitored after each dose and doses may 
be adapted if the exposure exceeds organ-specific maximum acceptability limits. As such, if 
the predicted MTCA exceeds the maximum acceptability limits for target organ exposure, the 
maximum radioactivity dose will be used instead. This feature was not considered in the 
simulation study, where it was assumed that a cumulative dose up to 15 GBq would induce an 
acceptable organ exposure. 
Prior distributions were elicited based on historical knowledge about the placebo DLT rate and 
the MTSA target. The following prior distributions are used in the trial: 
݌଴~ܾ݁ݐܽሺܽൌ1, ܾൌ9ሻ, 
MTSA~݃ܽ݉݉ܽ ሺݏ݄ܽ݌݁ൌ4, ݎܽݐ݁ൌ0.5ሻ, 
and 
2
1
0
0
*
)
(
logit
%)
33
logit(
)
(
logit
)
(
logit
d
d
MTSA
p
p
p
E



 
.
*
p
logit 
 - 
33%
logit 
ogit
%
33
logit
*
MTSA
*
2 
MTCA 
0
0
MTSA
p
l
E


 


 
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ߚ~݊݋ݎ݈݉ܽ ሺμ ൌ0, ݏ݀ൌ0.25ሻ. 
Based on these distributions, 20 dose-DLT curves from the prior distribution were simulated 
after Dose 1 (black) and after Dose 1 and 2 (red) (see Figure 3). The prior probability 
distributions for the MTSA is summarised in Table 10. The prior probability distributions for 
the MTCA is summarised in Table 11 
 
Figure 3 40 Random Observations (Curves) from the Prior Distribution 
 
Table 10 Prior Probability Distribution of MTSA 
Dose range for Cycle 1 
Prior MTSA probability 
2.5 GBq 
5.2% 
2.5 to 5 GBq 
20.6% 
5 to 7.5 GBq 
28.6% 
>7.5 GBq 
45.6% 
MTSA=Maximum tolerated single activity. 
Table 11 Prior Probability Distribution of MTCA 
Dose range (cumulative) 
Prior MTCA probability 
≤5 GBq 
32.5% 
5 to 10 GBq 
24.6% 
10 to 15 GBq 
15.7% 
>15 GBq 
27.2% 
MTCA= Maximum tolerated cumulative activity. 
Given any set of data, the prior distribution can be updated, yielding a posterior distribution of 
the parameters. From this posterior distribution many different quantities of relevance can be 
calculated: 
• 
E(p|d1, d2)=Posterior mean probability of DLT for Cycle 1 dose d1 and Cycle 2 dose d2. 
• 
TSd=(tolerable) Probability that the DLT rate is below 0.33, Pr(p≤0.33| d,0), for a Cycle 1 
dose d (d2=0). 
• 
QSd=Probability of Cycle 1 dose d being the maximum dose where E(p|d,0) ≤0.33. 
• 
TCd=(tolerable) Probability that the DLT rate is below 0.33, Pr(p≤0.33| d/2,d/2), for a 
cumulative dose d (d1=d2=d/2). 
• 
QCd=Probability of cumulative dose d being the maximum dose where E(p|d/2,d/2) 
≤0.33. 


 
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Note that, in this model, the MTSA and MTCA are parameters. They have a probability 
distribution. A consequence of the Bayesian modelling is the probabilities, QSd, which is the 
probability that a dose is the MTSA for Cycle 1 and QCd, which is the probability that a 
cumulative fractional dose is the MTCA after Cycle 2. This is a powerful question that cannot 
be answered from a frequentist perspective. 
19.5.2 
Trial Simulation Details 
This section present results of trial simulation study that was performed to determine the 
operational characteristics of the adaptive dose escalation procedure. The design of that 
simulation study is very similar to the actual study design, with some changes necessary to 
enable the automation of trial simulations. The impact of any discrepancy should be negligible. 
The trial design involves two sets of rules, namely: 
(1) 
dose-escalation rules for the next cohort when the current cohort completes Cycle 2, and 
(2) 
rules for Cycle 2 dosing after completion of Cycle 1. 
A cohort will be considered as ended once three subjects of the cohort complete Cycle 2 or 
early discontinue during Cycle 2. Subjects with DLTs in Cycle 1 will be discontinued prior to 
Cycle 2.  
Once five subjects are enrolled in a cohort, the cohort will be considered as ended, after all five 
subjects complete Cycle 2 or discontinue early during Cycle 1 or 2. 
For the purpose of simulations, the dose decisions will be made at the following milestones:  
• 
Cycle 2 dosing will be determined only once the full cohort, including any replacement 
subjects, completes Cycle 1 (as opposed to on an individual basis in the study). 
• 
The dose for the next cohort will be decided once the current cohort has ended. 
The timing of these decisions will slightly vary during the study, as it is currently planned to 
decide the Cycle 2 dose on an individual subject basis and to decide for the next cohort once up 
to three subjects in the current cohort are 3 weeks into Cycle 2. The impact of these changes 
should be minimal. 
The inter cohort dose escalation will be performed as follows: 
(1) 
The starting dose will be d=5 GBq fractionated into two administrations of 
d1=d2=2.5 GBq per cycle and the first cohort will include three subjects. 
(2) 
If there is no DLT during Cycle 1, the radioactivity for the next cohort will be increased 
by 3 GBq (1.5 GBq/cycle) up to 11 GBq (5.5 GBq/cycle) and then by 2 GBq 
(1 GBq/cycle) up to the last planned cohort of 15 GBq (7.5 GBq/cycle). Cohort size will 
be three subjects. 
(3) 
If at least one subject in a cohort reports any DLT, wait for the corresponding cohort 
(including any replacement) to end the study, then fit the Bayesian model to all available 
Cycle 1 and Cycle 2 data, and select next dose as the dose d at which QSd is maximum, 
or the maximum allowed dose if any of the following constraints are met: 
(a) 
if there are two DLTs out of three, three DLTs out of five, or three DTLs out of 
six subjects receiving a single or cumulative dose, d must be lower than or equal 
to that dose; 
(b) 
if there are three DLTs out of three, or at least three DLTs out of four, or at least 
four DLTs out of five, or at least four DLTs out of six subjects receiving a single 
or cumulative dose, d must be lower than that dose; 
(c) 
dose d must be at most 1 GBq larger than the maximum Cycle 1 dose tested 
previously. 


 
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Repeat steps 2 and 3 again, assigning the subjects/cohort to this dose. Terminate study 
enrolment when any of the following stopping rules happen: 
A 
the MTSA is precisely estimated: CV (MTSA) calculated as the inter-quartile 
range over the median is lower than 30%;  
B 
maximum possible dose (7.5 GBq) is safe: TS7.5>80% and d1=7.5 GBq 
administered; 
C 
minimum dose tested (2.5 GBq) is toxic: TS2.5 <20%;  
D 
total sample size for next dose is already ≥6. 
The MTSA will be declared to be found when study stops for criteria A or D. 
Individual dosing decision for the second treatment cycle will be done as follows:  
• 
Subject will be eligible for Cycle 2 only if subject had no DLT during Cycle 1. Subjects 
with DLTs in Cycle 1 will be discontinued and replaced with a maximum of two 
replacements. 
• 
The same fractional dose as in Cycle 1 will be repeated during Cycle 2 (d2=d1), if the 
dose having the largest probability to be the MTCA is larger than 2 x d1. 
• 
The fractional dose for Cycle 2 will be decreased to d2=MTCA-d1 dose, if the predicted 
cumulative exposure after Cycle 2 is above the MTCA target. In this situation, the 
cumulative exposure after two cycles should not exceed the MTCA. 
The study will be terminated when all cohorts have ended the study, as defined above. 
19.5.3 
Simulation Scenarios 
Five dose-DLT profiles were considered to evaluate the operational characteristics of the 
adaptive dose escalation trial (see Figure 4 and Table 12 below). The five scenarios are: 
Scenario A – Maximum dose safe: This scenario represents a negative scenario under which 
all doses are safe for the two dosing occasions. The true MTSA (15 GBq) and true MTCA 
(30 GBq) are larger than the maximum possible doses in the study.  
Scenario B - Late MTCA: This is a scenario is which the MTCA=MTSA=14 GBq. All Cycle 
1 doses are safe. After Cycle 2, cumulative doses up to and including 14 GBq are safe. The 
probability of a DLT is gradually increasing across all dose levels.  
Scenario C – Early MTCA: In this scenario, the rate of DLT progression is faster over doses 
so that the MTSA (7 GBq) during Cycle 1 appears near the end of the dosage range. The MTCA 
after Cycle 2 is 9 GBq. 
Scenario D - Toxic: Under this scenario, all doses are toxic, with a DLT rate of 46% at the 
lowest single dose of 2.5 GBq or at the repeated cumulative dose of 5 GBq. The MTSA (2 GBq) 
is below but close to the lowest single dose of 2.5 GBq. The MTCA is also equal to 2 GBq, so 
that any Cycle 2 dosing is toxic. 
Scenario E - Peak: In this scenario, there is a step function in the probability of DLTs occurring 
in the middle of the dose escalation process during Cycle 1 and early in Cycle 2. The first doses 
up to and including MTSA=5.5 GBq are very safe (p=5%), and all subsequent single doses are 
toxic (p=80%). After Cycle 2, the MTCA is 5 GBq and all subsequent doses are toxic. 


 
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Figure 4 Dose versus DLT Rates After Cycle 1 and Cycle 2 Simulation Scenarios 
 
Table 12 Simulated Dose-DLT Probabilities 
Dose (GBq) 
A: Safe 
B: Late MTD 
C: Early MTD 
D: Toxic 
E: Peak 
Cycle 1 
2.5 
7% 
7% 
10% 
46% 
5% 
3.0 
8% 
8% 
12% 
60% 
5% 
3.5 
8% 
8% 
14% 
72% 
5% 
4.0 
9% 
9% 
16% 
82% 
5% 
4.5 
9% 
10% 
18% 
89% 
5% 
5.0 
10% 
10% 
21% 
93% 
5% 
5.5 
11% 
11% 
23% 
96% 
5% 
6.0 
11% 
12% 
26% 
98% 
80% 
6.5 
12% 
13% 
30% 
99% 
80% 
7.0 
13% 
14% 
33% 
99% 
80% 
7.5 
14% 
15% 
37% 
100% 
80% 
Cycle 2 
5.0 
7% 
10% 
15% 
46% 
5% 
6.0 
8% 
12% 
18% 
60% 
80% 
7.0 
8% 
13% 
21% 
72% 
80% 
8.0 
9% 
15% 
26% 
82% 
80% 
9.0 
9% 
17% 
30% 
89% 
80% 
10.0 
10% 
20% 
36% 
93% 
80% 
11.0 
11% 
22% 
41% 
96% 
80% 
12.0 
11% 
25% 
47% 
98% 
80% 
13.0 
12% 
28% 
53% 
99% 
80% 
14.0 
13% 
32% 
58% 
99% 
80% 
15.0 
14% 
35% 
64% 
100% 
80% 
DLT=dose limiting toxicity, MTD=maximum tolerated dose. 
19.5.4 
Operational Characteristics 
We used 1000 trial simulations to monitor the following properties of the adaptive design under 
the five scenarios: 
• 
accuracy and precision of the MTSA and MTCA 
• 
probability of archiving each of the four stopping rules (MTSA precision, last dose is 
safe, first dose is toxic, maximum sample size) 
• 
total sample size after Cycle 1 and Cycle 2 


 
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• 
total number of cohorts 
• 
number and proportion of subjects being overdosed during Cycle 1 and Cycle 2 
(i.e. relative to the true MTSA and MTCA, respectively) 
• 
subject distribution across dose levels. 
Calculations were performed in R statistical software version 2.7.2 and using the BRugs 
package running on OpenBUGS version 2.2.0 for the Bayesian estimation. The posterior 
distribution was estimated using one MCMC chain based on 1000 iterations, after a burn-in of 
2000 samples. The initial values were set to p0=5%, MTD=5 GBq and β=0. Convergence was 
monitored by visual inspection of the diagnosis plots for a sample dataset spread across all five 
scenarios. 
19.5.5 
Simulation Results 
The operational characteristics for the five trial simulation scenarios are presented in Table 13. 
The mean (SD) sample size per dose is shown in Figure 5. 
A box plot of the total sample size is in Figure 6 for Cohort 1 and in  
Figure 8 for Cohort 2. 
The number of cohorts is in  
Figure 8 
. 
Overall, simulations performed as expected, under all scenarios, taking into account the 
constraints about the maximum fold-increase, the repeated dosing, the overdose control and the 
maximum sample size. The dose escalation for Cycle 1 was pursued up to the top single dose 
of 7.5 GBq under a similar pattern for the Safe, Early and Late scenarios, where the MTSA was 
either above the top dose (Safe, Late) or close to it (Early). Under the Toxic scenario, only low 
doses were administered, with an MTSA estimated near the first single dose (2.5 GBq) in most 
trials. When the MTSA and MTCA were within the dosage range (Peak), the escalation was 
performed up to the target dose of 5 to 5.5 GBq, followed by an adaptation around it. The 
MTSA and MTCA were found with precision in most trials and their relative errors remain 
good. There was a high proportion of trials stopped with the MTSA found (either based on CV 
or sample size criteria). As expected, sample size and cohort size were larger when escalation 
had to proceed up to the top doses (Safe, Late, Early) than when the MTSA was low (Toxic and 
Peak). In 80% of trial simulations, the total number of subjects was not larger than 28 in a 
maximum of seven cohorts. The number of overdoses was low in Cycle 1. It did not increase 
during Cycle 2, except when the second dose brought more toxicity (Early, Peak). 
These results validate the use of the Bayesian model and the adaptive dose escalation plan for 
this study. 


 
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Table 13 Main Operational Characteristics for the Five Trial Simulation Scenarios 
Criterion 
A: Safe 
B: Late 
C: Early 
D: Toxic 
E: Peak 
% stops for reason: 2.5 GBq is toxic 
 
 
 
23.4 
 
% stops for reason: 7.5 GBq is safe 
58.9 
46.4 
5.90 
 
 
% stops for reason: CV (MTSA)≤30% 
34.0 
42.4 
69.0 
34.1 
92.1 
% stops for reason: N≥6 
7.10 
11.2 
25.1 
42.5 
7.90 
% trials (MTSA>top dose) 
94.9 
92.5 
48.8 
. 
0.8 
% trials (MTSA<first dose) 
. 
. 
. 
38.1 
. 
Median MTSA (GBq) 
10.5 
9.9 
7.4 
2.7 
4.8 
Median MTSA Rel. Error (%) [a] 
30.2% 
29.2% 
15.3% 
34.2% 
13.8% 
Mean CV (MTSA) (%) 
28.8% 
28.9% 
28.9% 
43.5% 
21.5% 
Median MTCA (GBq) 
17.4 
14.7 
9.5 
4.2 
6.2 
Median MTCA Rel. Error (%) [a] 
41.9% 
19.7% 
16.9% 
112% 
25.2% 
Mean CV (MTCA) (%) 
17.3% 
26.9% 
39.5% 
54.2% 
25.7% 
Mean (SD) number of overdosed subjects (Cycle 
1) 
0.0 (0.0) 
0.0 (0.0) 
1.8 (2.1) 
9.1 (3.6) 
5.5 (1.5) 
[Min, Max] 
[0.0, 0.0] 
[0.0, 0.0] 
[0.0, 5.0] 
[5.0, 19.0] [0.0, 14.0] 
Mean (SD) number of overdosed subjects (Cycle 
2) 
0.0 (0.0) 
1.7 (1.5) 
6.3 (2.9) 
3.6 (1.9) 
7.8 (1.9) 
[Min, Max] 
[0.0, 0.0] 
[0.0, 3.0] 
[0.0, 12.0] [0.0, 9.0] 
[0.0, 15.0] 
Mean (SD) number of subjects (Cycle 1) 
17.5 (3.0) 17.7 (3.3) 18.7 (4.3) 9.1 (3.6) 
15.9 (2.5) 
[Min, Max] 
[5.0, 25.0] [5.0, 28.0] [5.0, 31.0] [5.0, 19.0] [5.0, 28.0] 
Mean (SD) number of subjects (Cycle 2) 
15.7 (2.5) 15.7 (2.7) 14.3 (3.3) 3.6 (1.9) 
10.8 (2.0) 
[Min, Max] 
[2.0, 21.0] [2.0, 21.0] [2.0, 21.0] [0.0, 9.0] 
[2.0, 18.0] 
Mean (SD) number of cohorts 
5.3 (0.8) 
5.3 (0.9) 
5.1 (1.1) 
2.0 (0.9) 
4.4 (0.6) 
[Min, Max] 
[1.0, 7.0] 
[1.0, 7.0] 
[1.0, 7.0] 
[1.0, 4.0] 
[1.0, 7.0] 
CV=coefficient of variation; Max=maximum; Min=minimum; MTSA=maximum tolerated single activity. 
a 
Rel. Error=|MTDtrue-MTDmedian|/MTDtrue 


 
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Figure 5 Mean (SD) Sample Size per Single or Cumulative Dose Level for the Five Simulation Scenarios 
 
 
Mean (+sd) number of subjects
scenario = E
scenario = D
scenario = C
scenario = B
scenario = A
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
10.5
11
11.5
12
12.5
13
13.5
14
14.5
15
Cumulative Dose (GBq)
0
2
4
6
0
2
4
6
0
2
4
6
0
2
4
6
0
2
4
6


 
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Figure 6 Boxplot of Total Number of Subjects During Cycle 1 for the Five Simulation Scenarios 
 
 
Figure 7 Boxplot of Total Number of Subjects During Cycle 2 for the Five Simulation Scenarios 
 
A
B
C
D
E
Simulation scenario
5
10
15
20
25
30
Number of subjects (Cycle 1)
A
B
C
D
E
Simulation scenario
0
5
10
15
20
Number of subjects (Cycle 2)


 
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Figure 8 Boxplot of Total Number of Cohorts for the Five Simulation Scenarios 
 
 
A
B
C
D
E
Simulation scenario
1
2
3
4
5
6
7
Number of cohorts


 
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19.6 
Attachment 6 – RECIST to PERCIST  
 
 
 
 
 


 
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19.7 
Attachment 7 – Protocol Amendment #7 Summary 


 
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PROTOCOL VERSION 8.0 
STUDY NUMBER: 
D-FR-01087-001 
PROTOCOL TITLE: 
An international multicentre, open-label first in human phase I/II study to evaluate the safety, tolerability, 
biodistribution and antitumour activity of 177Lu-3BP-227 for the treatment of subjects with solid tumours 
expressing neurotensin receptor 1 
AMENDED PROTOCOL VERSION 
NUMBER AND DATE 
Version 8.0: 12 June 2020 
THE FOLLOWING AMENDMENTS ARE PROPOSED: 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
Cover Page, 
Agreement 
Protocol Version 7.0, dated 20 June 2019 
Protocol Version 8.0, dated 12 June 2020 
Administrative update 
Cover Page 
Serious Adverse Event Reporting 
Fax: 
 
Serious Adverse Event Reporting 
Fax Number: 
 
USA and Latin America Fax Number: 
 
 
Administrative update 
Cover Page 
Sponsor Authorised Protocol Approver 
Name, Title: 
 
 
 
 
 
 
 
 
 
Sponsor Authorised Protocol Approver 
Name, Title: 
 
 
 
 
Administrative update 
Cover page 
Sponsor Medical Monitor 
Name, Title: 
 
 
 
 
 
 
Sponsor Medical Monitor 
Name, Title: 
 
  
 
 
Administrative update 
Agreement 
Sponsor 
Name:
 
 
 
Sponsor 
Name: 
 
 
Administrative update 
Synopsis, 2.1 
STUDY HYPOTHESIS 
Phase I 
177Lu-3BP-227 is sufficiently well-tolerated to permit 
clinical investigation in the phase II part. 
STUDY HYPOTHESIS 
Phase I 
177Lu-3BP-227 is sufficiently well-tolerated to permit 
clinical investigation in phase II. 
Clarification 
Synopsis, 2.2 
STUDY HYPOTHESIS 
Phase II 
STUDY HYPOTHESIS 
Phase II 
FDA request to clarify the eligible 
subject 
population: 
inclusion 
PPD
PPD
PPD
PPD
PP
D
PPD
PPD
PPD
PPD


 
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Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
177Lu-3BP-227 yields higher objective response rates in 
subjects who have NTSR1 expressing metastatic or
locally advanced cancers, based on RECIST version 1.1 
by central review and as compared with the historical 
ORR obtained by current standard-of-care treatment for 
each tumour type. 
177Lu-3BP-227 yields higher objective response rates in 
subjects who have NTSR1 expressing cancers that are
unresectable, locally advanced or metastatic, based 
on RECIST version 1.1 by central review and as 
compared with the historical ORR obtained by current 
standard-of-care treatment for each tumour type. 
criterion should clearly state 
nonresectable locally advanced 
disease. 
Synopsis, 1.5, 1.7, 
3.1.1, 3.1.2, 4.1, 
4.2.1, 4.3 
...subjects with metastatic or locally advanced... 
...subjects with unresectable, locally advanced or 
metastatic... 
FDA request to clarify the eligible 
subject 
population: 
inclusion
criterion should clearly state 
nonresectable locally advanced 
disease 
Synopsis, 3.2.1 
Secondary objectives 
Phase I 
… 
b) 
To determine the radiation dosimetry of 177Lu-
3BP-227 (organ exposure to radiation) after each 
administration. 
Secondary objectives 
Phase I 
… 
b) 
To determine the radiation dosimetry of 177Lu-
3BP-227 (organ exposure to radiation). 
Clarification 
Synopsis, 3.3.1 
Exploratory objectives 
Phase I/II 
a) 
To explore the correlation between the tumour 
uptake of 
177Lu-3BP-227 and the NTSR1
expression on tumours. 
b) 
To explore renal and haematological safety by 
measuring urinary specific biomarkers and
deoxyribonucleic 
acid-double 
strand 
breaks 
(DNA-DSB) in peripheral lymphocytes (at 
selected centres). 
c) 
To evaluate the tumour microenvironment, 
transcriptomics, and other markers of interest for 
the disease through assessment of tumour biopsies. 
d) 
To explore genomic alterations in circulating cell-
free DNA (cfDNA) as compared to germline 
DNA. 
Exploratory objectives 
Phase I/II 
a) To explore the correlation between the tumour 
uptake 
of 
177Lu-3BP-227 
and 
the 
NTSR1 
expression on tumours. 
b) To explore renal safety by measuring urinary 
specific biomarkers. 
c) To 
evaluate 
the 
tumour 
microenvironment, 
transcriptomics, and other markers of interest for 
the disease through assessment of tumour biopsies. 
d) To explore genomic alterations in circulating cell-
free DNA (cfDNA) and in germline DNA. 
Assessment of haematological 
safety markers (DNA-DSB in 
peripheral lymphocytes) removed 
and clarification of the genomic 
alteration assessment 
Synopsis, 4.4.3 
Exploratory endpoints 
• Tumour microenvironment and other markers of 
interest (such as NTSR1 expression, Ki67, gene 
Exploratory endpoints 
• 
Tumour microenvironment and other markers of 
interest (such as NTSR1 expression, Ki67, gene 
Clarification 


 
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Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
expression and DNA-DSB) in tumour biopsies taken 
at baseline, at EOCT visit or at disease progression, 
whichever occurs earlier; 
expression and DNA damage) in tumour biopsies 
taken at baseline, at EOCT visit or at disease 
progression, whichever occurs earlier; 
Synopsis, 4.4.3 
Exploratory endpoints 
(c) Number of DNA-DSB per cell in peripheral 
lymphocytes and the correlation with absorbed 
dose in the blood at baseline and , 4 and 72 to 96 
hours after each administration (in selected centres 
only). 
Exploratory endpoint deleted 
Assessment of haematological 
safety markers (DNA-DSB in 
peripheral lymphocytes) removed 
Synopsis, 4.2.1.1, 
19.5.1 
The MTCA is defined as the maximum tolerated 
cumulative activity that may be administered following 
fractionated i.v. administrations of at least 4 weeks 
apart, so that:  
• No more than 33% of the subjects experience a dose 
limiting toxicity (DLT) during Cycle 1 or 2 and 
• The cumulative radiation in each target organ does 
not exceed the acceptability limits. 
The MTCA is defined as the maximum tolerated 
cumulative activity that may be administered following 
fractionated i.v. administrations of at least 4 weeks 
apart, so that:  
• 
No more than 33% of the subjects experience a dose 
limiting toxicity (DLT) during Cycles 1 and/or 2 
and 
• 
The cumulative radiation in each target organ does 
not exceed the acceptability limits. 
Clarification 
Synopsis, 4.7.1.1 
The DLTs are defined ... DLT assessment period (from 
the 
first 
administration 
of 
177Lu-3BP-227 
to 
EOCT/ED): 
... 
• Grade 4 thrombocytopenia for seven or more 
consecutive days; 
• bleeding requiring transfusion with Grade 3 
thrombocytopenia; 
• any Grade 3 or higher laboratory abnormalities on 
haemoglobin requiring transfusion for >4 weeks;  
• any Grade 3 or higher laboratory abnormalities on
aspartate 
amino 
transferase/alanine 
amino 
transferase (AST/ALT) and/or bilirubin, which do 
not resolve in ≤4 weeks;  
• any Grade 3 or higher chronic kidney disease 
(estimated glomerular filtration rate (eGFR) <30 
mL/min/1.73 m2), which does not resolve within 1 
The DLTs are defined ... DLT assessment period (from 
the 
first 
administration 
of 
177Lu-3BP-227 
to 
EOCT/ED): 
... 
• 
Grade 3 or 4 thrombocytopenia (platelet count 
decreased) with  clinically meaningful bleeding 
(i.e. 
requiring 
urgent 
hospitalisation 
or 
transfusion to manage the bleeding); 
• 
Grade 4 thrombocytopenia for seven or more 
consecutive days; 
• 
Any Grade 3 anaemia (Hb<8.0 g/dL; transfusion
indicated) or Grade 4 anaemia (life-threatening 
consequences; urgent intervention indicated); 
• 
Any Grade 3 or higher laboratory abnormalities in 
aspartate 
aminotransferase/alanine 
aminotransferase (AST/ALT) with accompanying 
Grade 2 or higher bilirubin (Hy’s law); 
FDA request to revise the DLT 
criteria to adequately describe the 
grading as stated in the CTCAE 
v5.0 dictionary: 
- Grade 4 thrombocytopenia with 
a clinically significant bleeding is 
a DLT, irrespective of the duration 
of thrombocytopenia. In addition, 
revised the DLT criterion so a 
Grade 3 thrombocytopenia with a 
clinically meaningful bleeding 
(i.e. 
requiring 
urgent 
hospitalisation or transfusion) is a 
DLT. 
- Clarified the haemoglobin DLT 
criterion 
- Revised the ALT/AST DLT 
criteria so a Grade 3 ALT/AST 


 
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Section 
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Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
week on nephroprotective treatment (e.g. forced 
diuresis); 
• any Grade 3 or higher GI AE with the following 
specifications: Grade 4 (life threatening) nausea, 
vomiting, diarrhoea, constipation, dry mouth or 
Grade 3 nausea, vomiting, diarrhoea, constipation 
not resolved to Grade ≤2 within 48 hours despite 
optimal adequate medical management; 
x any toxicity related to 177Lu-3BP-227 resulting in a 
treatment delay of more than four weeks due to 
either delayed recovery to baseline or resolution of 
any AE of Grade ≤2 (exception of alopecia and 
lymphopenia). 
... 
• 
Any Grade 3 or higher renal injury/toxicity 
(estimated glomerular filtration rate (eGFR) <30 
mL/min/1.73 m2); 
• 
Any Grade 3 or higher GI AE, not resolved to 
Grade ≤2 within 48 hours despite optimal 
adequate 
medical 
management, 
with 
the 
following specifications: 
- 
Grade 3 nausea, vomiting (inadequate oral 
caloric or fluid intake; tube feeding, total 
parenteral 
nutrition 
or 
hospitalisation 
indicated) 
- 
Grade 3 diarrhoea (increase of ≥7 stools per 
day over baseline; hospitalisation indicated;
severe increase in ostomy output compared 
to baseline; limiting self-care ADL) or Grade 
4 diarrhoea (life-threatening consequences; 
urgent intervention indicated) 
- 
Grade 3 constipation (obstipation with 
manual evacuation indicated; limiting self-
care activities of daily living) or Grade 4 
constipation (life-threatening consequences; 
urgent intervention indicated); 
x Any toxicity related to 177Lu-3BP-227 resulting in a 
treatment delay of more than four weeks due to 
either delayed recovery to baseline or resolution of 
any AE to Grade ≤2 (with the exception of alopecia 
and lymphopenia). 
... 
increase simultaneous with a 
Grade 2 increase in bilirubin is 
considered a DLT (Hy’s law). 
- Revised the DLT criteria so 
Grade 3 renal injury/toxicity is a 
DLT, irrespective of the toxicity 
being “chronic” or acute. 
- Revised the DLT criteria to 
delete Grade 4 nausea and dry 
mouth (there is no Grade 4 nausea 
toxicity described in the CTACE 
v5.0 dictionary). 
Synopsis, 4.2.1.4 
Study design following phase I dose escalation 
results 
Upon termination of phase I dose escalation and/or 
determination upon reaching MTCA and stated jointly 
by the safety review committee (SRC) and the sponsor, 
and in consideration of the accumulated subject data, 
cohorts of subjects will be studied to further 
characterise safety and efficacy of 177Lu-3BP-227. 
Study design following phase I dose escalation 
results 
Upon completion of the phase I dose escalation or upon 
reaching the MTCA and confirmed jointly by the 
safety review committee (SRC) and the sponsor, and in 
consideration of the accumulated subject data, cohorts 
of subjects will be studied to further characterise the 
safety and efficacy of 177Lu-3BP-227. 
Clarification 


 
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Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
Synopsis, 5.1.1 
Inclusion criteria: 
(3a) 
Histologically 
or 
cytologically 
confirmed 
metastatic or locally advanced disease and no
compelling treatment option as per standard-of-
care 
and 
documented 
decision 
by 
a 
multidisciplinary oncology board including a 
specialist of the concerned pathology. 
Inclusion criteria: 
(3) 
Histologically 
or 
cytologically 
confirmed 
unresectable, locally advanced or metastatic
disease and has received prior lines of standard-
of-care chemotherapy/treatment and has no 
further suitable treatment options and a 
documented decision by a multidisciplinary 
oncology board including a specialist of the 
concerned pathology. 
FDA request to clarify the 
inclusion criterion to clearly state 
that no further suitable treatment 
options are available for subjects 
eligible for the study 
Synopsis, 5.1.1 
Inclusion criteria: 
(5) Tumour tissue expressing NTSR1, as determined 
by 
uptake 
of 
177Lu-3BP-227 
(screening 
formulation) in tumour lesions being judged by the 
investigator to more avid than in the non-tumoral 
surrounding tissue based on whole body scan 
(planar scintigraphy); single photon emission 
computed 
tomography 
(SPECT)/ 
computed 
tomography (CT) can be performed as per 
investigator’s judgement. 
Inclusion criteria: 
(5) 
Tumours showing:  
(a) uptake 
of 
177Lu-3BP-227 
(screening 
formulation) 
in 
known 
primary 
or 
metastatic 
sites 
as 
judged 
by 
the 
investigator 
to 
be 
greater 
than 
background; or 
(b) uptake 
of 
111In-3BP-227 
in 
known 
primary or metastatic sites (for subjects 
who 
participated 
in 
Study D-FR-01087-002) as judged by the 
investigator 
to 
be 
greater 
than 
background. 
To allow inclusion of subjects 
screened for NTSR1+ in the 
D-FR-01087-002 phase I study 
(111In-IPN01087) 
in 
the 
D-FR-01087-001 
phase I
(177Lu-IPN01087) study. 
Synopsis, 5.1.1 
Inclusion criteria: 
(12a) Female subjects must not be pregnant or 
lactating at study entry and during the course of 
the study and must not become pregnant for at 
least 6 months following the last study treatment. 
Women of childbearing potential must agree to 
use a highly effective method of contraception 
(see note below). Because CT scanning is part of 
the long-term follow up (every 12 ±2 weeks), 
female subjects should not become pregnant 
until the end of study assessments. 
(13a) … 
Inclusion criteria: 
(12) Female subjects must not be pregnant or lactating 
at study entry and during the course of the study 
and must not become pregnant for at least 6 
months following the last study treatment. 
Women of childbearing potential must agree to 
use a highly effective method of contraception
(see note below). 
(13) … 
Clarification that inclusion criteria 
are related to study treatment 
procedures 
Synopsis, 5.2 
Exclusion criteria: 
(1) 
Prior treatment received 
Exclusion criteria: 
(1) 
Prior treatment received 
Clarification 


 
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Section 
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Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
(a) Any antitumour treatment since last 
documentation of disease progression 
(a) 
Any antitumour treatment since last 
documented disease progression 
Synopsis, 4.4.3 
Exploratory endpoints 
… 
c) 
Genomic profiling in circulating cfDNA as
compared to germline DNA. 
Exploratory endpoints 
… 
c) 
Genomic profiling in circulating cfDNA and in 
germline DNA. 
Clarification 
1.5 
Rationale for the Study 
... 
177Lu-3BP-227 could be investigated in those subjects 
who exhausted available effective chemotherapy and 
their tumour tissue overexpresses NTSR1, knowing that 
the percentage of CRC tumours expressing NTSR1 is 
very high, with high degree of expression (see Section 
1.7). 
Rationale for the Study 
... 
177Lu-3BP-227 could be investigated in those subjects 
who have received prior lines of standard-of-care 
chemotherapy/treatment and have no further 
suitable treatment options and their tumour tissue 
overexpresses NTSR1, knowing that the percentage of 
CRC tumours expressing NTSR1 is very high, with 
high degree of expression (see Section 1.7). 
FDA request to clarify the 
inclusion criterion to clearly state 
that no further suitable treatment 
options are available for subjects 
eligible for the study 
1.7 
In this FIH study, the subject population enrolled to 
receive the IMP will be restricted to PDAC, CRC, GC, 
squamous-cell carcinoma of head and neck (SCCHN) 
and ES, which are locally advanced and expressing 
NTSR1. 
… 
Tumours/metastases expressing NTSR1 will be 
identified and documented through the lesion uptake of 
177Lu-3BP-227 (at low dose) during the screening 
period.  
In this FIH study, the subject population enrolled to 
receive the IMP will be restricted to PDAC, CRC, GC, 
GIST, squamous-cell carcinoma of head and neck 
(SCCHN) and ES, which are unresectable, locally 
advanced or metastatic and expressing NTSR1. 
… 
Tumours/metastases expressing NTSR1 will be 
identified and documented through the lesion uptake of 
177Lu-3BP-227 (at low dose) during the screening 
period. Subjects who participated in the imaging 
study, Study D‑FR‑01087‑002, with 111In-3BP-227 
(also called 111In-IPN01087) and who have an uptake 
of 111In-3BP-227 in tumour lesions that is more avid 
than in the nontumoural surrounding tissue based 
on whole body imaging (planar scintigraphy), as 
judged by the investigator, can also be considered 
for enrolment in this study, provided that they fulfil 
all other inclusion criteria and do not meet any of the 
exclusion 
criteria 
and 
were 
imaged 
with 
111In-3BP-227 
before 
the 
first 
treatment 
administration (therapeutic dose) of 177Lu-3BP-227. 
To allow inclusion of subjects 
screened for NTSR1+ in the 
D-FR-01087-002 phase I study 
(111In-IPN01087) 
in 
the 
D-FR-01087-001 
phase I
(177Lu-IPN01087) study. 


 
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RATIONALE FOR CHANGE 
WAS 
IS 
1.8 
The participating subjects will be closely monitored 
during the study and during follow-up for 2 years after 
the last administration. 
The participating subjects will be closely monitored 
during the study and during the long-term follow-up 
period until lost to follow-up, withdrawal of consent, 
death or a maximum of 5 years, whichever occurs 
first. 
To extend the long-term follow-up
period from 2 years to a maximum 
of 5 years based on peptide 
receptor 
radionuclide 
therapy 
experience 
on 
the 
risks 
of 
developing 
secondary 
malignancies, and the median time 
to 
occurrence 
of 
such 
malignancies. This will ensure 
continued benefit-risk assessment 
of 177Lu-3BP-227 for a longer 
period of time after the end of 
treatment. 
4.2.1 
The study screening period includes a screening 
administration of 177Lu-3BP-227 to assess the tumour 
uptake of each subject by whole body scan (planar 
scintigraphy); single photon emission computed 
tomography (SPECT)/CT can be done at the
investigator’s discretion to further evaluate the tumour 
uptake; only subjects with a tumour uptake higher than 
nontumoural 
surrounding 
tissue 
(based 
on 
investigator’s decision) will be deemed eligible for 
treatment. 
The study screening period includes a screening 
administration of 177Lu-3BP-227 to assess the tumour 
uptake of each subject by whole body scan (planar 
scintigraphy, 1 or 2 timepoint(s) at the investigator’s 
discretion) and optional single photon emission 
computed tomography (SPECT)/CT scans (up to 2 at 
the investigator’s discretion). Only subjects with a 
tumour uptake higher than nontumoural surrounding 
tissue (based on investigator’s decision) will be deemed 
eligible for treatment. 
After 
reviewing 
subjects’ 
SPECT/CT images at different 
timepoints 
following 
the 
therapeutic 
dose 
of 
177Lu-IPN01087, it is concluded 
that the quality of SPECT image 
with respect to the background 
noise has substantially improved 
at 
the 
48-hour 
and 
later
timepoints. 
Considering 
the 
significant number of screen 
failures due to lack of radioactive 
uptake, which is contrary to the 
information 
available 
in 
the
literature on the expression of 
NTSR1 
receptor, 
the 
image 
acquisition timepoint has been 
moved to 48 hours after the 
screening dose. 
4.2.1 
… 
The screening period will last 3 weeks but can be 
extended by up to 2 weeks if this is required for 
logistical reasons. 
The screening period will last 3 weeks but can be 
extended by up to 2 weeks if this is required for 
logistical reasons. Subjects who participated in the 
imaging 
study, 
Study D‑FR‑01087‑002, 
with 
To allow inclusion of subjects 
screened for NTSR1+ in the 
D-FR-01087-002 phase I study 
(111In-IPN01087) 
in 
the 


 
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Section 
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RATIONALE FOR CHANGE 
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IS 
111In-3BP-227 (also called 111In-IPN01087) and who 
have an uptake of 111In-3BP-227 in tumour lesions 
that is more avid than in the nontumoural 
surrounding tissue based on whole body imaging 
(planar scintigraphy), as judged by the investigator, 
can also be considered for enrolment in this study, 
provided that they fulfil all other inclusion criteria 
and do not meet any of the exclusion criteria and 
were imaged with 111In-3BP-227 before the first 
treatment administration (therapeutic dose) of 
177Lu-3BP-227. 
D-FR-01087-001 
phase I 
(177Lu-IPN01087) study. 
4.2.1 
A long-term follow-up lasting 24 months will start after 
the 
end 
of 
last 
cycle 
(either 
EOCT, 
early 
discontinuation (ED) visit or end of additional cycles 
(EOAC)) and subjects will be followed up every 
3 months (±2 weeks) until 24 months or death,
whichever occurs first. 
A long-term follow-up period will start after the EOCT, 
early discontinuation (ED) or end of additional cycles 
(EOAC) visit and subjects will be followed up every 
3 months 
(±2 weeks) 
until 
lost 
to 
follow-up,
withdrawal of consent, death or a maximum of 
5 years, whichever occurs first. 
Duration of long-term follow-up
updated 
4.2.1 
Figure 1 
Long-term follow up 
24 months 
 
Figure 1 
Long-term follow up 
5 years 
Figure updated to show new 
long-term follow-up period 
4.2.1 
Figure 1 
New footnote added 
Figure 1 
Footnote added: 
Note: Population screened includes subjects with 
unresectable disease. 
FDA request to clarify the eligible 
subject 
population, 
i.e. 
nonresectable locally advanced or 
metastatic disease. 
4.2.1.2 
The size of the cohorts will be three to five treated 
subjects, to secure a minimum of three evaluable 
subjects per cohort who completed 2 cycles of 
treatment. 
Once 
five 
subjects 
receive 
one 
administration of 177Lu-3BP-227 in a cohort, enrolment 
will be stopped in that cohort. A cohort will be 
considered as completed once three subjects of the 
cohort complete Cycle 2 or early discontinue during 
Cycle 2 (except for cohort 1, see Proceeding to the Next
Cohort described in Section 4.2.1.4). 
The size of the cohorts will be three to five treated 
subjects, to secure a minimum of three evaluable 
subjects per cohort who completed 2 cycles of 
treatment. A cohort will be considered as completed 
once three subjects of the cohort complete Cycle 2 or 
early discontinue during Cycle 2 (except for cohort 1, 
see Proceeding to the Next Cohort described in Section 
4.2.1.4). If a subject replacement is needed to 
complete the cohort enrolment, see Section 4.7.1.3
for replacement rules. 
Clarification of the maximum 
number of subjects per cohort. 
4.2.1.3 
… 
… 
Clarification 


 
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RATIONALE FOR CHANGE 
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In the first step, in order to minimise the number of 
subjects receiving subtherapeutic activity, the inter-
cohort radioactivity escalation will be performed by 
increment of 3 GBq (1.5 GBq per administration), up to 
the first study drug related AE (Grade 2 or higher, 
except hair loss) or until a DLT occurs. 
In the first step, in order to minimise the number of 
subjects receiving subtherapeutic activity, the inter-
cohort radioactivity escalation will be performed by 
increment of 3 GBq (1.5 GBq per administration), up to 
the first study drug related treatment-emergent AE 
(TEAE) (Grade 2 or higher, except hair loss) or until a 
DLT occurs. 
4.5 
For the phase I, the maximum duration of subject 
participation in the core trial is 21 weeks. However, if a 
clinical benefit is observed, subjects may receive up to 
four additional cycles after the EOCT, provided they 
have an acceptable tolerability profile, the organ dose 
limits are not exceeded and according to investigator’s 
judgement, subject’s discretion and must be discussed 
with and agreed by the sponsor. 
For the phase I, the maximum duration of subject
participation in the core trial is 21 weeks. However, if,
according to the investigator, a subject has clinical 
benefit, the subject may receive up to four additional 
cycles after the EOCT, provided they have an 
acceptable tolerability profile and the organ dose limits 
are not exceeded. This is at the subject’s discretion and 
must be discussed and agreed with the sponsor. 
Clarification 
4.5 
In all cases, a long-term follow-up lasting 24 months
will start after the last cycle is administered (after
EOCT, ED visit or EOAC) and subjects will be 
followed up every three months (±2 weeks). 
In all cases, a long-term follow-up period will start after 
the EOCT, ED or EOAC visit and subjects will be 
followed up every three months (±2 weeks) until lost 
to follow-up, withdrawal of consent, death or a 
maximum of 5 years, whichever occurs first. 
Duration of long-term follow-up
updated 
4.7.1 
Individual Discontinuation Rules 
... 
If any of the following occur, no further treatment will 
be administered: 
• 
subject withdraws their consent to further 
treatment; 
... 
Individual Discontinuation Rules 
... 
If any of the following occur, no further treatment will 
be administered: 
• 
life-threatening toxicities outside of the DLT 
reporting period  
• 
subject withdraws their consent to further 
treatment; 
... 
FDA 
request 
to 
revise 
the 
discontinuation rules so if there 
are 
life-threatening 
toxicities 
outside of the DLT period, 
treatment is discontinued. 
5.2 
(1) 
Prior treatment received: 
… 
(b) Any chemotherapy within 3 weeks or 
nitrosourea prior to first treatment IMP 
administration 
(1) 
Prior treatment received: 
… 
(b) Any chemotherapy within 3 weeks or 
nitrosourea within 6 weeks prior to first 
treatment IMP administration 
Revision of inconsistent exclusion 
criteria between synopsis and core 
text. 
6.2 
New text added 
If the COVID-19 pandemic prevents subjects from 
coming to the site, subjects can have their study visit 
Clarification 
following 
COVID-19 pandemic. 


 
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RATIONALE FOR CHANGE 
WAS 
IS 
assessments 
performed 
remotely 
as 
judged 
appropriate by the investigator. This must be 
discussed 
with 
the 
sponsor 
before 
being 
implemented. In such a case, the investigator will 
perform a telemedicine visit and will make every 
effort, where applicable, to contact the subject’s 
general practitioner or specialist physician to ensure 
all important medical information and safety 
event(s) occurring since the last visit are collected. 
Guidance on how to collect protocol-planned 
assessments will be provided to the investigator in a 
separate document. This document will be filed in 
the electronic trial master file. Independent ethics 
committees 
(IECs)/institutional 
review 
boards 
(IRBs) will be notified of the changes as applicable 
locally. Of note, as the adapted visit deviates from 
the regular protocol plan, the changes will be 
recorded 
as 
protocol 
deviations 
related 
to 
COVID-19. 
6.2.2.2 
If according to the investigator, a subject has clinical 
benefit, good tolerability of the compound and if the
organ dose limits are not exceeded, he/she can receive 
up to four additional cycles after EOCT. For these 
subjects, an EOAC visit will be done 6 weeks after last 
dose administration. 
If, according to the investigator, a subject has clinical 
benefit, the subject may receive up to four additional 
cycles after the EOCT, provided they have an 
acceptable tolerability profile and the organ dose 
limits are not exceeded. This is at the subject’s 
discretion and must be discussed and agreed upon 
with the sponsor. For these subjects, an EOAC visit 
will be done 6 weeks after last dose administration. 
 
Clarification  
6.2.3 
For both phase I and phase II, a long-term follow-up
period will start after ED, EOCT or after EOAC and 
subjects will be followed up every 3 months (±2 weeks) 
until 24 months or death, whichever occurs first. 
For both phase I and phase II, a long-term follow-up
period will start after the ED, EOCT or EOAC visit and 
subjects will be followed up every 3 months (±2 weeks) 
until lost to follow-up, withdrawal of consent, death 
or a maximum of 5 years, whichever occurs first. 
Duration of long-term follow-up
updated 
6.2.3 
… 
New text added 
… 
Five Years After the EOCT, ED or EOAC Visit  
Specific 
assessments 
to 
be 
performed during the long-term
safety follow-up detailed. 


 
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In the long-term follow-up period, subjects will be 
followed up every 3 months (±2 weeks) until lost to 
follow-up, withdrawal of consent, death or a 
maximum of 5 years, whichever occurs first. The 
following safety assessments will be performed by 
the site: these assessments can be performed on-site 
or by remote visit: 
• 
Survival status 
• 
Haematology 
and 
biochemistry 
tests 
(haemoglobin, platelet count, white blood cell 
count (absolute counts), AST, ALT, total 
bilirubin (with conjugated bilirubin if total 
bilirubin 
is 
abnormal 
i.e. 
outside 
the 
laboratory normal range), creatinine and 
urea) performed until the start of new 
antitumour treatment or up to 2 years after the 
EOCT, ED or EOAC visit, whichever comes
first. Laboratory tests can be performed 
locally; results should be collected from the 
local laboratory. 
• 
All AEs and serious adverse events (SAEs) are 
to be reported up to 6 months after the EOCT, 
ED or EOAC visit or until new antitumour 
treatment starts, whichever comes first.
Thereafter, only AEs and SAEs related to the 
IMP or study procedure should be reported for 
the remainder of the safety follow up period. 
• 
Subsequent antitumour treatment 
All collected data will be recorded in the eCRF. 
6.3.1 
…. 
New text added 
… 
Any further antitumour treatment for the disease 
under study that may have been taken during the 
long-term follow-up period should be reported on 
the prior and concomitant medications page of the 
eCRF. 
Details of requirements during the 
long-term safety follow-up added. 


 
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RATIONALE FOR CHANGE 
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7.1.1 
One vial can contain up to 17.5 GBq of 177Lu-3BP-227, 
this amount takes into account decay to ensure the 
administration of the highest planned activity of 7.5 
GBq of 177Lu-3BP-227 from the vial. 
One vial can contain up to 17.5 GBq of 177Lu-3BP-227 
at the end of manufacturing, this amount takes into 
account decay to ensure the administration of the 
highest planned activity of 7.5 GBq of 177Lu-3BP-227 
from the vial. 
Clarification 
7.1.1.2 
… 
The screening and treatment IMP are formulated in a 
solution 
of 
water 
for 
injection 
containing 
DiethyleneTriaminePentaAcetate (DTPA) to complex 
free 177Lu and ascorbic acid to protect the drug product 
from radiolysis and to have a longer shelf life. The IMP 
consists of a sterile clear solution, free from visible
particles, filled in 25 mL Type I borosilicate glass vials, 
closed with a chlorobutyl rubber stopper and crimped 
with aluminium seal. 
… 
The screening and treatment IMP are formulated in a 
solution of sterile water for injection containing 
DiethyleneTriaminePentaAcetate (DTPA) to complex 
free 177Lu and ascorbate buffer to protect the drug 
product from radiolysis and to extend the shelf life. The 
IMP consists of a sterile clear to slightly yellow
solution, free of suspended particles, filled in 25 mL
Type I borosilicate glass vials, closed with a chlorobutyl 
rubber stopper and crimped with aluminium seal. 
Clarification 
7.1.3 
… 
In case of central manufacturing by the central 
manufacturing organisation, the IMP should be stored 
between +2°C and +8°C. 
Since the IMP shelf life will vary depending on the 
manufacturing setup (decentralised or centralised) and 
potentially on any updates supported by available 
updated supporting data during the conduct of the study, 
it is referred to the IMP label for the exact shelf life. 
… 
In case of manufacturing by the central manufacturing 
organisation, the IMP should be stored between +2°C 
and +8°C. 
Since the IMP shelf life will vary depending on the 
mode of manufacturing (decentralised or centralised) 
and potentially on supporting data generated during the 
conduct of the study, the exact shelf life is indicated on 
the IMP label. 
Clarification 
8.1.1 
… 
All AEs irrespective of causality up to 6 month 
follow-up from end of treatment period should be 
reported to the sponsor. AEs reported after this 
timepoint up to 2-year follow-up should be reported if 
evaluated as related to the IMP by the investigator. 
… 
All AEs, irrespective of causality, are to be reported 
to the sponsor up to 6 months after the EOCT, ED or 
EOAC visit or until new antitumour treatment 
starts, whichever comes first. After this timepoint, up 
to the end of the 5-year follow-up period, AEs should 
only be reported if the event is evaluated as related to 
the IMP or study procedure by the investigator. 
Clarification 
of 
reporting 
requirements during the long-term
safety follow-up 
8.1.1 
… 
Events that are reported during the study and cannot be 
differentiated with PD should be captured as AE/SAEs. 
Death due to disease progression should be reported as 
… 
Events that cannot be differentiated from progressive 
disease (PD) should be captured as AE/SAEs. Death 
due to disease progression should be reported as an 
Clarification 


 
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SAE irrespective of causality if reported during the 
study period and its early follow-up up to 6 months after 
the last dose of study drug. 
SAE irrespective of causality if reported during the 
study period and up to 6 months after the end of the 
cycle of the last dose of study drug. 
8.1.2.3 
Any AE/SAE occurring during the study, from 
informed consent up to 6 months after long term 
follow-up period start (after EOCT or EOAC or ED), 
must be reported to the sponsor. 
Any AE considered related to IMP administration that 
the investigator becomes aware of after completion of 
the EOS/ED visit must be reported to the sponsor and 
will be recorded in the safety database. EOS for AE 
reporting is defined as the end of 24-month follow-up
or death. 
Any AEs/SAEs, irrespective of causality, are to be 
reported to the sponsor up to 6 months after the
EOCT, ED or EOAC visit or until new antitumour 
treatment starts, whichever comes first. After this 
timepoint, up to the end of the 5-year follow-up 
period, AEs/SAEs should only be reported if the 
event is evaluated as related to the IMP or study 
procedure by the investigator. 
Any AE considered related to IMP administration that 
the investigator becomes aware of after completion of 
the EOS/ED visit must be reported to the sponsor and 
will be recorded in the eCRF. EOS for AE reporting is 
defined as the end of the 5-year follow-up or death. 
Clarification 
of 
reporting 
requirements during the long-term
safety follow-up 
8.1.3 
New text added 
In addition to the above criteria, any additional AE 
that the sponsor or an investigator considers serious 
should be immediately reported to the sponsor. This 
includes any suspected or confirmed coronavirus 
COVID-19 (SARS CoV-2) infection (seriousness 
criteria should be “other medically significant” if no 
other 
seriousness 
criteria 
are 
present 
(e.g. 
hospitalisation)). 
In case of suspected or confirmed COVID-19 
infection, 
the 
IMP 
administration 
may 
be 
temporarily 
discontinued 
depending 
on 
the 
subject’s clinical presentation. In some cases, the 
investigator may request a subject be retested before 
the IMP administration is resumed. 
Clarification 
following 
COVID-19 pandemic. 
8.1.3 
Any appropriate means of notification may be used. 
Email is the preferred method of SAE notification. 
If email is not available, facsimile transmission is the 
alternative method. In rare circumstances and in the 
absence of facsimile equipment, notification by 
telephone is acceptable. 
Clarification  


 
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8.1.5 
If the investigator becomes aware of a pregnancy 
occurring in the partner of a subject participating in the 
study, this should be reported to the sponsor. After the 
partner has given written consent, the investigator 
should counsel the woman, discuss the risks of
continuing with the pregnancy and the possible effects 
on the foetus. Monitoring of the subject’s partner should 
continue until conclusion of the pregnancy, which may 
involve follow-up after the subject’s involvement in the 
study has ended. 
Pregnancies with a conception date within 90 days after 
subject’s dosing must also be reported to the 
investigator for onward reporting to the sponsor. 
The investigator is to report to the sponsor if they
become aware of a pregnancy occurring in the partner 
of a subject participating in the study. If the female 
partner gives her consent, the pregnancy outcome 
should be followed up and reported. 
If there is an abnormal pregnancy outcome or an AE 
reporting in the foetus/neonate/child following 
exposure to the IMP during an Ipsen-sponsored 
clinical study, the information will be collected in 
two clinical study SAE report forms, one for the 
mother and one for the foetus/neonate/child. 
Pregnancies (in female subjects and partners of male 
subjects) with a conception date within 90 days after 
subject’s dosing must also be reported to the 
investigator for onward reporting to the sponsor. 
To provide guidance to the 
physician about the reporting 
requirements 
for 
pregnancy 
occurring in female partner of 
childbearing 
potential 
and 
separate reporting of AEs/SAEs 
for the foetus/neonate/child and 
mother. 
8.2.4 
… 
During screening period, a triplicate 12-lead ECG will 
be recorded to check eligibility criteria by measuring 
the ECG parameters, in particular the QTc (Fridericia's 
correction, QTcF) interval in order to exclude subjects 
with high/abnormal QT values before the screening 
administration. Afterwards, single 12-lead ECG 
recordings will be performed at the end of 177Lu-3BP-
227 screening infusion and 4 hours after the end of 
177Lu-3BP-227 infusion. 
At each treatment administration, a triplicate 12-lead
ECG will be recorded on Day 1 before the infusion 
(baseline).  
Afterwards, single 12-lead ECGs, will be recorded on 
Day 1 just after 177Lu-3BP-227 infusion, at 4 hours after 
the end of 177Lu-3BP-227 infusion and on Day 2 at 24 
hours after the end of 177Lu-3BP-227 infusion as well as 
at EOCT and EOAC visits. 
… 
During the screening period, a triplicate 12-lead ECG 
will be recorded to check eligibility criteria by 
measuring the ECG parameters, in particular the QTc 
(Fridericia's correction, QTcF) interval in order to 
exclude subjects with high/abnormal QT values before 
the screening administration (minus 15 minutes).
Afterwards, single 12-lead ECG recordings will be 
performed at the end of 177Lu-3BP-227 screening 
infusion (±15 minutes) and 4 hours after the end of 
177Lu-3BP-227 infusion (±30 minutes). 
At each treatment administration, a triplicate 12-lead 
ECG will be recorded on Day 1 before the infusion 
(baseline) (minus 15 minutes).  
Afterwards, single 12-lead ECGs, will be recorded on 
Day 1 just after 177Lu-3BP-227 infusion (±15 minutes), 
at 4 hours (±30 minutes) after the end of 177Lu-3BP-
227 infusion and on Day 2 at 24 hours (±4 hours) after 
the end of 177Lu-3BP-227 infusion as well as at EOCT 
and EOAC visits. 
Clarification 


 
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RATIONALE FOR CHANGE 
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8.2.4 
Table 6 Timepoints and Replicates of 12-lead ECG
Recordings 
Timepoint column: 
Before infusion  
End of infusion  
4 hours after the end of infusion 
Before infusion  
End of infusion  
4 hours after the end of infusion 
24 hours after the end of infusion 
Table 6 Timepoints and Replicates of 12-lead ECG
Recordings 
Timepoint column: 
Before infusion (minus 15 minutes) 
End of infusion (±15 minutes) 
4 hours (±30 minutes) after the end of infusion 
Before infusion (minus 15 minutes) 
End of infusion (±15 minutes) 
4 hours (±30 minutes) after the end of infusion 
24 hours (±4 hours) after the end of infusion 
Clarification 
9.1.2 
... 
The samples for urine total activity concentration 
analysis will be taken from urine collected during four 
different periods at Cycle 1 only: from the start of the 
177Lu-3BP-227 infusion to 6 hours, 6 to 12 hours, 12 to 
24 hours and 24 to 48 hours after the end of infusion 
(from the start of the 177Lu-3BP-227 infusion to 6 hours 
after the end of the infusion only for US sites), with an
initial void collection shortly before the infusion and a
final collection 48 hours after the end of 177Lu-3BP-227
infusion. 
... 
The samples for urine total activity concentration 
analysis will be taken from urine collected during four 
different periods at Cycle 1 only: from the start of the 
177Lu-3BP-227 infusion to 6 hours, 6 to 12 hours, 12 to 
24 hours and 24 to 48 hours after the end of infusion 
(from the start of the 177Lu-3BP-227 infusion to 6 hours 
after the end of the infusion only for US sites). Subjects 
should void shortly before the 177Lu-3BP-227 infusion 
(not to be collected) and shortly before the end of the 
last collection period. 
Clarification 
9.2 
During the treatment period, to improve the 
determination of the biokinetics of 177Lu-3BP-227 and 
perform an absolute quantification of radioactivity in 
target organs, whole body scans (planar scintigraphy) 
and SPECT/CT will be performed at Cycles 1 and 2 at 
the following timepoint ranges just after the end of 
177Lu-3BP-227 infusion: 
• Day 1: 0 to 1 hour (before urination) and 2 to 4 hours
• Day 2: 16 to 24 hours 
• Day 3: 40 to 48 hours 
• Day 4: 72 to 96 hours 
During the treatment period, to improve the 
determination of the biokinetics of 177Lu-3BP-227 and 
perform an absolute quantification of radioactivity in 
target organs, whole body scans (planar scintigraphy) 
and SPECT/CT will be performed at Cycles 1 and 2 at
the following timepoints just after the end of 
177Lu-3BP-227 infusion: 
• Day 1: 4 (±2) hours 
• Day 2: 24 (±6) hours 
• Day 3: 48 (±6) hours 
• Day 4: 72 to 96 hours 
• Day 7s to 8: 138 to 168 hours  
To 
optimise 
the 
dosimetry 
evaluation through adaptation of 
the imaging schedule 


 
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At the timepoint between 16 to 24 hours, SPECT/
standard dose CT will be performed. For all other time 
points, SPECT/low dose CT will be performed. 
 
Within each cycle, a single SPECT/standard dose CT 
will be performed. For all other time points, 
SPECT/low dose CT will be performed. Details of the 
procedures will be provided in the Image 
Acquisition Guidelines. 
9.2 
… 
After the second and fourth additional administrations, 
a single whole body scan and SPECT/standard dose CT 
between 16 and 24 hours will be performed. 
… 
After the second and fourth additional administrations, 
a single whole body scan and SPECT/standard dose CT 
at 48 (±6) hours will be performed. 
Change of timepoint to 48 hours 
where the quality of SPECT 
images (with respect to the 
background noise) is expected to 
be improved 
9.3.2 
… 
The samples for urine 3BP 227 concentration analysis 
will be taken from urine collected during four different 
periods at Cycle 1 only: from the start of the infusion to 
6 hours, 6 to 12 hours, 12 to 24 hours and 24 to 48 hours 
after the start of infusion (from the start of the infusion 
to 6 hours after the end of the infusion only in US sites),
with an initial void collection shortly before the 
infusion and a final collection 48 hours after the end of 
177Lu-3BP-227 infusion. 
… 
The samples for urine 3BP 227 concentration analysis 
will be taken from urine collected during four different 
periods at Cycle 1 only: from the start of the infusion to 
6 hours, 6 to 12 hours, 12 to 24 hours and 24 to 48 hours 
after the start of infusion (from the start of the infusion 
to 6 hours after the end of the infusion only in US sites).
Subjects should void shortly before the 177Lu-3BP-227 
infusion (not to be collected) and shortly before the 
end of the last collection period. 
Clarification 
10.1.2 
… 
After EOCT or EOAC, subjects will be followed up 
every 3 months (±2 weeks) to further evaluate the 
efficacy (by CT or MRI) until 24 months, disease 
progression, administration of any other chemotherapy 
or radiotherapy, or death, whichever occurs first (see 
Section 6.2.3). 
… 
After the EOCT, ED or EOAC visit, subjects will be 
followed up every 3 months (±2 weeks) to further 
evaluate the efficacy (by CT or MRI) until disease 
progression, administration of any other chemotherapy 
or radiotherapy, lost to follow-up, withdrawal of 
consent, death or a maximum of 2 years, whichever 
occurs first (see Section 6.2.3). After disease 
progression is confirmed, no further CT/MRI scans 
will be required for tumour/disease assessment. The 
survival status and safety of the subjects will 
continue 
to 
be 
monitored 
as 
indicated 
in 
Section 8.1.2.3 until lost to follow-up, withdrawal of 
consent, death or a maximum of 5 years, whichever 
occurs first. 
Clarification 
of 
requirements 
during the long-term follow-up.  


 
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RATIONALE FOR CHANGE 
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IS 
10.1.3 
After EOCT, subjects will be followed up every 
3 months 
(±2 
weeks) 
 to 
further evaluate 
the 
efficacy (by CT or MRI) until 24 months, disease 
progression, administration of any other chemotherapy 
or radiotherapy, or death, whichever occurs first (see 
Section 6.2.3). 
After the EOCT, ED or EOAC visit, subjects will be 
followed 
up 
every 
3 months 
(±2 
weeks) 
 to 
further evaluate the efficacy (by CT or MRI) until 
disease progression, administration of any other 
chemotherapy or radiotherapy, lost to follow-up, death 
or a maximum of 2 years, whichever occurs first (see 
Section 6.2.3). 
Updated 
long-term 
follow-up 
period. 
10.4 
10.4 DNA Double Strand Breaks in Peripheral 
Lymphocytes 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section deleted 
Assessment of DNA-DSB in 
peripheral lymphocytes removed 
10.5 
10.5 Genomic Profiling in Circulating Cell-free
DNA 
 
 
 
 
 
10.4 Genomic Profiling in Circulating Cell-free 
DNA and Germline DNA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
CCI
CCI
CCI
CCI


 
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IS 
 
 
 
 
 
 
 
 
 
 
 
 
10.6 
10.7 Tumour Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.6 Tumour Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification on biopsy collection 
and wording added for subjects 
participating in the imaging study 
CCI
CCI
CCI
CCI


 
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12.3.1 
Subjects in each phase of the study will have 2-year
safety follow-up after the end of the last 177Lu-3BP-227
cycle.  
Subjects in each phase of the study will have a 5-year 
safety follow-up after the EOCT, ED or EOAC visit. 
Updated 
long-term 
follow-up 
period. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoint changed: 
Cycle 1 Day 8  
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoint changed: 
Cycle 1 Day 7  
To amend the visit schedule to 
align with the change in imaging 
schedule 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoint changed: 
Cycle 2 Day 8  
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoint changed: 
Cycle 2 Day 7  
To amend the visit schedule to
align with the change in imaging 
schedule 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoints updated 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
To 
optimise 
the 
dosimetry 
evaluation through adaptation of 
the imaging schedule 
CCI


 
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RATIONALE FOR CHANGE 
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IS 
 
Timepoint added at Cycle 1 Day 7 and Cycle 2 Day 7 
for: 
Planar scintigraphy 
SPECT/CT scan 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoint deleted: 
Haematology and biochemistry at Day 2 of Cycle 1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoint deleted 
Day 2 samples were initially 
proposed for the safety evaluation 
of the short-term effects (within 
24 hours) of the IMP on laboratory 
parameters. Following evaluation 
of 
these 
results 
after 
IMP 
administration in the patients 
treated so far, there was no change 
in 
the 
laboratory 
parameters 
within 
24 hours 
of 
IMP 
administration. Therefore, these 
laboratory tests do not add any 
value to the clinical safety or 
efficacy assessment. The sites can 
still perform the laboratory tests 
on Day 2, as on any other day, if 
needed. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Peripheral lymphocytes for DNA-DSB (selected 
centres) [s] assessment at Day 1 of Cycle 1, Day 4 of 
Cycle 1, Day 1 of Cycle 2 and Day 4 of Cycle 2 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Assessment deleted 
Assessment removed 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoints deleted 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Timepoints were  removed from the long-term 
follow-up for the following assessments: 
ECOG performance status  
Vital signs  
Body weight 
Urinalysis 
Clarification 
of 
requirements 
during the long-term follow-up. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Clarification 
of 
requirements 
during the long-term follow-up. 


 
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Section 
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Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
New assessment added 
New assessment added for the long-term follow-up: 
Survival status 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote b: 
follow-up visits will take place every 3 months and will 
start after the last cycle of IMP administration.  
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote b: 
follow-up visits will take place every 3 months 
(±2 weeks) and will start after the EOCT, ED or 
EOAC visit. Efficacy will be assessed until disease 
progression, 
administration 
of 
any 
other 
chemotherapy or radiotherapy, lost to follow-up, 
withdrawal of consent, death or a maximum of 
2 years, whichever occurs first (see Section 6.2.3). 
After disease progression is confirmed, no further 
CT/MRI scans will be required for tumour/disease 
assessment. The survival status and safety of the 
subjects will continue to be monitored as indicated 
in Section 8.1.2.3 until lost to follow-up, withdrawal 
of consent, death or a maximum of 5 years, 
whichever occurs first. 
Clarification 
of 
requirements 
during the long-term follow-up. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote k: 
ten whole body scans (planar scintigraphy) and 
SPECT/CT acquisitions will be performed during the 
treatment 
period. 
Whole 
body 
scans 
(planar 
scintigraphy) and SPECT/CT scan will be performed 
just after the end of the 177Lu 3BP-227 infusion at 0 to 
1 hour (before urination), 2 to 4 hours, 16 to 24 hours, 
40 to 48 hours and at 72 to 96 hours. SPECT/standard 
dose CT will be performed at the 16 to 24 hour 
timepoint, SPECT/low dose CT will be performed at all 
other timepoints.  
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote k: 
eleven whole body scans (planar scintigraphy) and 
SPECT/CT acquisitions will be performed during the 
treatment 
period. 
Whole 
body 
scans 
(planar 
scintigraphy) and SPECT/CT scan will be performed at 
the following timepoints just after the end of 177Lu-
3BP-227 infusion: Day 1: 4 (±2) hours, Day 2: 24 (±6) 
hours, Day 3: 48 (±6) hours, Day 4: 72 to 96 hours, 
and Days 7 to 8: 138 to 168 hours. Within each cycle, 
a single SPECT/standard dose CT will be performed. A
SPECT/low dose CT will be performed at all other 
timepoints. Details of the procedures will be provided 
in the Image Acquisition Guidelines.  
To 
optimise 
the 
dosimetry 
evaluation through adaptation of 
the imaging schedule 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
After 
reviewing 
subjects’ 
SPECT/CT images at different 


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 160 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
Footnote k: 
… 
At screening, planar scintigraphy will be performed 
after screening administration of 
177Lu-3BP-227;
SPECT/CT can be performed as per investigator’s 
judgement. 
Footnote k: 
… 
At screening, planar scintigraphy (1 or 2 timepoint(s) 
at the investigator’s discretion) and optional
SPECT/CT scans (up to 2 at the investigator’s 
discretion) 
will be performed after screening 
administration of 177Lu-3BP-227. 
timepoints 
following 
the 
therapeutic 
dose 
of 
177Lu-IPN01087, it is concluded 
that the quality of SPECT image 
with respect to the background 
noise has substantially improved 
at 
the 
48-hour 
and 
later 
timepoints. 
Considering 
the 
significant number of screen 
failures due to lack of radioactive 
uptake, which is contrary to the 
information 
available 
in 
the
literature on the expression of 
NTSR1 
receptor, 
the 
image 
acquisition timepoint has been 
moved to 48 hours after the 
screening dose. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote n: 
prior to and at the end of 177Lu-3BP-227 infusion (0) as 
well as 30±5 minutes, 90±15 minutes, 4 hours±10
minutes after the end of 177Lu-3BP-227 infusion. 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote n: 
prior to and at the end of 177Lu-3BP-227 infusion (0) as 
well 
as 
30±5 minutes, 
90±15 minutes, 
4 hours±30 minutes after the end of 177Lu-3BP-227 
infusion. 
To homogenise the time window 
duration between vital signs and 
PK samples 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote o: 
during the screening period, a triplicate 12-lead ECG 
will be recorded before the screening administration, 
and a single 12-lead ECG will be recorded at the end of 
177Lu-3BP-227 infusion and 4 hours after the end of 
infusion. At each treatment administration, a triplicate
12-lead ECG will be recorded on Day 1 before the 
infusion (baseline) and a single 12-lead ECG recordings 
at the end of 177Lu-3BP-227 infusion, at 4 hours after 
the end of 177Lu-3BP-227 infusion and on Day 2 at 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote o: 
during the screening period, a triplicate 12-lead ECG 
will be recorded before the screening administration 
(minus 15 minutes), and a single 12-lead ECG will be 
recorded at the end of 
177Lu-3BP-227 infusion 
(±15 minutes) and 4 hours (±30 minutes) after the end 
of infusion. At each treatment administration, a 
triplicate 12-lead ECG will be recorded on Day 1 before 
the infusion (baseline) (minus 15 minutes) and a single 
12-lead ECG recordings at the end of 177Lu-3BP-227 
Clarification 


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 161 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
24 hours after the end of 177Lu-3BP-227 infusion as 
well as at EOCT. In any case, 12-lead computerised
standard ECG , will be recorded in supine position after 
at least 5 minutes of rest. 
infusion (±15 minutes), at 4 hours after the end of 
177Lu-3BP-227 infusion (±30 minutes) and on Day 2 at 
24 hours after the end of 177Lu-3BP-227 infusion 
(±4 hours) as well as at EOCT. All 12-lead 
computerised standard ECGs will be recorded in the 
supine position after at least 5 minutes of rest. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote s: 
samples for DNA-DSB will be taken, starting from 
Cohort 3, at each administration at the following 
timepoints: before infusion (baseline), 4 hours and 72 to 
96 hours after the end of 177Lu 3BP-227 infusion. 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote s: 
one blood sample for germline DNA will be collected 
at screening (after confirmation of 177Lu-3BP-227 
tumour uptake) or at Day 1 of Cycle 1 before the
infusion 
Collection of germline DNA 
modified to allow more flexibility 
to the sites for biobanking blood 
collection and to avoid blood 
sampling from screening failure 
subjects. 
19.1 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
New footnote added 
Table 8 Schedule of Assessments for Phase I – Dose 
Escalation 
Footnote z: 
Any AEs/SAEs, irrespective of causality, are to be 
reported to the sponsor up to 6 months after the 
EOCT, ED or EOAC visit or until new antitumour 
treatment starts, whichever comes first. After this 
timepoint, up to the end of the 5-year follow-up 
period, AEs/SAEs should only be reported if the 
event is evaluated as related to the IMP or study 
procedure by the investigator. 
Clarification 
of 
requirements 
during the long-term follow-up. 
CCI


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 162 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Timepoint changed: 
Additional cycles Day 8 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Timepoint changed: 
Additional cycles Day 7 
To amend the visit schedule to 
align with the change in imaging 
schedule 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Timepoints updated 
 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Timepoint added at Day 7 for: 
Planar scintigraphy 
SPECT/CT scan 
To 
optimise 
the 
dosimetry 
evaluation through adaptation of 
the imaging schedule 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote a: 
ceCT/MRI will be done at Cycles 4 and 6 only. 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote a: 
ceCT/MRI will be done every 2 cycles during 
additional administrations, to confirm the clinical 
benefit after 2 additional administrations (i.e. at 
Cycle 4 and EOAC). In case of early discontinuation, 
Clarification of when ceCT/MRI 
scans should be performed during 
additional cycles, to be consistent 
with 
the 
core 
trial 
period 
assessments. 
CCI


 
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Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 163 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
the CeCT/MRI should be performed at the ED visit, 
to confirm any disease progression. 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote b: 
full dosimetry assessment will be performed after the 
first and third additional administrations as described 
for Cycles 1 and 2. After the second and fourth 
additional 
administrations, 
only 
a 
single 
SPECT/standard dose CT at 16 to 24 hours will be 
performed 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote b: 
full dosimetry assessment will be performed after the 
first and third additional administrations as described 
for Cycles 1 and 2. After the second and fourth 
additional 
administrations, 
only 
a 
single 
SPECT/standard dose CT at 48 (±6) hours will be 
performed 
Change of timepoint to 48 hours 
where the quality of SPECT 
images (with respect to the 
background noise) is expected to 
be improved 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote c: 
After  the first and the third additional administration, 
blood samplings will be performed just before 177Lu-
3BP-227 infusion (baseline), at the end of infusion of 
177Lu-3BP-227 (0), 5 minutes ±1 minute, 30 minutes ±5 
minutes, 1 hour ±5 minutes and 4 hours ±30 minutes, 6 
hours ±30 minutes, 8 hours ±1 hour, 24 hours ±2 hours 
and 48 hours ±2 hours, and 72 to 96 hours ±2 hours. 
After the second and fourth additional administrations a 
single blood collection will be performed at 24 hours 
only (as close as possible to the SPECT/CT). 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote c: 
After  the first and the third additional administration, 
blood samplings will be performed just before 
177Lu-3BP-227 infusion (baseline), at the end of 
infusion of 177Lu-3BP-227 (0), 5 minutes ±1 minute, 
30 minutes ±5 minutes, 90 minutes ±15 minutes and 
4 hours ±30 minutes, 24 hours ±2 hours and 48 hours 
±2 hours, and 72 to 96 hours ±2 hours. After the second 
and fourth additional administrations a single blood 
collection will be performed at 24 hours only (as close 
as possible to the SPECT/CT). 
Clarification 
of 
inconsistency 
between 
core 
trial 
period 
assessments and additional cycle 
assessments 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote d: 
prior to and at the end of 177Lu-3BP-227 infusion (0) as 
well as 30±5 minutes, 90±15 minutes, 4 hours±10
minutes after the end of 177Lu-3BP-227 infusion. 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote d: 
prior to and at the end of 177Lu-3BP-227 infusion (0) as 
well as 30±5 minutes, 90±15 minutes, 4 hours±30
minutes after the end of 177Lu-3BP-227 infusion. 
Clarification 
of 
inconsistency 
between 
core 
trial 
period 
assessments and additional cycle
assessments 
19.1 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote e: 
at each cycle, a triplicate 12-lead ECG will be 
recorded on Day 1 before the infusion (baseline). A 
single 12-lead  computerised standard ECG, with 
Table 9 Schedule of Assessment for Additional Cycles 
in Case of Clinical Benefit and Good Tolerability 
Footnote e: 
at each cycle, a triplicate 12-lead ECG will be recorded 
on Day 1 before the infusion (baseline) (minus 
15 minutes). A single 12-lead  computerised standard 
Clarification 


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 164 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
paper printout, will be recorded in supine position after 
at least 5 minutes of rest during each cycle on Day 1 at 
the end of 177Lu-3BP-227 infusion and at 4 hours after 
the end of 177Lu-3BP-227 infusion as well as at EOAC. 
ECG, with paper printout, will be recorded in supine 
position after at least 5 minutes of rest during each cycle 
on Day 1 at the end of 177Lu-3BP-227 infusion 
(±15 minutes) and at 4 hours (±30 minutes) after the 
end of 177Lu-3BP-227 infusion as well as at EOAC. 
 
 
 
19.2 
Assessment in blood sampling summary table: 
Core trial 
Clinical laboratory tests [a] 
-Maximum blood volume per sample (mL): 25 
-Maximum number of blood samples: 11 
-Maximum total volume (mL): 275 
 
 
 
 
 
 
Assessment in blood sampling summary table: 
Core trial 
Clinical laboratory tests [a] 
-Maximum blood volume per sample (mL): 25 
-Maximum number of blood samples: 10 
-Maximum total volume (mL): 250 
 
 
 
 
 
 
Amend blood volumes to reflect 
change in assessments 
CCI
CCI
CCI


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 165 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
-Maximum number of blood samples: 1 
-Maximum total volume (mL): 10 
-Maximum number of blood samples: 2 
-Maximum total volume (mL): 20 
19.2 
Assessment in blood sampling summary table: 
EOCT/ED 
 
 
Assessment in blood sampling summary table: 
EOCT/ED 
 
 
 
Amend blood volumes to reflect 
change in assessments 
19.2 
Blood sampling summary table: 
Total volume over study period: Approximately 900
mL 
Blood sampling summary table: 
Total volume over study period: Approximately 
820 mL 
 
 
 
 
 
19.3 
The following assessments in the haematology table 
were removed from the LTFU: 
RBC count 
Haematocrit 
MCV 
LTFU timepoints deleted 
Clarification 
of 
requirements 
during the long-term follow-up. 
19.3 
Footnote added to the clinical chemistry table 
Footnote added to the clinical chemistry table: 
a 
only to be performed if the total bilirubin is 
abnormal i.e. outside the laboratory normal range 
The testing of conjugated bilirubin 
has been made optional because 
the 
differentiation 
between 
conjugated 
vs 
unconjugated 
bilirubin is usually needed only if 
the total bilirubin is elevated, to 
find 
the 
cause 
of 
hyperbilirubinemia. Hence the
conjugated bilirubin test is not 
required if the value of total 
bilirubin is within the laboratory 
normal range.   
19.3 
LTFU assessment added 
 
The following assessment in the clinical chemistry table 
was added to the LTFU: 
Total bilirubin 
Clarification 
of 
requirements 
during the long-term follow-up. 
19.3 
The following assessments in the clinical chemistry 
table were removed from the LTFU: 
Albumin 
LTFU timepoints deleted 
Clarification 
of 
requirements 
during the long-term follow-up. 
CCI
CCI
CCI


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 166 of 167 
 
Section 
Version 7.0, 20 June 2019 
Version 8.0, 12 June 2020 
RATIONALE FOR CHANGE 
WAS 
IS 
ALP 
Calcium 
Chloride 
CRP 
eGFR 
Glucose 
Potassium 
Sodium 
Total bilirubin 
Total cholesterol 
Total protein 
TG 
Uric acid 
19.3 
Assessment in clinical chemistry table 
Glucose (fasting) 
Assessment in clinical chemistry table 
Glucose  
Clarification 
19.3 
Urinalysis table 
New assessment added 
Urinalysis table 
Specific gravity added  
Clarification for consistency with
the eCRF 
19.3 
The following assessments in the urinalysis table were 
removed from the LTFU: 
Bilirubin 
Blood 
Glucose 
Ketones 
Leucocytes 
Nitrite 
pH 
Protein 
Proteinuria 
Urobilinogen 
Proteinuria (urine collection) 
LTFU timepoints deleted 
Clarification 
of 
requirements 
during the long-term follow-up. 


 
CONFIDENTIAL 
 
Study number D-FR-01087-001 - Protocol v 8.0 Date: 12 June 2020 
Page 167 of 167 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-01087-001 
AMENDED PROTOCOL 
VERSION NUMBER AND 
DATE 
Version 8.0, 12 June 2020 
SUBSTANTIAL  
 
NON-SUBSTANTIAL
 
 
REASON(S) FOR CHANGES 
 
The protocol was amended to update the following: 
x 
Clarification of the inclusion criteria for subject selection as 
follows: 
- 
to clearly state nonresectable locally advanced disease  
- 
to clearly state that no further suitable treatment options 
are available for subjects eligible for the study 
x 
Allow subjects screened and found positive for NTSR1 in the 
111In-IPN01087 phase I diagnostic study to take part in this study 
without having the diagnostic dose of 177Lu-IPN01087 during the 
screening phase 
x 
Extend the long-term follow-up period from 2 years to a maximum 
of 5 years or until lost to follow-up, withdrawal of consent or 
death, whichever occurs first. 
x 
Revision of the DLT criteria to adequately describe the grading as 
stated in the CTCAE v5.0 dictionary 
x 
Revision of the subject discontinuation rules so if there are life 
threatening toxicities outside of the DLT period, treatment will be 
discontinued 
x 
Optimise the dosimetry evaluation through adaptation of the 
imaging schedule 
x 
Clarification of biopsy collection 
x 
Clarification about COVID-19 added following the recent 
pandemic 
x 
 
 
x 
Make various clarifications and minor corrections for consistency 
Other Action Required? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 
CCI

SAP_001.pdf: 
Document Name: dfr01087001 16.1.9 statistical analysis plan
Approved
Clinical
12-Jul-2021 07:31:31 GMT+0000
Clinical
12-Jul-2021 08:19:54 GMT+0000
Clinical
12-Jul-2021 09:45:45 GMT+0000
PPD
PPD
PPD


IPSEN GROUP 
D-FR-01087-001 
 
SAP final version 2.0: 06 July 2021 
1/71 
CONFIDENTIAL 
 
STATISTICAL ANALYSIS PLAN 
 
AN INTERNATIONAL MULTICENTRE, OPEN-LABEL FIRST IN HUMAN PHASE I/II 
STUDY TO EVALUATE THE SAFETY, TOLERABILITY, BIODISTRIBUTION AND 
ANTITUMOUR ACTIVITY OF 177LU-3BP-227 FOR THE TREATMENT OF SUBJECTS 
WITH SOLID TUMOURS EXPRESSING NEUROTENSIN RECEPTOR 1 
 
 
 
 
PROTOCOL VERSION AND DATE: 
VERSION 8.0 – 12 JUNE 2020  
 
SAP Version 
Date 
Final version 2.0 
 
06 July 2021 


IPSEN GROUP 
D-FR-01087-001
SAP final version 2.0: 06 July 2021 
2/71 
CONFIDENTIAL 
STUDY NUMBER: 
D-FR-01087-001
EUDRACT NUMBER 
2017-001263-20 
PROTOCOL TITLE: 
AN INTERNATIONAL MULTICENTRE, OPEN-LABEL 
FIRST IN HUMAN PHASE I/II STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY, BIODISTRIBUTION 
AND ANTITUMOUR ACTIVITY OF 177LU-3BP-227 FOR 
THE TREATMENT OF SUBJECTS WITH SOLID 
TUMOURS EXPRESSING NEUROTENSIN RECEPTOR 1 
SAP VERSION: 
Final version 2.0 
SAP DATE: 
06 July 2021 
Further to your review and agreement to the Statistical Analysis Plan version indicated 
above, please sign to indicate approval for your area of responsibility: 
RESPONSIBILITY  
NAME, TITLE & OFFICE SIGNATURE 
DATE 
Ipsen  
 
 
Ipsen Innovation 
5 Avenue du Canada 
91940 Les Ulis, France 
Ipsen 
 
 
 
Ipsen Innovation 
5 Avenue du Canada 
91940 Les Ulis, France 
Ipsen  
 
 
  
Ipsen Biopharm Ltd 
102 Park Drive, Milton Park, 
Abingdon, OX14 4RY, 
United Kingdom 
RESPONSIBILITY  
NAME, TITLE & OFFICE SIGNATURE DATE 
 
 
 
Biotrial Biometrics 
7-9 Rue Jean-Louis Bertrand
35042 Rennes Cedex, France
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical Analysis Plan version became the Final Statistical Analysis Plan 
09-Jul-2021
PPD
PPD
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PPD
PPD
PPD
PPD
PPD
PPD


IPSEN GROUP 
D-FR-01087-001 
 
SAP final version 2.0: 06 July 2021 
3/71 
CONFIDENTIAL 
 
History of Changes 
New Version Number 
Date Old 
Version 
Date New 
Version 
Reason for Change 
Page 
Section 
Was 
Is 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IPSEN GROUP 
D-FR-01087-001 
 
SAP final version 2.0: 06 July 2021 
4/71 
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 7 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 11 
1.1 
Study objectives ............................................................................................................. 11 
1.1.1 
Primary objective ......................................................................................... 11 
1.1.2 
Secondary Study Objectives ........................................................................ 11 
1.1.3 
Exploratory Study Objectives ...................................................................... 11 
1.2 
Study design ................................................................................................................... 11 
1.2.1 
Study population ......................................................................................... 13 
1.2.2 
Study duration ............................................................................................. 13 
1.3 
Methods and procedures .............................................................................................. 14 
1.3.1 
Subject identification and allocation to study treatment ........................... 14 
1.3.2 
Subjects assessments ................................................................................... 14 
1.3.2.1 
Safety assessments ....................................................................................... 14 
1.3.2.2 
Pharmacodynamic/efficacy assessments ..................................................... 16 
1.3.2.3 
Pharmacokinetics, biodistribution and dosimetry ....................................... 16 
1.3.2.4 
Exploratory assessments .............................................................................. 17 
1.3.2.5 
Other assessments ........................................................................................ 18 
1.3.2.6 
Withdrawal/discontinuation ......................................................................... 18 
1.3.3 
Schedule of assessments ............................................................................. 19 
1.3.4 
Planned sample size .................................................................................... 25 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 25 
2.1 
Screened population ..................................................................................................... 25 
2.2 
Included population ...................................................................................................... 25 
2.3 
Safety population .......................................................................................................... 25 
2.4 
Pharmacodynamic/Efficacy population ...................................................................... 25 
2.4.1 
Pharmacodynamic population .................................................................... 25 
2.4.2 
Primary pharmacodynamic population...................................................... 25 
2.5 
Pharmacokinetic population ........................................................................................ 25 
2.5.1 
177Lu-3BP-227 Pharmacokinetic population ............................................. 25 
2.5.1.1 
177Lu-3BP-227 blood pharmacokinetic population ................................... 25 
2.5.1.2 
177Lu-3BP-227 urine pharmacokinetic population ...................................... 25 
2.5.2 
3BP-227 Pharmacokinetic population ....................................................... 26 
2.5.2.1 
3BP-227 plasma pharmacokinetic population ............................................. 26 
2.5.2.2 
3BP-227 urine pharmacokinetic population ................................................ 26 
2.6 
Dosimetry population ................................................................................................... 26 
2.7 
Primary population ....................................................................................................... 26 
3 
STATISTICAL METHODS ........................................................................................ 26 
3.1 
Statistical analysis strategy .......................................................................................... 26 
3.1.1 
Safety endpoints .......................................................................................... 26 


IPSEN GROUP 
D-FR-01087-001 
 
SAP final version 2.0: 06 July 2021 
5/71 
CONFIDENTIAL 
3.1.2 
Pharmacodynamic/efficacy endpoints ....................................................... 27 
3.1.3 
Pharmacokinetics, biodistribution and dosimetry endpoints .................... 27 
3.1.3.1 
Biodistribution and pharmacokinetic endpoints for 177Lu-3BP-227 ........... 27 
3.1.3.2 
Pharmacokinetic endpoints for 3BP-227 ..................................................... 28 
3.1.3.3 
Radiation dosimetry endpoints for 177Lu-3BP-227 ...................................... 29 
3.1.4 
Exploratory endpoints ................................................................................. 30 
3.1.5 
Multiplicity .................................................................................................. 30 
3.1.6 
Significance testing and estimation ............................................................ 30 
3.2 
Analysis methods ........................................................................................................... 30 
3.2.1 
Safety ........................................................................................................... 30 
3.2.1.1 
Adverse events .............................................................................................. 30 
3.2.1.2 
Laboratory data ........................................................................................... 32 
3.2.1.3 
Physical examination ................................................................................... 33 
3.2.1.4 
Vital signs ..................................................................................................... 33 
3.2.1.5 
ECG .............................................................................................................. 33 
3.2.1.6 
Holter ECG .................................................................................................. 34 
3.2.1.7 
ECOG ........................................................................................................... 34 
3.2.1.8 
Serum and urine pregnancy tests ................................................................. 34 
3.2.1.9 
Specific renal safety biomarkers .................................................................. 34 
3.2.2 
Missing data and outliers ............................................................................ 34 
3.2.2.1 
Missing data ................................................................................................. 34 
3.2.2.2 
Missing or incomplete dates ........................................................................ 34 
3.2.2.3 
Outliers ........................................................................................................ 35 
3.2.3 
Subject disposition ....................................................................................... 35 
3.2.4 
Withdrawals ................................................................................................. 35 
3.2.5 
Demographic and baseline characteristics ................................................ 36 
3.2.6 
Medical and surgical history ...................................................................... 36 
3.2.7 
Baseline signs and symptoms related to studied disease or previous 
studied disease therapy ................................................................................ 36 
3.2.8 
Prior chemotherapy for studied disease ..................................................... 36 
3.2.9 
Prior immunotherapy for studied disease .................................................. 36 
3.2.10 
Prior radiotherapy for studied disease ....................................................... 37 
3.2.11 
Prior surgical procedures for studied disease ............................................ 37 
3.2.12 
Studied disease ............................................................................................ 37 
3.2.13 
Subject compliance ..................................................................................... 38 
3.2.14 
Prior and concomitant medications ........................................................... 39 
3.2.15 
Concomitant medications for studied disease ............................................ 39 
3.2.16 
Prior and concomitant non-drug therapies ................................................ 39 
3.2.17 
Concomitant surgical procedures ............................................................... 40 
3.2.18 
Pharmacodynamics/efficacy analyses ........................................................ 40 
3.2.18.1 
Best Overall Response ................................................................................. 40 
3.2.18.2 
Objective Response Rate .............................................................................. 41 


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3.2.18.3 
Disease Control Rate ................................................................................... 41 
3.2.18.4 
Progression-Free Survival ........................................................................... 41 
3.2.18.5 
Overall Survival ........................................................................................... 41 
3.2.18.6 
Metabolic tumour response .......................................................................... 42 
3.2.18.7 
Tumour markers in serum ............................................................................ 42 
3.2.19 
Pharmacokinetics, biodistribution and dosimetry analyses ...................... 42 
3.2.19.1 
Analysis methods .......................................................................................... 42 
3.2.19.2 
Analyses on blood pharmacokinetics of 177Lu-3BP-227 .............................. 43 
3.2.19.3 
Analyses on urine pharmacokinetics of 177Lu-3BP-227 ............................... 43 
3.2.19.4 
Analyses on plasma pharmacokinetics of 3BP-227 ..................................... 44 
3.2.19.5 
Analyses on urine pharmacokinetics of 3BP-227 ........................................ 44 
3.2.19.6 
Biodistribution analysis for 177Lu-3BP-227 ................................................. 44 
3.2.19.7 
Radiation dosimetry analysis of 177Lu-3BP-227 .......................................... 44 
3.2.20 
Exploratory analyses ................................................................................... 45 
3.2.21 
Derived data ................................................................................................. 45 
3.2.22 
Rules and data formats ............................................................................... 45 
3.2.23 
Pooling of Centres ....................................................................................... 45 
3.2.24 
Interim analysis ........................................................................................... 46 
3.2.25 
Role of Safety Review Committee (SRC) .................................................... 46 
3.2.26 
Covariates and analysis of subgroups ........................................................ 46 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 46 
4.1 
Hardware ....................................................................................................................... 46 
4.2 
Software ......................................................................................................................... 46 
4.3 
Validation programs ..................................................................................................... 46 
4.4 
Restitution of the programs ......................................................................................... 47 
5 
CHANGES FROM PROTOCOL ................................................................................ 47 
6 
REFERENCES .............................................................................................................. 47 
7 
APPENDICES TO THE SAP ...................................................................................... 48 
 
LIST OF FIGURES 
Figure 1 Flow of Dose Escalation Cohorts and SRC Meetings ........................................... 12 
 
LIST OF TABLES 
Table 1 
Study Schedule of Assessments (dose escalation) ............................................. 20 
Table 2 
Study Schedule of Assessments (additional cycles in case of clinical benefit 
and good tolerability) .......................................................................................... 24 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
Adverse Event 
ALT: 
Alanine aminotransferase 
AST: 
Aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Class 
BLQ: 
Below the Limit of Quantification 
BMI: 
Body Mass Index 
BOR: 
Best Overall Response 
BSAP: 
Bone Specific Alkaline Phosphatase 
CA: 
Cancer Antigen 
CEA: 
Carcinoembryonic Antigen 
ceCT/MRI: 
Contrast 
enhanced 
Computed 
Tomography/Magnetic 
Resonance Imaging 
cfDNA: 
Cell-Free DNA 
CI: 
Confidence Interval 
CR: 
Complete Response 
CRC: 
Colorectal Cancer 
CV: 
Coefficient of Variation 
DCR:  
Disease Control Rate  
DLT: 
Dose Limiting Toxicity 
DNA:  
Deoxyribonucleic acid 
DNA-DSB: 
Deoxyribonucleic acid-double strand breaks 
eCRF: 
Electronic Case Report Form 
ECG: 
Electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
ED: 
Early Discontinuation 
eGFR 
Estimated Glomerular Filtration Rate 
EOAC: 
End Of Additional Cycles 
EOCT: 
End Of Core Trial 
ES: 
Ewing Sarcoma 
FOV: 
Field of View 
GBq: 
Gigabecquerel 
GC: 
Gastric Cancer 
GIST: 
Gastrointestinal Stromal Tumours 


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GST: 
alphaglutathione S-transferase 
GSTP1: 
glutathione S-transferase P1 
Gy: 
Gray 
ICH: 
International Conference on Harmonisation 
IGF-1: 
Insulinlike Growth Factor 1  
IMP: 
Investigational Medicinal Product 
i.v. 
Intravenous 
KIM-1: 
Kidney Injury Molecule-1 
KM: 
Kaplan-Meier 
LDH: 
Lactate Dehydrogenase 
LOQ: 
Limit Of Quantification 
MACA: 
Maximum Administered Cumulative Activity 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MTCA: 
Maximum Tolerated Cumulative Activity 
MTSA: 
Maximum Tolerated Single Activity 
NCA: 
Non-Compartmental Analysis 
NCI-CTCAE: 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NE: 
Not Evaluable 
NTSR1: 
Neurotensin receptor 1 
ORR: 
Objective Response Rate 
OS: 
Overall Survival 
PD:  
Pharmacodynamics/Progressive Disease 
PDAC: 
Pancreatic Ductal Adenocarcinoma 
PFS: 
Progression-Free Survival 
PK: 
Pharmacokinetics 
PR: 
Partial Response 
PTH: 
Parathyroid Hormone 
QRS: 
QRS interval duration 
QT: 
Time interval for ventricular depolarisation and repolarisation 
QTc: 
Corrected QT interval 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
SAP: 
Statistical Analysis Plan  
SAE: 
Serious Adverse Event 
SAS®: 
Statistical Analysis System® 


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SCCHN: 
Squamous-Cell Carcinoma of Head and Neck  
SD: 
Standard Deviation/Stable Disease 
SI: 
International System 
SRC: 
Safety Review Committee 
SV: 
Sievert 
TEAE: 
Treatment Emergent Adverse Event 
TFLs:  
Tables, Figures and Listings  
TIAC: 
Time-Integrated Activity Coefficient 
TPA: 
Tissue Polypeptide Antigen 
TSH: 
Thyroid-Stimulating Hormone 
WHO-DD: 
World Health Organisation – Drug Dictionary 


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Information reported in this document is only related to Phase I dose escalation part of the 
study. 


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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective is to establish the safety and tolerability of fractionated 
intravenous (i.v.) administrations of 177Lu-3BP-227 in subjects with unserectable, 
locally advanced or metastatic cancers expressing Neurotensin Receptor 1 
(NTSR1).   
1.1.2 
Secondary Study Objectives 
The secondary objectives are:  
• To determine the whole-body distribution of 177Lu-3BP-227 and pharmacokinetics 
(PK) of both 177Lu-3BP-227 and 3BP-227. 
• To determine the radiation dosimetry of 177Lu-3BP-227 (organ exposure to 
radiation) after each administration. 
• To describe the preliminary antitumour activity of 177Lu-3BP-227.  
1.1.3 
Exploratory Study Objectives 
The exploratory objectives are:  
• To explore the correlation between the tumour uptake of 177Lu-3BP-227 
and the NTSR1 expression on tumours. 
• To explore renal safety by measuring urinary specific biomarkers. 
• To evaluate the tumour microenvironment, transcriptomics, and other markers of 
interest for the disease through assessment of tumour biopsies. 
• To explore genomic alterations in circulating cell-free DNA (cfDNA) and in 
germline DNA. 
• To collect gene mutation status for correlation with clinical outcome. 
• To collect biobank samples for future analysis of circulating markers (optional, 
additional informed consent required). 
• To generate a model integrating PK, dosimetry, antitumour activity and safety 
data. 
1.2 
Study design  
This is a multicentre, open-label phase I/II study of 177Lu-3BP-227 in subjects with 
unresectable, locally advanced or metastatic solid tumours expressing NTSR1 who 
have exhausted their available standard-of-care treatment options and/or are 
deemed suitable for treatment with 177Lu-3BP-227 as per the investigator’s clinical 
assessment and/or their individual disease state. The study consists of a phase I with 
a dose escalation part (and potential expansion cohorts) and a phase II either in 
selected or over multiple indications in a basket approach. The purpose of the 
radioactivity escalation part is to determine the maximum tolerated cumulative 
(MTCA). 
 
During phase I, it is planned to enrol subjects with unresectable, locally advanced, 
or metastatic tumours expressing NTSR1 originating from either the: 
• Pancreas (Pancreatic Ductal Adenocarcinoma, PDAC); 
• Colon and rectum (Colorectal Cancer, CRC); 
• Stomach (Gastric Cancer, GC);  
• Gastrointestinal Stromal Tumours, (GIST); 


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• Head and neck region (Squamous-Cell Carcinoma of Head and Neck, SCCHN); 
• Bone (Ewing Sarcoma, ES). 
 
 
 
 
Following eligibility confirmation, it is anticipated that a maximum of 30 subjects 
will receive the 177Lu-3BP-227 therapeutic dose in up to six cohorts with four 
escalation steps. Three to five subjects will be treated per cohort in order to yield a 
minimum of three evaluable subjects per radioactivity level, treated at the full 
planned radioactivity amount fractionated into two administrations. Once five 
subjects are enrolled in a cohort, the enrolment will be stopped in that cohort. Once 
the dose escalation part has been completed, the MTCA level may be repeated in an 
additional cohort. 
 
Figure 1 Flow of Dose Escalation Cohorts and SRC Meetings 
 
A=administration of study compound; EOCT=end of core trial; SRC=Safety Review Committee. 
SRC1=Decision on start of next cohort 
SRC2=Confirmation or adjustment of A2 in next cohort 
 
The cumulative starting activity will be 5 GBq fractionated into two administrations 
(2×2.5 GBq). The cumulative maximum activity will be 15 GBq activity (2×7.5 
GBq). However, if the MTCA is not reached and if limiting organ dose levels are 
not exceeded, an additional cohort with three administrations at 7.5 GBq may be 
added, leading to a cumulative activity of 22.5 GBq. 
 
Of note, for each cohort in the dose escalation part, if a subject has clinical benefit 
and an acceptable tolerability profile, and if the organ dose limits are not exceeded, 
up to four additional cycles of 177Lu-3BP-227 can be administered every 4 weeks 
after the end of the core trial (EOCT). The safety data evaluation will be conducted 
by the sponsor. The decision to administer additional cycles is based on the 
investigator’s judgement and subject’s discretion and must be discussed with and 
agreed by the sponsor. 
 
The MTCA is defined as the maximum tolerated cumulative activity that may be 
administered following fractionated i.v. administrations of at least 4 weeks apart, so 
that: 
• No more than 33% of the subjects experience a dose limiting toxicity (DLT) 
during Cycles 1 and/or 2 and 
• The cumulative radiation in each target organ does not exceed the acceptability 
limits. 
 
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The DLTs are defined for any of the following Investigational Medicinal Product 
(IMP)-related Adverse Events (AEs) according to National Cancer Institute - 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale version 
5.0, that occur during the defined DLT assessment period (from the first 
administration of 177Lu-3BP-227 to EOCT/ Early Discontinuation (ED)): 
• Grade 4 neutropenia for seven or more consecutive days. 
• Febrile neutropenia or neutropenic infection (defined as a documented infection 
with neutrophil count decreased Grade 3 or 4). 
• Grade 3 or 4 thrombocytopenia (platelet count decreased) with clinically 
meaningful bleeding (i.e. requiring urgent hospitalisation or transfusion to manage 
the bleeding). 
• Grade 4 thrombocytopenia for seven or more consecutive days. 
• Any Grade 3 anaemia (Hb<8.0 g/dL; transfusion indicated) or Grade 4 anaemia 
(life-threatening consequences; urgent intervention indicated). 
• Any Grade 3 or higher laboratory abnormalities in aspartate 
aminotransferase/alanine aminotransferase (AST/ALT) with accompanying Grade 2 
or higher bilirubin (HY’s law). 
• Any Grade 3 or higher renal injury/toxicity (estimated glomerular filtration rate 
(eGFR) <30 mL/min/1.73 m2). 
• Any Grade 3 or higher GI AE, not resolved to Grade ≤2 within 48 hours despite 
optimal adequate medical management, with the following specifications: 
 - Grade 3 nausea, vomiting (inadequate oral caloric or fluid intake; tube feeding, 
total parenteral nutrition or hospitalisation indicated) 
 - Grade 3 diarrhoea (increase of ≥7 stools per day over baseline; hospitalisation 
indicated; severe increase in ostomy output compared to baseline; limiting self-care 
activities of daily living (ADL)) or Grade 4 diarrhoea (life-threatening 
consequences; urgent intervention indicated) 
 - Grade 3 constipation (obstipation with manual evacuation indicated; limiting 
self-care ADL) or Grade 4 constipation (life-threatening consequences; urgent 
intervention indicated); 
• Any toxicity related to 177Lu-3BP-227 resulting in a treatment delay of more than 
four weeks due to delayed recovery to baseline or resolution of any AE to Grade ≤2 
(exception of alopecia and lymphopenia). 
• Grade 5 toxicity (death). 
1.2.1 
Study population 
 and up to 30 subjects will receive the 177Lu-3BP-227 
therapeutic dose. 
1.2.2 
Study duration 
The maximum duration of subject participation in the core trial is 21 weeks. 
However, if, according to the investigator, a subject has clinical benefit the subject 
may receive up to four additional administrations after the EOCT, provided the 
subject has an acceptable tolerability profile and the organ dose limits are not 
exceeded.  
A long-term follow-up period will start after the last cycle is administered (after 
EOCT, ED visit or End Of Additional Cycles (EOAC)) and subjects will be 
followed up every three months (±2 weeks) until lost to follow-up, withdrawal of 
consent, death or a maximum of 5 years, whichever occurs first.
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1.3 
Methods and procedures 
1.3.1 
Subject identification and allocation to study treatment 
All screened subjects must be identifiable throughout the study. The investigator 
will maintain a list of all subjects screened, with subject numbers and names, to 
enable records to be found at a later date, if required. 
1.3.2 
Subjects assessments 
1.3.2.1 
Safety assessments 
• 
Adverse events (AEs) monitored from the time that the subject gives informed 
consent and throughout the study, elicited by direct, nonleading questioning or by 
spontaneous reports. All AEs, irrespective of causality, should be reported to the 
sponsor up to 6 month after the EOCT, ED and EOAC visit or until new antitumour 
treatment starts, whichever comes first. AEs reported after this timepoint up to the 
end of the 5-year follow-up should only be reported if evaluated as related to the IMP 
or study procedure by the investigator; 
• 
Clinical safety assessments: 
• 
Physical examination assessed at screening, at Day 1 pre-dose (and up 
to 24 hours (replaced by up to 48 hours from protocol V7.0) before IMP 
infusion for cycle 1 only), Day 15 and Day 29 of both cycles 1 and 2, at 
EOCT/ED visit, at Day 1 and Day 29 of each additional cycle (if 
applicable), at EOAC/ED visit (if applicable) and every 3 months 
during long-term follow-up. Any clinically significant physical 
examination findings (abnormalities) observed during the study will be 
reported as AEs; 
• 
Vital signs measured at screening (prior to infusion, at the end of 
infusion, 30 minutes after infusion, 60 minutes after infusion (replaced 
by 90 minutes after infusion from protocol V7.0) and 4 hours after 
infusion), at Day 1 (prior to infusion, at the end of infusion, 30 minutes 
after infusion, 60 minutes after infusion (replaced by 90 minutes after 
infusion from protocol V7.0) and 4 hours after infusion), Day 2, Day 3, 
Day 8, Day 15, Day 22 and Day 29 of both cycles 1 and 2, at EOCT/ED 
visit, at Day 1 (prior to infusion, at the end of infusion, 30 minutes after 
infusion, 60 minutes after infusion (replaced by 90 minutes after 
infusion from protocol V7.0) and 4 hours after infusion), Day 2, Day 3, 
Day 8, Day 15, Day 22 and Day 29 of each additional cycle (if 
applicable), at EOAC/ED visit (if applicable) and every 3 months 
during long-term follow-up including supine systolic and diastolic 
blood pressures, supine heart rate and body temperature; 
• 
Body weight measured at screening, at Day 1 pre-dose (and up to 24 
(replaced by up to 48 hours from protocol V7.0) hours before IMP 
infusion for cycle 1 only), Day 15 and Day 29 of both cycles 1 and 2, at 
EOCT/ED visit, at Day 1, Day 15 and Day 29 of each additional cycle 
(if applicable), at EOAC/ED visit (if applicable) and every 3 months 
during long-term follow-up; 
• 
12-lead electrocardiograms (ECGs) measured at screening (a triplicate 
12-lead ECG before infusion and a single 12-lead ECG at the end of 
infusion and 4 hours after the end of infusion), at Day 1 (a triplicate 12-
lead ECG before infusion and a single 12-lead ECG at the end of 


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infusion and 4 hours after the end of infusion) and Day 2 at 24 hours of 
both cycles 1 and 2, at EOCT/ED visit, at Day 1 (a triplicate 12-lead 
ECG before infusion and a single 12-lead ECG at the end of infusion 
and 4 hours after the end of infusion) of each additional cycle (if 
applicable) and at EOAC/ED visit (if applicable), including corrected 
QT (QTc) calculated using Fridericia methodology as well as their 
clinical significance; 
• 
24-hour 3-lead holter ECGs starting before IMP infusion at Day 1 of 
both cycles 1 and 2; 
• 
Clinical haematology and biochemistry laboratory tests measured at 
screening, at Day 1 pre-dose (and up to 24 hours (replaced by up to 48 
hours from protocol V7.0) before IMP the infusion for cycle 1 only), 
Day 2 (for cycle 1 only) (removed from protocol V8.0), Day 8, Day 15, 
Day 22 and Day 29 of both cycles 1 and 2, at EOCT/ED visit, at Day 1, 
Day 2, Day 8, Day 15, Day 22 and Day 29 of each additional cycle (if 
applicable), at EOAC/ED visit (if applicable) and every 3 months 
during long-term follow-up: 
- 
Haematology: full blood count including red blood cells count, 
haemoglobin, haematocrit, mean corpuscular volume, white 
blood 
cell 
count 
with 
differential 
count 
(neutrophils, 
eosinophils, basophils, lymphocytes, monocytes), platelet count; 
- 
Blood biochemistry: urea, uric acid, creatinine, total bilirubin, 
conjugated bilirubin (direct) (only to be performed if the total 
bilirubin is abnormal i.e. outside the laboratory normal range 
from protocol V8.0), chloride, sodium, potassium, calcium, 
Alkaline phosphatase, Aspartate aminotransferase, Alanine 
aminotransferase, albumin, total protein, total cholesterol, 
triglycerides, fasting glucose, estimated Glomerular Filtration 
Rate (eGFR) and C reactive protein. 
• 
Clinical urinalysis laboratory tests measured at screening, at Day 1 pre-
dose (and up to 24 (replaced by up to 48 hours from protocol V7.0) 
hours before IMP the infusion for cycle 1 only), Day 2 (for cycle 1 
only), Day 3 (for cycle 1 only) and Day 29 of both cycles 1 and 2, at 
EOCT/ED visit, at Day 1 and Day 29 of each additional cycle (if 
applicable), at EOAC/ED visit (if applicable) and every 3 months during 
long-term follow-up: 
- 
pH, proteins, ketones, glucose, nitrite, bilirubin, urobilinogen, 
leucocytes and blood as well as 24h sample creatinine clearance 
(removed from protocol V7.0) and protein excretion rate (only 
in case of positive dipstick). 
• 
Clinical hormones laboratory tests measured at screening and at 
EOCT/ED visit: 
- 
Cortisol, Thyroid-Stimulating Hormone (TSH), ft4, Insulin-like 
Growth Factor 1 (IGF-1) and Parathyroid Hormone (PTH); 
Hormones analysis will be analysed in subjects who do not have 
substitution or therapy impacting one of the respective pituitary axis 
(e.g. no cortisol sampling in subjects who receive corticosteroids, no 


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thyroid-stimulating hormone and free thyroxine sampling in subjects 
who have thyroxine substitution). 
• 
Eastern Cooperative Oncology Group (ECOG) performance status scale 
measured at screening, at Day 1 of both cycles 1 and 2, at EOCT/ED 
visit, at Day 1 of each additional cycle (if applicable), at EOAC/ED 
visit (if applicable) and every 3 months during long-term follow-up; 
• 
Serum pregnancy tests measured at screening and urine pregnancy tests 
measured at Day 1 of both cycles 1 and 2, at EOCT/ED visit, at Day 1 
of each additional cycle (if applicable) and at EOAC/ED visit (if 
applicable); 
• 
 
 
 
 
 
 
  
1.3.2.2 Pharmacodynamic/efficacy assessments 
• Tumour assessment according to Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria v1.1 for target and non-target lesions assessed locally (by 
ceCT/MRI)  at screening, at Day 1 of cycle 1 (removed from protocol V7.0), at 
EOCT/ED visit, at Day 29 of second and fourth additional cycles (if applicable), at 
EOAC/ED visit (if applicable) and every 3 months during long-term follow-up; 
• Tumour assessment according to PERCIST criteria v1.0 for target and non-
target lesions assessed locally at Day 1 of cycle 1, at EOCT/ED visit and at 
EOAC/ED visit (if applicable); 
• Tumour markers in serum assessed at Day 1 of both cycles 1 and 2, at 
EOCT/ED visit, at Day 1 of each additional cycle (if applicable) and at EOAC/ED 
visit (if applicable) including Carcinoembryonic antigen (CEA) (all subjects), Cancer 
Antigen (CA) 19-9 (all subjects except SCCHN), CA72-4 (subjects with GC) 
(removed from protocol V7.0), Tissue Polypeptide antigen (TPA) (subjects with 
SCCHN) (removed from protocol V7.0) and serum Lactate Dehydrogenase (LDH) 
and Bone Specific Alkaline Phosphatase (BSAP) for ES;  
1.3.2.3 Pharmacokinetics, biodistribution and dosimetry 
• Blood samples for pharmacokinetic evaluation of 
177Lu-3BP-227 are collected 
just before the 177Lu-3BP-227 infusion (baseline), at the end of infusion (0), 5 
minutes ±1 minute, 30 minutes ±5 minutes, 1 hour ±5 minutes (replaced by 90 
minutes ±15 minutes from protocol V7.0), 4 hours ±30 minutes, 24 hours ±2 hours, 
48 hours ±2 hours, 72 to 96 hours post infusion for both cycles 1 and 2 and for both 
first and third additional cycles (if applicable) and at 24 hours after the second and 
fourth additional cycles (if applicable); 
• Urine collection for evaluation of the renal excretion of 
177Lu-3BP-227 are 
collected during four different periods at cycle 1: from 0 (i.e. start of infusion) to 6 
hours, 6 to 12 hours, 12 to 24 hours and 24 to 48 hours after the end of infusion 
(from the start of the IMP infusion to 6 hours after the end of the infusion only for 
US sites);
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• Blood samples for pharmacokinetic evaluation of 3BP-227 are collected at 
cycle 1 only before the infusion (baseline), at the end of infusion of 
177Lu-3BP-227 
(0), 5 minutes±1 minute, 30 minutes ±5 minutes, 1 hour ±5 minutes (replaced by 90 
minutes ±15 minutes from protocol V7.0), 4 hours ±30 minutes, 6 hours ±30 
minutes, 10 hours ±1 hour (replaced by 8 hours ±1 hour from protocol V7.0), 24 
hours ±2 hours and 48 hours ±2 hours after the end of infusion of 177Lu-3BP-227; 
• Urine collection for evaluation of the renal excretion of 3BP-227 are collected 
during four different periods at cycle 1: from 0 (i.e. start of infusion) to 6 hours, 6 to 
12 hours, 12 to 24 hours and 24 to 48 hours after the start of infusion (from the start 
of the IMP infusion to 6 hours after the end of the infusion only for US sites); 
• Planar scintigraphy (whole body scan) are performed at screening after 177Lu-
3BP-227 infusion, and at 0 to 1 hour (before urination) (removed from protocol 
V7.0), 4 (±2) hours, 24 (±6) hours, 48 (±6) hours, 72 to 96 hours (from protocol 
V7.0) and 138 to 168 hours (from protocol V8.0) after the end of 177Lu-3BP-227 
infusion for both cycles 1 and 2 and for both first and third additional cycles (if 
applicable). After the second and fourth additional cycles (if applicable), a single 
planar scintigraphy at 48 (±6) hours will be performed.   
• SPECT/CT are performed at screening after 177Lu-3BP-227 infusion, and at 0 
to 1 hour (before urination) (removed from protocol V7.0), 4 (±2) hours, 24 (±6) 
hours, 48 (±6) hours, 72 to 96 hours (from protocol V7.0) and 138 to 168 hours 
(from protocol V8.0) after the end of 177Lu-3BP-227 infusion for both cycles 1 and 2 
and for both first and third additional cycles (if applicable). After the second and 
fourth additional cycles (if applicable), a SPECT/CT at 48 (±6) hours will be 
performed.   
Planar scintigraphy and SPECT/CT will enable assessment of the biokinetic of 177Lu-
3BP-227 via an absolute quantification of radioactivity in target lesions and 
discernible organs. 
1.3.2.4 Exploratory assessments
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1.3.2.5 Other assessments 
• Demographics (sex, ethnicity, race) and baseline characteristics (age, body 
height, body weight, Body Mass Index (BMI)); 
• Post-menopausal status; 
• Medical history, including ongoing medical history; 
• Baseline signs and symptoms related to studied disease or previous studied 
disease therapy; 
• Studied disease (Pancreatic Ductal Adenocarcinoma history, Colorectal 
Carcinoma history, Stomach Carcinoma history, GIST history, SCCHN history, 
Ewing Sarcoma history); 
• Prior chemotherapy for studied disease; 
• Prior immunotherapy for studied disease; 
• Prior radiotherapy for studied disease; 
• Prior surgical procedures for studied disease; 
• Prior and concomitant medications; 
• Concomitant medications for studied disease; 
• Prior and concomitant non-drug therapies; 
• Concomitant surgical procedures. 
1.3.2.6 Withdrawal/discontinuation 
In accordance with the Declaration of Helsinki and the applicable country’s 
acceptance, each subject is free to withdraw from the study at any time for any 
reason.  
The investigator will be responsible for monitoring subject compliance. A subject 
can be withdrawn from the study at any time if the investigator or the sponsor 
determines that the subject is not in compliance with the study protocol.  
The investigator has the right to withdraw a subject from the study in the event of 
concurrent illness, AEs, or other reasons concerning the health or well-being of the 
subject, or in the case of lack of cooperation.  
If any of the following occur, no further treatment will be administered:  
• life-threatening toxicities outside of the DLT reporting period; 
• subject withdraws their consent to further treatment;  
• cumulative kidney dose exceeds 23 Gy;  
• cumulative bone marrow dose exceeds 2 Gy, as determined by blood-based or 
 
image-based dosimetry;  
• cumulative liver dose exceeds 30 Gy;  
• occurrence of a DLT for phase I dose escalation only.  
All cases of discontinuation will be discussed between the investigator and the 
sponsor. 
 
 
 
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1.3.3 
Schedule of assessments 
Here are the schedules of assessments extracted from the current version of the 
protocol:
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Table 1 
Study Schedule of Assessments (dose escalation) 
 
Procedures and 
assessments 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
Screening 
Treatment Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 
[d] 
D2 
D3 
D4 
D5 
D7 
D 15 D 22 
D29 
D1 
[e] 
D2 D3 D4 D5 D7 
D15 
D22 
D29 
D43 
Visit window 
(days) 
+1 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+1 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+7 
±14 
Informed consent 
x 
Inclusion/exclusion criteria 
x 
x 
Subject demographics and 
height 
x 
Medical and disease history 
x 
ECOG performance status 
x 
x 
x 
x 
ceCT/MRI 
x [f] 
x 
x 
18F-FDG-PET 
x [g] 
x 
177Lu-3BP-227 
screening administration 
x 
Tumour biopsy 
x [i] 
x 
AE=adverse event; ceCT/MRI=contrast enhanced computed tomography/magnetic resonance imaging; cfDNA=cell-free deoxyribonucleic acid; D=Day; ECG=electrocardiogram; 
ECOG=Eastern 
Cooperative Oncology Group; ED=early discontinuation; EOCT=end of core trial; IMP=investigational medicinal product; NTSR1=neurotensin receptor 1; 
PET=positron emission tomography; 
PK=pharmacokinetic; SPECT=single photon emission computed tomography. 
a 
the ED visit will take place within 14 days after ED from the study and at the latest 5 weeks after the last IMP administration, the visit will correspond to an EOCT visit. For 
subjects who received the screening IMP administration and found ineligible to participate to the study, an ED visit will be performed within 5 weeks (+ 2 weeks) after the IMP 
screening administration 
to assess the safety. At least, clinical laboratory tests (e.g. haematology and biochemistry), AEs and concomitant medication/therapy will be collected. If 
the subject is not able to come for an 
on-site visit, the visit may be performed by phone call. The clinical laboratory tests may be done locally. 
b follow-up visits will take place every 3 months (±2 weeks) and will start after the EOCT, ED or EOAC visit. Efficacy will be assessed until disease progression, administration 
of any other chemotherapy or radiotherapy, lost to follow-up, withdrawal of consent, death or a maximum of 2 years, whichever occurs first (see Section 6.2.3). After disease 
progression is confirmed, no further CT/MRI scans will be required for tumour/disease assessment. The survival status and safety of the subjects will continue to be monitored as 
indicated in Section 8.1.2.3 until lost to follow-up, withdrawal of consent, death or a maximum of 5 years, whichever occurs first. 
c 
the screening period can be extended by two weeks if this is required for logistical reasons. 
d Day 1 of Cycle 1 is the day of the first treatment administration. Day 1 of Cycle 2 and each potential subsequent cycle may coincide with Day 29 of the previous cycle if all 
safety assessments are performed and allow for the next administration. 
e 
in case of toxicity requiring a delay, the next treatment administration will be delayed by up to 4 weeks. 
f 
whole body ceCT or ceMRI including brain unless a similar exam has already been performed within 1 month prior to Day -21.  
g Cycle 1 Day 1 18FDG-PET between Day -21 and Day 1. 
h screening administration will be done after confirmation of eligibility (i.e. after all other screening assessments have been performed), minimum 1 week before the first 
treatment administration. 


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CONFIDENTIAL 
Table 1 Study Schedule of Assessments (dose escalation) (continued) 
Procedures and 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
assessments 
Screening 
Treatment Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 
[d] 
D2 
D3 
D4 
D5 
D7 
D 15 D 22 D29 
D1 
[d] 
D2 D3 D4 D5 D7 D15 D22 
D29 
D43 
Visit window 
(days) 
+1 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+1 
+1 
±1 
±1 
+7 
(+28) 
[e] 
+7 
±14 
177Lu-3BP-227 
treatment administration 
x 
x 
Blood sampling for 
177Lu-3BP-227 PK [j] 
x 
x 
x 
x 
x 
x 
x 
x 
Planar scintigraphy [k] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SPECT/CT scan [k] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood sampling for 
3BP-227 PK [l] 
x 
x 
x 
Urine sampling for 
177Lu-3BP-227 PK [m] and 
3BP-227 PK [t] 
x 
x 
x 
i 
in case subject consents to have a biopsy and in case it can be accomplished with reasonable safety, a tumour biopsy will be taken during screening from the primary or 
metastatic lesion, whichever is accessible, ideally on lesions which are positive for NTSR1 on 177Lu 3BP-227 SPECT/CT following IMP screening administration, as soon as 
177Lu uptake has been confirmed. If not, archival tissue from a previous tumour biopsy can be used for exploratory analysis (tumour microenvironment analysis and 
transcriptomics). 
j 
eighteen blood samples will be collected during the treatment period. Blood samplings will be performed just before the 177Lu-3BP-227 infusion (baseline), at the end of 
infusion (0), 5 minutes ±1 minute, 30 minutes ±5 minutes, 90 minutes ±15 minutes and 4 hours ±30 minutes, 24 hours ±2 hours, 48 hours ±2 hours and 72 to 96 hours post infusion. 
k eleven whole body scans (planar scintigraphy) and SPECT/CT acquisitions will be performed during the treatment period. Whole body scans (planar scintigraphy) and 
SPECT/CT scan will be performed at the following timepoints just after the end of 177Lu-3BP-227 infusion: Day 1: 4 (±2) hours, Day 2: 24 (±6) hours, Day 3: 48 (±6) hours, Day 
4: 72 to 96 hours, and Days 7 to 8: 138 to 168 hours. Within each cycle, a single SPECT/standard dose CT will be performed. A SPECT/low dose CT will be performed at all other 
timepoints. Details of the procedures will be provided in the Image Acquisition Guidelines. At screening, planar scintigraphy (1 or 2 timepoint(s) at the investigator’s discretion) and 
optional SPECT/CT scans (up to 2 at the investigator’s discretion) will be performed after screening administration of 177Lu-3BP-227. 
l 
ten blood samples will be collected at cycle 1. Blood samplings will be performed just before 177Lu-3BP-227 infusion (baseline), at the end of infusion of 177Lu-3BP-227 (0), 
5 minutes ±1 minute, 30 minutes ±5 minutes, 90 minutes ±15 minutes and 4 hours ±30 minutes, 6 hours ±30 minutes, 8 hours ±1 hour, 24 hours ±2 hours and 48 hours ±2 hours 
after the end of infusion of 177Lu-3BP-227. 
m four urine samples will be collected during the treatment period at the following time periods and only for Cycle 1: from the start of the IMP infusion to 6 hours, 6 to 12 hours, 
12 to 24 hours, and 24 to 48 hours (from the start of the IMP infusion to 6 hours after the end of the infusion only for US sites) after the end of 177Lu-3BP-227 infusion. 


IPSEN GROUP 
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CONFIDENTIAL 
Table 1 Study Schedule of Assessments (dose escalation) (continued) 
 
Procedures 
and 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
assessments 
Screening 
Treatment 
Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 [d] 
D2 
D3 D4 D5 D7 D 15 D 22 D29 D1[d] D2 D3 D4 D5 D7 D15 D22 D29 
D43 
Visit window 
(days) 
 
 
+1  
 
+1 ±1 ±1 +7 
(+28) 
[e] 
 
 
+1  
 
+1 ±1 ±1 
+7 
(+28) 
[e] 
+7 
±14 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x x x x 
x 
x 
x 
x 
x [z] 
Physical examination 
x 
x [y]  
 
 
 
 
x  
x 
x  
 
 
 
 
x  
x 
x 
 
Vital signs 
x [n] 
x 
[n] 
x 
x  
 
x 
x 
x 
x x [n] x x  
 
x 
x 
x 
x 
x 
 
Body weight 
x 
x [y]  
 
 
 
 
x  
x 
x  
 
 
 
 
x  
x 
x 
 
ECG (12-lead) [o] 
x 
x 
x  
 
 
 
 
 
 
x 
x  
 
 
 
 
 
 
x 
 
24-hour 3-lead Holter ECG 
[p] 
 
x 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
 
 
Haematology and 
biochemistry [w] 
x 
x [y]  
 
 
 
x 
x 
x 
x 
x  
 
 
 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x [y] 
x 
x  
 
 
 
 
x 
x  
 
 
 
 
 
 
x 
x 
 
Prior/concomitant 
medication/therapy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x x x x 
x 
x 
x 
x 
x 
n prior to and at the end of 177Lu-3BP-227 infusion (0) as well as 30±5 minutes, 90±15 minutes, 4 hours±30 minutes after the end of 177Lu-3BP-227 infusion. 
o during the screening period, a triplicate 12-lead ECG will be recorded before the screening administration (minus 15 minutes), and a single 12-lead ECG will be recorded at the 
end of 177Lu-3BP-227 infusion (±15 minutes) and 4 hours (±30 minutes) after the end of infusion. At each treatment administration, a triplicate 12-lead ECG will be recorded on 
Day 1 before the infusion (baseline) (minus 15 minutes) and a single 12-lead ECG recordings at the end of 177Lu-3BP-227 infusion (±15 minutes), at 4 hours after the end of 
177Lu-3BP-227 infusion (±30 minutes) and on Day 2 at 24 hours after the end of 177Lu-3BP-227 infusion (±4 hours) as well as at EOCT. All 12-lead computerised standard ECGs 
will be recorded in the supine position after at least 5 minutes of rest. 
p starting before 177Lu-3BP-227 infusion, a 24-hour 3-lead continuous ECG Holter will be recorded.
CCI
 


IPSEN GROUP 
D-FR-01087-001 
 
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CONFIDENTIAL 
Table 1 Study Schedule of Assessments (dose escalation) (continued) 
 
Procedures 
and 
CORE TRIAL [v] 
EOCT 
or 
ED [a] 
Long-term 
Follow-up 
[b] 
assessments 
Screening 
Treatment 
Period 
Cycle 1 
Cycle 2 
D-21 to D-1 
[c] 
D1 [d] 
D2 
D3 D4 D5 D7 D 15 D 22 D29 D1[d] D2 D3 D4 D5 D7 D15 D22 D29 
D43 
Visit window 
(days) 
 
 
+1  
 
+1 ±1 ±1 +7 
(+28) 
[e] 
 
 
+1  
 
+1 ±1 ±1 
+7 
(+28) 
[e] 
+7 
±14 
Pregnancy test [q] 
x 
x 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
x 
 
Hormone analysis [r] 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Tumour markers in serum  
x 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
x 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
q serum pregnancy test will be performed at the screening visit. A urine pregnancy test will be performed on Day1 prior to IMP administration and at EOCT/ED.  
r sample for hormone analysis (NTSR1 organ expressing) should be taken at the closest to 08:00. 
s 
 
t four urine samples will be collected during the treatment period at the following time periods and only for Cycle 1: from the start of the IMP infusion to 6 hours, 6 to 12 hours, 
12 to 24 hours, and 24 to 48 hours after the start of 177Lu-3BP-227 infusion (from the start of the infusion to 6 hours after the end of the infusion only for US sites). 
u 
 
 
 
v if an additional cohort of subjects is recruited to receive 3 cycles of therapy as described in the Study Design (dose escalation part Phase I), the schedule of assessments for the 
third cycle of therapy is to be the same as the schedule of assessments for Cycle 2. 
w additional safety assessments including haematology and biochemistry can be done if clinically indicated. 
x urine samples will be collected (and frozen) at the following timepoints: Cycle 1: Day 1: early morning, before the infusion (baseline), Day 3: early morning (48 hours after the 
end of 177Lu-3BP-227 infusion at the latest) and EOCT/ED: early morning. 
y on Day 1, assessments to be done predose and up to 48 hours before IMP infusion. 
z Any AEs/SAEs, irrespective of causality, are to be reported to the sponsor up to 6 months after the EOCT, ED or EOAC visit or until new antitumour treatment starts, whichever 
comes first. After this timepoint, up to the end of the 5-year follow-up period, AEs/SAEs should only be reported if the event is evaluated as related to the IMP or study procedure 
by the investigator. 
CCI
 
CCI
CCI
CCI


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CONFIDENTIAL 
Table 2 
Study Schedule of Assessments (additional cycles in case of clinical benefit and good tolerability) 
 
Procedures and assessments 
Additional cycles 
EOAC or ED [g] 
D1 
D2 
D3 
D4 
D5 
D7 
D15 
D22 
D29 
D43 
Visit window (days) 
+1 
+1 
±1 
±1 
+7 
(+28) 
+7 
ECOG performance status 
x 
x 
ceCT/MRI [a] 
x 
x 
18F-FDG-PET 
x 
177Lu-3BP-227 treatment administration 
x 
Planar scintigraphy [b] 
x 
x 
x 
x 
x 
SPECT/CT scan [b] 
x 
x 
x 
x 
x 
Blood sampling for 177Lu 3BP-227 PK [c] 
x 
x 
x 
x 
AEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
x 
Vital signs 
x [d] 
x 
x 
x 
x 
x 
x 
x 
Body weight 
x 
x 
x 
x 
ECG (12-lead) [e] 
x 
x 
Haematology and biochemistry 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
Prior/concomitant medication/therapy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test [f] 
x 
x 
Tumour markers in serum 
x 
x 
AE=adverse event; ceCT/MRI=contrast enhanced computed tomography/magnetic resonance imaging; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOAC=end of additional cycles; IMP=investigational medicinal product; PET=positron emission tomography; PK=pharmacokinetic; SPECT=single photon emission computed tomography.  
(a) 
ceCT/MRI will be done every 2 cycles during additional administrations, to confirm the clinical benefit after 2 additional administrations (i.e. at Cycle 4 and EOAC). In case of early 
discontinuation, the ceCT/MRI should be performed at the ED visit, to confirm any disease progression. 
(b) 
full dosimetry assessment will be performed after the first and third additional administrations as described for Cycles 1 and 2. After the second and fourth additional administrations, 
only a single SPECT/standard dose CT at 48 (±6) hours will be performed 
(c) 
After the first and the third additional administration, blood samplings will be performed just before 177Lu-3BP-227 infusion (baseline), at the end of infusion of 177Lu-3BP-227 (0), 5 
minutes ±1 minute, 30 minutes ±5 minutes, 90 minutes ±15 minutes and 4 hours ±30 minutes, 24 hours ±2 hours and 48 hours ±2 hours, and 72 to 96 hours ±2 hours. After the second 
and fourth additional administrations a single blood collection will be performed at 24 hours only (as close as possible to the SPECT/CT). 
(d) 
prior to and at the end of 177Lu-3BP-227 infusion (0) as well as 30±5 minutes, 90±15 minutes, 4 hours±30 minutes after the end of 177Lu-3BP-227 infusion. 
(e) 
at each cycle, a triplicate 12-lead ECG will be recorded on Day 1 before the infusion (baseline) (minus 15 minutes). A single 12-lead computerised standard ECG, with paper printout, 
will be recorded in supine position after at least 5 minutes of rest during each cycle on Day 1 at the end of 177Lu-3BP-227 infusion (±15 minutes) and at 4 hours (±30 minutes) after the 
end of 177Lu-3BP-227 infusion as well as at EOAC. 
(f) 
a urine pregnancy test will be performed on Day 1 prior to IMP administration. 
(g) 
the ED visit will take place within 14 days after ED from the study and at the latest 5 weeks after the last IMP administration. 


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1.3.4 
Planned sample size 
As this is primarily a descriptive safety and tolerability study, the total number of 
subjects is not based on a formal statistical sample size calculation.  
The actual sample size required to adequately determine the MTCA/ Maximum 
Tolerated Single Activity (MTSA) during dose escalation depends on the initial 
dose, rate of dose escalation and the observed dose-toxicity and dose/radiation 
exposure relationships. Simulation studies have been performed to quantify the 
operational characteristics (i.e. precision of the MTCA/MTSA, sample size, number 
of subjects being over/under dosed) of the adaptive dose-escalation design under a 
number of plausible dose-DLT relationship scenarios. Based on experience, the 
chosen sample size of three to five subjects per cohort is considered sufficient to 
fulfill the objectives of the study. It is anticipated that approximately 30 subjects 
will be required to establish the MTCA or Maximum Administered Cumulative 
Activity (MACA).  
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1 
Screened population 
The screened population is all screened subjects in the study i.e. who signed the 
informed consent. 
2.2 
Included population 
The included population is all screened subjects who are included in the study and 
received the therapeutic dose. 
2.3 
Safety population 
The safety population is all subjects who received at least one dose of study 
medication (including screening administration).  
2.4 
Pharmacodynamic/Efficacy population 
2.4.1 
Pharmacodynamic population 
The pharmacodynamic population is all subjects who received at least one 
therapeutic dose and with available post-baseline pharmacodynamics/efficacy data. 
2.4.2 
Primary pharmacodynamic population 
The primary pharmacodynamic population for tumour response is all subjects who 
have received at least two therapeutic doses of 177Lu-3BP-227 and reached the end 
of Cycle 2 or EOCT visit with available post-baseline tumour assessment based on 
RECIST criteria v1.1 and with no major protocol deviations with an impact on the 
analysis. 
2.5 
Pharmacokinetic population 
2.5.1 
177Lu-3BP-227 Pharmacokinetic population 
2.5.1.1 
177Lu-3BP-227 blood pharmacokinetic population 
The 177Lu-3BP-227 blood pharmacokinetic population is all subjects with blood 
dosimetry data and with no major protocol deviations with an impact on 177Lu-3BP-
227 blood PK analysis. 
2.5.1.2 
177Lu-3BP-227 urine pharmacokinetic population 
The 177Lu-3BP-227 urine pharmacokinetic population is all subjects with urine 
dosimetry data and with no major protocol deviations with an impact on 177Lu-3BP-
227 urine PK analysis. 


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2.5.2 
3BP-227 Pharmacokinetic population 
2.5.2.1 
3BP-227 plasma pharmacokinetic population 
The 3BP-227 plasma pharmacokinetic population is all subjects with plasma 3BP-
227 concentration data and with no major protocol deviations with an impact on 
3BP-227 plasma PK analysis. 
2.5.2.2 
3BP-227 urine pharmacokinetic population 
The 3BP-227 urine pharmacokinetic population is all subjects with urine 3BP-227 
concentration data and with no major protocol deviations with an impact on 3BP-
227 urine PK analysis. 
2.6 
Dosimetry population 
The dosimetry population is all subjects with organ dosimetry data and with no 
major protocol deviations with an impact on dosimetry analysis. 
2.7 
Primary population 
The primary objective of this study is safety and tolerability, therefore the primary 
population for analysis is the safety population.  
The pharmacodynamics/efficacy analyses will be based on the pharmacodynamic 
population, except analyses on tumour response which will be based on the primary 
pharmacodynamic population and overall survival which will be based on the 
included population. 
The 177Lu-3BP-227 blood pharmacokinetic analyses will be based on the 177Lu-
3BP-227 blood Pharmacokinetic population. 
The 177Lu-3BP-227 urine pharmacokinetic analyses will be based on the 177Lu-3BP-
227 urine Pharmacokinetic population. 
The 3BP-227 plasma pharmacokinetic analyses will be based on the 3BP-227 
plasma Pharmacokinetic population. 
The 3BP-227 urine pharmacokinetic analyses will be based on the 3BP-227 urine 
Pharmacokinetic population. 
The 177Lu-3BP-227 pharmacokinetic analyses in discernible organs and target 
lesions will be based on the dosimetry population. 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline [1]. 
Statistical analyses described in this document will be performed by Biotrial 
Biometrics, Rennes, France. 
3.1.1 
Safety endpoints 
The safety endpoints are: 
• 
Treatment Emergent Adverse Events (TEAEs), including information on  
seriousness, intensity, drug relationship and DLTs; 
• 
Clinical laboratory evaluations for haematology, biochemistry, urinalysis, 
hormones and shift tables; 
• 
Clinical safety endpoints: physical examination, vital signs, body weight, BMI, 
12-lead ECGs, 24h 3-lead holter ECGs, serum and urine pregnancy tests, 
ECOG and specific renal safety biomarkers. 


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3.1.2 
Pharmacodynamic/efficacy endpoints 
The pharmacodynamics/efficacy endpoints are: 
• 
Objective Response Rate (ORR): proportion of subjects with a best overall 
response (BOR) characterised as either a Complete Response (CR) or Partial 
Response (PR) according to RECIST criteria v1.1 relative to the total number 
of evaluable patients;  
• 
Disease Control Rate (DCR): proportion of patients with a BOR characterised 
as Complete Response (CR), Partial Response (PR) or stable disease (SD) 
according to RECIST criteria v1.1 relative to the total number of evaluable 
patients; 
• 
Progression-Free Survival (PFS) from first treatment administration until 
progression, according to RECIST criteria v1.1; 
• 
Overall Survival (OS) from first treatment administration until death, 
according to RECIST criteria v1.1; 
• 
Metabolic tumour responses according to PERCIST criteria v1.0; 
• 
Changes in tumour markers in serum relevant and specific to the underlying 
tumour disease. 
3.1.3 
Pharmacokinetics, biodistribution and dosimetry endpoints 
3.1.3.1 
Biodistribution and pharmacokinetic endpoints for 177Lu-3BP-227 
The PK parameters will be derived by non-compartmental analysis (NCA) from 
individual blood concentrations of 177Lu-3BP-227 (calculated sample activity):  
Concentrations will be decay-corrected for sampling time according to the following 
formula after substraction of pre-infusion concentration: 
 
A0 = At*exp((ln(2)/ t1/2)*∆t) where t1/2 = 6.647 days. 
With At the radioactivity at the measurement time, A0 radioactivity at the sampling 
time and ∆t the time between sampling and measurement time in days. 
 
The PK parameters are the following: 
• 
Cmax (Bq/mL): Maximum observed 177Lu-3BP-227 concentration ;  
• 
Tmax (h): Time of maximal observed 177Lu-3BP-227 concentration ;  
• 
AUC0-48 (MBq/mL*h): Area under the concentration-time curve of 177Lu-3BP-
227 from start of infusion to 48 hours; 
• 
AUC0-tlast (MBq/mL*h): Area under the concentration-time curve of 177Lu-
3BP-227 from start of infusion to time t corresponding to the last quantifiable 
concentration; 
• 
AUC0-∞ (MBq/mL*h): Area under the concentration-time curve from start of 
infusion to calculated as follows: 
AUC0-∞ = AUC0-tlast + Clast/λz, 
with Clast as the last quantifiable concentration 
• 
t1/2 (h): terminal half-life of activity concentrations of 177Lu-3BP-227; 
• 
CL (L/h): Total clearance calculated as follows: 
                         CL= Dose / AUC0-∞; 
• 
Vdz (L): Volume of distribution calculated as follows: 
                         Vdz = CL / λz. 


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• 
MRT (h): Mean residence time      
  MRT = AUMC0-∞;/AUC0-∞; 
with AUMC0-∞: Area under the first moment curve from zero to infinity 
 
The following PK parameters will be derived by NCA of the individual urine 
concentrations of 177Lu-3BP-227: 
• 
Ci x Vi (Bq) at each time interval with Ci : concentrations (calculated sample 
activity) decay-corrected for start of infusion time (using the same formula as for 
blood)  and Vi: collected volume 
• 
Ae (Bq): Cumulative activity of drug excreted in urine during 48 hours, 
calculated as follows: 
                          Ae = ∑ Ci x Vi 
• 
Fe (%): fraction of the administered drug excreted in urine during 48 hours 
• 
CLR (L/h): Renal clearance calculated as follows: 
                         CLR = Ae / AUC0-48 
 
The following biodistribution parameters will be derived for target lesions and 
organs of interest (healthy liver, bone marrow, left kidney, right kidney, spleen and 
pancreas) by NCA from individual activity uptake of 177Lu-3BP-227:  
• 
Cmax (GBq): Maximum observed 177Lu-3BP-227 activity uptake;  
• 
Tmax (h): Time of maximal observed 177Lu-3BP-227 activity uptake;  
• 
AUC0-tlast (GBq*h): [(Area under the concentration-time curve of 177Lu-3BP-
227 from start of infusion to time t corresponding to the last quantifiable 
activity uptake (%) in %*h) * Radioactivity administered in GBq]; 
• 
AUC0-∞ (GBq*h): [(Area under the concentration-time curve of 177Lu-3BP-227 
from start of infusion to infinity in %*h) * Radioactivity administered in GBq]; 
AUC0-∞ = AUC0-tlast + Clast/λz, 
with Clast as the last quantifiable concentration 
• 
MRT (h): Mean residence time  
       MRT = AUMC0-∞;/AUC0-∞; 
with AUMC0-∞: Area under the first moment curve from zero to infinity 
3.1.3.2 
Pharmacokinetic endpoints for 3BP-227 
The following PK parameters will be derived by NCA of the plasma concentration-
time profiles during cycle 1: 
• 
Cmax (ng/mL): Maximum observed 3BP-227 plasma drug concentration; 
• 
AUC0-tlast (ng/mL*h): Area under the plasma concentration-time curve of 3BP-
227 from start of infusion to time t corresponding to the last quantifiable 
concentration 
• 
AUC0-∞ (ng/mL*h): Area under the plasma concentration-time curve of 3BP-
227from start of infusion to infinity calculated as follows:  
AUC0-∞ = AUC0-tlast + Clast/λz, 
with Clast as the last quantifiable concentration 
• 
t1/2 (h): Terminal elimination half-life calculated as follows: 
                          t1/2 = Ln(2)/λz 


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• 
CL (L/h): Total clearance from plasma calculated as follows: 
                         CL = Dose / AUC0-∞ 
• 
Vz (L): Volume of distribution from plasma calculated as follows: 
                         Vdz = CL / λz 
• 
MRT (h): Mean residence time  
       MRT = AUMC0-∞;/AUC0-∞; 
with AUMC0-∞: Area under the first moment curve from zero to infinity 
 
The following PK parameters will be derived by NCA of the individual urine 
concentrations: 
• 
Ci x Vi (ng) at each time interval with Ci : concentrations  and Vi: collected 
volume 
• 
Ae (ng): Cumulative amount of drug excreted in urine during 48 hours, 
calculated as follows: 
                          Ae = ∑ Ci x Vi 
• 
Fe (%): fraction of the administered drug excreted in urine during 48 hours 
• 
CLR (L/h): Renal clearance calculated as follows: 
                         CLR = Ae / AUC0-tlast 
3.1.3.3 
Radiation dosimetry endpoints for 177Lu-3BP-227 
The following parameters will be evaluated (only in organs and target lesions 
showing uptake):  
• 
Organs receiving the highest absorbed dose by cycle; 
• 
Specific absorbed dose to the target lesions (Gy/GBq) by cycle;  
• 
Specific absorbed dose per organ (Gy/GBq) by cycle; 
• 
Time-Integrated Activity Coefficient (TIAC) (or residence time) per organ and 
to the target lesions by cycle;  
• 
Whole body effective dose (Sv) 
• 
Whole body effective dose per administered activity (Sv/GBq) 
• 
Absorbed doses on cycle 1 and cumulative absorbed doses on cycles 1 and 
cycle 2 per organ and to the target lesions (Gy). 
 
The absorbed dose to the target lesions and discernible organs (i.e. organs showing 
uptake) will be evaluated by image-based analysis. It relies on the visual 
identification of the regions of interest on the images and determination of activity 
and absorbed doses using Planet Dose solution (Dosisoft). The organs considered 
for 177Lu-3BP-227 image based dosimetry assessment will be the following: 
Healthy Liver, Total Liver, Bone marrow, Left Kidney, Right Kidney, Intestine 
(large & small), Spleen, Pancreas, Stomach wall, Right ovary, Left ovary, Uterus, 
Right testis, Left testis, Thymus, Right thyroid gland, Left thyroid gland, Prostate 
gland and total body. Additional organs may be added later on.  
In addition to the image-based analysis, the absorbed doses of all organs will be 
evaluated by model-based analysis (OLINDA/EXM version 1.0) using TIAC 
estimates from the image-based analysis.  
Effective dose will be evaluated by model-based analysis. 


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Finally, absorbed dose in red marrow will also be computed assuming 
proportionality on activity measures in blood samples (blood based method). 
 
Absorbed doses and specific absorbed doses will be also presented on kidney 
(left+right) using the average of left kidney and right kidney. 
 
Details on the different calculations are provided in the Dosimetry Analysis Plan of 
the study. 
3.1.4 
Exploratory endpoints 
Exploratory endpoints will be described in a dedicated SAP. 
3.1.5 
Multiplicity 
There is no plan for multiple testing adjustments in this study.  
3.1.6 
Significance testing and estimation 
All statistical tests will be one-sided at the 5% level of significance. 
3.2 
Analysis methods 
3.2.1 
Safety 
All safety data will be included in the data listings and summary tables will be based 
on the safety population. 
3.2.1.1 
Adverse events 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) latest version at Ipsen coding department at the time of corresponding 
database lock and NCI-CTCAE version 5.0 will be used for the grade’s 
classification. 
Listings will be presented by treatment group, subject, start date-time, primary 
system organ class, preferred term and reported term for all AEs recorded during the 
study, after IMP screening administration, for core trial, additional cycles and 
follow-up long term separately. 
Listings of all AEs, serious adverse events (SAE), AEs leading to withdrawal and 
listing of deaths will also be presented. 
TEAEs will be flagged (*) in the listing of AEs and will be summarised. 
 
A TEAE for the IMP screening administration is defined as any AE that occurs after 
the IMP screening administration if: 
- 
It was not present prior to IMP screening administration and it had onset 
before the first dose of IMP during core trial, or  
- 
It was present prior to receiving the IMP screening administration but the 
grade increased between IMP screening administration and the first dose of 
IMP during core trial, 
- 
It was present prior to receiving the IMP screening administration, the grade 
is the same but the causality changed to “related” between IMP screening 
administration and the first dose of IMP during core trial. 
 
A TEAE for the core trial period is defined as any AE that occurs during the core 
trial period of the study if: 


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- 
It was not present prior to first dose of IMP during core trial period and it 
had onset before the EOCT/ED visit, or  
- 
It was present prior to receiving the first dose of IMP during core trial period 
but the grade increased between first dose of IMP during core trial period 
and EOCT/ED visit, 
- 
It was present prior to receiving the first dose of IMP during core trial 
period, the grade is the same but the causality changed to “related” between 
first dose of IMP during core trial period and EOCT/ED visit. 
 
A TEAE for the additional cycles period is defined as any AE that occurs during the 
additional cycles period of the study if: 
- 
It was not present prior to EOCT visit and it had onset before the EOAC/ED 
visit, or  
- 
It was present prior to EOCT visit but the grade increased between EOCT 
visit and EOAC/ED visit, 
- 
It was present prior to EOCT visit, the grade is the same but the causality 
changed to “related” between EOCT visit and EOAC/ED visit. 
 
A TEAE for the long-term follow-up period is defined as any AE that occurs during 
the long-term follow-up period of the study if: 
- 
It was not present prior to EOCT/ED visit or EOAC/ED visit, or  
- 
It was present prior to EOCT/ED visit or EOAC/ED visit but the grade 
increased between EOCT/ED visit or EOAC/ED visit and end of study, 
- 
It was present prior to EOCT/ED visit or EOAC/ED visit, the grade is the 
same but the causality changed to “related” between EOCT/ED visit or 
EOAC/ED visit and end of study. 
In addition, adverse events will be assigned to a specific cycle of treatment for core 
trial and additional cycles. This assignment will be based on the start date of the 
adverse event: if the AE start date is on or after the date of treatment X and before 
the date of treatment X+1 (or if the subject does not receive a treatment X+1 or the 
treatment X+1 date is missing), then the TEAE will be assigned to Treatment Cycle 
X. 
 
An overall summary table of all AEs will be presented by treatment group and 
overall, by cycle (if applicable) and overall, after IMP screening administration, for 
core trial, additional cycles and follow-up long term separately. In addition, an 
overall summary table will be presented by pooling cycles from core trial and 
additional cycles. 
TEAEs will be summarised by treatment group and overall with the number and 
percentage of subjects with AEs classified by primary system organ class and 
preferred term, by cycle (if applicable) and overall, after IMP screening 
administration, for core trial, additional cycles and follow-up long term separately. 
The number of occurrences of a TEAE will also be presented. 
In addition, summary tables will also be presented for related TEAEs, SAEs, related 
SAEs, non-serious TEAEs, TEAEs by decreasing frequency, TEAEs by NCI-
CTCAE worst grade (for NCI-CTCAE worst grade ≥ 3) and TEAEs by most serious 
causality (category related only). 


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Summary of TEAEs and related TEAEs will be also summarised by pooling cycles 
from core trial and additional cycles. 
DLTs during cycle 1 or 2 (i.e. occurring between the first administration of 177Lu-
3BP-227 and EOCT/ED) will be summarised by treatment group and overall with the 
number and percentage of subjects with DLTs classified by primary system organ 
class and preferred term. The number of occurrences of a DLT will also be 
presented. 
The number of subjects with at least one DLT or NCI-CTCAE grade ≥ 2 (excluding 
hair loss) will be tabulated by treatment group and overall, by cycle and overall. 
Listings of all DLTs will also be presented. 
 
Depending on the number of cases, for all SAEs linked to COVID-19, a summary 
table will also be provided by treatment group and overall, presenting the number of 
patients by SOC and PT, by pooling core trial, additional cycles and follow-up long 
term. Listings of all SAEs linked to COVID-19 will also be presented. 
 
In the event of multiple reports of the same preferred term being reported by the 
same subject, the NCI-CTCAE worst grade (grade 5 > grade 4 > grade 3 > grade 2 > 
grade 1) and the most serious causality (related > not related) will be chosen. 
3.2.1.2 
Laboratory data 
Haematological and biochemistry toxicities will be recorded and graded according to 
the NCI-CTCAE criteria, version 5.0. 
A separate listing of normal ranges for standard international (SI) units will be 
provided (by age and gender where relevant) for all laboratory data (whenever 
relevant) as well as a listing of NCI-CTCAE grades with corresponding laboratory 
ranges. 
Laboratory data (haematology, biochemistry, urinalysis and hormones) will be listed 
in SI units and abnormal values will be flagged (High [H], Low [L], clinically 
significant [CS], NCI-CTCAE grade [G] (for haematology and biochemistry)) where 
applicable, for core trial, additional cycles and follow-up long term separately (only 
core trial for hormones). Any unscheduled laboratory assessments will be flagged 
[U] in the listings. 
In addition, a listing will be presented of all values for a subject with at least a 
clinically significant abnormal laboratory value. 
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to first IMP administration. 
For haematology and biochemistry, summary statistics will be presented by treatment 
group at each scheduled assessment for actual values and changes from baseline, for 
core trial, additional cycles and follow-up long term separately. 
Shift tables from baseline to each applicable post baseline visit will be presented by 
treatment group using the number and percentage of subjects with low, normal or 
high values, for core trial, additional cycles and follow-up long term separately. 
The NCI-CTCAE worst grade by subject, by cycle and overall, will be summarised 
by treatment group, for core trial, additional cycles and follow-up long term 
separately as well as by pooling cycles from core trial and additional cycles. All non-
missing post-baseline values (including unscheduled visits and retest measurements 
if any) will be used to derive the worst grade. 


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A listing of NCI–CTCAE grade 3 and 4 toxicities will be produced. For white blood 
cells, neutrophils, platelets and haemoglobin, with associated Grade 3 or 4 toxicities, 
nadir and day to nadir will be calculated and listed. 
Additionally, a listing of out of range values with parameters that could not be 
graded using NCI-CTCAE grade will be provided with the H and L flags. 
Box plots and scatter plots over time will be provided with all treatment groups on 
the same graph for the following parameters: haemoglobin, neutrophils, white blood 
cells, platelet count, ASAT, ALAT, alkaline phosphatase, creatinine, eGRF, total and 
conjugated bilirubin. 
 
For continuous urinalysis, summary statistics will be presented by treatment group at 
each scheduled assessment for actual values and changes from baseline. 
For categorical urinalysis (negative/trace/positive) frequency tables will be presented 
at each scheduled assessment by treatment group.  
Shift tables from baseline to each applicable post baseline visit will be presented by 
treatment group using the number and percentage of subjects in each category, for 
core trial, additional cycles and follow-up long term separately. 
For hormones, summary statistics will be presented by treatment group at each 
scheduled assessment for actual values and changes from baseline, for core trial.  
Hormones analysis will be analysed in subjects who do not have substitution or 
therapy impacting one of the respective pituitary axis (e.g. no cortisol sampling in 
subjects who receive corticosteroids, no thyroid-stimulating hormone and free 
thyroxine sampling in subjects who have thyroxine substitution). 
3.2.1.3 
Physical examination 
A listing with the date and status of assessment of test will be provided by treatment 
group, subject and date, for core trial, additional cycles and follow-up long term 
separately. 
3.2.1.4 
Vital signs 
Vital signs (supine systolic and diastolic blood pressures, heart rate, weight, BMI and 
temperature) will be listed at each assessment by treatment group and subject, for 
core trial, additional cycles and follow-up long term separately. Any unscheduled 
vital signs will be flagged [U] in the listing.  
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to first IMP administration. 
Summary statistics by treatment group will be presented at each scheduled 
assessment for actual values and changes from baseline, whatever the position, for 
core trial, additional cycles and follow-up long term separately. 
For interpretation of clinical significance (normal / abnormal, not clinically 
significant / abnormal, clinically significant / not evaluable), a frequency table will 
be presented by treatment group at each post-dose assessment, for core trial, 
additional cycles and follow-up long term separately. 
3.2.1.5 
ECG 
ECG results will be listed at each assessment by treatment group and subject, for 
core trial and additional cycles separately. Any unscheduled ECG will be flagged [U] 
in the listing. 


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The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to first IMP administration. 
In case of triplicate ECGs, the mean will serve as analysable data. 
3.2.1.6 Holter ECG 
Holter ECG results will be listed at each assessment by treatment group and subject. 
Any unscheduled Holter ECG will be flagged [U] in the listing. 
3.2.1.7 ECOG 
ECOG will be summarised by treatment group at each scheduled assessment and will 
be listed at each assessment by treatment group and subject, for core trial, additional 
cycles and follow-up long term separately. 
3.2.1.8 Serum and urine pregnancy tests 
Results for serum and urine pregnancy tests will be summarised by treatment group 
at each scheduled assessment and will be listed at each assessment by treatment 
group and subject, for core trial and additional cycles separately.  
3.2.1.9 Specific renal safety biomarkers 
3.2.2 
Missing data and outliers 
3.2.2.1 Missing data 
No missing value will be replaced. 
If a value required a retest, the last reliable non-missing value will be taken into 
account if measured before the first administration of IMP; and the first non-missing 
reliable value for post-baseline assessments. An assessment will be considered 
reliable if it is performed without any technical problem and if the result is within the 
range of plausible values.  
Any repeat or additional assessments performed will be included in the individual 
subject data listings. 
If there is a significant number of missing values for a subject (or if there is 
confirmed data appearing spurious), a decision will be made following consultation 
with the sponsor regarding the handling of these data in summaries, prior to database 
freeze. 
3.2.2.2 Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following 
methods will be used: 
The most conservative approach will be systematically considered (i.e. if the onset 
date of an AE/concomitant medication is missing / incomplete, it is assumed to have 
occurred during the study treatment phase (e.g. a TEAE for AEs) except if the partial 
onset date or other data [stop date, …] indicates differently).
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A missing/incomplete date of medical history or disease diagnosis will be assumed to 
have occurred before any study treatment. 
Where this is possible, the derivations based on a partial date will be presented as 
superior inequalities (e.g. for an AE started in FEB2004 after the administration 
performed on 31JAN2004, the days since last dose will be “≥ 2”, similarly the 
duration of ongoing AEs or medication will be “≥ xx” according to the start and last 
visit dates). 
3.2.2.3 
Outliers 
Any outlier identified prior to database lock which is impossible/unplausable will be 
excluded from the analysis. For other identified outliers, the impact should be 
assessed by performing the statistical analysis with the actual values and at least one 
other analysis eliminating or reducing the outlier effect. 
3.2.3 
Subject disposition 
The number of subjects screened, included, discontinued and completed at each step 
of the study (core trial, additional cycles and long-term follow-up) will be tabulated 
by treatment group and overall on the screened population for core trial and on the 
included population for additional cycles and long-term follow-up and corresponding 
information will be listed. The number of subjects exposed and impacted by COVID-
19 pandemic as well as the number of discontinued subjects due to COVID-19 will 
be also tabulated by treatment group and overall, by pooling core trial, additional 
cycles and long-term follow-up. 
The number of subjects included in each analysis population will be presented by 
treatment group and overall for the safety population. 
A listing of the inclusion and exclusion criteria not met will be provided by treatment 
group and subject and subject eligibility will also be listed. 
The reasons for subject exclusions from each population will also be tabulated by 
treatment group and overall on the included population. 
A summary table will present the extent of subject duration in the study for each 
treatment group and overall on the included population, for both core trial and long-
term follow-up. The definition of the length of study duration is calculated from the 
date of informed consent form to the last study visit in each period. 
A listing of dates of assessments and dates of hospitalisation will be presented by 
subject for each treatment group, for core trial, additional cycles and long-term 
follow-up separately. The number and percentage of subjects at each planned visit 
during the study will be presented by treatment group and overall for the included 
population, for core trial, additional cycles and long-term follow-up separately. 
A listing of subjects screened but not included with the reason for screen failure will 
be presented by subject. 
3.2.4 
Withdrawals 
Discontinued subjects will be listed with their reasons for withdrawal and a summary 
table of the number and percentage of subjects who withdrew from the study and the 
reasons for withdrawal will be presented by treatment group and overall for the 
included population, for core trial, additional cycles and long-term follow-up 
separately. 


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3.2.5 
Demographic and baseline characteristics 
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to first IMP administration. 
All demographic (sex, race and ethnicity) and baseline characteristics (age, height, 
body weight and BMI at baseline) as well as postmenopausal status will be listed by 
treatment group and subject. 
Summary statistics will be provided for demographic and baseline characteristics by 
treatment group and overall on the included population. 
3.2.6 
Medical and surgical history 
Medical and surgical history will be coded using MedDRA latest version at Ipsen 
coding department at the time of database lock. 
Listing will present the primary system organ class, the preferred term and the 
reported term. The listing will be sorted by treatment group, subject, start date, 
primary system organ class, preferred term and reported term. 
A frequency table of the number and percentage of subjects will be provided for all 
medical and surgical history by primary system organ class and preferred term for 
each treatment group and overall for the included population. 
3.2.7 
Baseline signs and symptoms related to studied disease or previous studied disease 
therapy 
Baseline signs and symptoms will be coded using MedDRA latest version at Ipsen 
coding department at the time of database lock. 
Listing will present the primary system organ class, the preferred term and the 
reported term. The listing will be sorted by treatment group, subject, start date, 
primary system organ class, preferred term and reported term. 
A frequency table of the number and percentage of subjects will be provided for all 
baseline signs and symptoms by primary system organ class and preferred term for 
each treatment group and overall for the included population. 
3.2.8 
Prior chemotherapy for studied disease 
Prior chemotherapy for studied disease will be coded using WHO-DD with the latest 
version at Ipsen coding department at the time of database lock. The therapeutic class 
will correspond to the second level of Anatomic Therapeutic Class (ATC) code, 
which corresponds to the first three digits. 
Listing will be presented for the therapeutic class, preferred name and reported name. 
The listing will be sorted by treatment group, subject, chronological start date, 
therapeutic class, preferred name and reported name. 
A frequency table of the number and percentage of subjects with at least one prior 
chemotherapy for studied disease will be provided by therapeutic class and preferred 
name for each treatment group and overall on the included population. 
3.2.9 
Prior immunotherapy for studied disease 
Prior immunotherapy for studied disease will be coded using WHO-DD with the 
latest version at Ipsen coding department at the time of database lock. The 
therapeutic class will correspond to the second level of Anatomic Therapeutic 
Class (ATC) code, which corresponds to the first three digits. 


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Listing will be presented for the therapeutic class, preferred name and reported name. 
The listing will be sorted by treatment group, subject, chronological start date, 
therapeutic class, preferred name and reported name. 
A frequency table of the number and percentage of subjects with at least one prior 
immunotherapy for studied disease will be provided by therapeutic class and 
preferred name for each treatment group and overall on the included population. 
3.2.10 
Prior radiotherapy for studied disease 
Listing will present the primary system organ class, the preferred term and the 
reported term. The listing will be sorted by treatment group, subject, start date, 
primary system organ class, preferred term and reported term. 
A frequency table of the number and percentage of subjects with at least one prior 
radiotherapy and by number of radiotherapies will be provided by treatment group 
and overall on the included population. 
3.2.11 
Prior surgical procedures for studied disease 
Prior surgical procedures for studied disease will be coded using MedDRA 
Dictionary with the latest version at Ipsen coding department at the time of database 
lock.  
Listing will present the primary system organ class, the preferred term and the 
reported term. The listing will be sorted by treatment group, subject, start date, 
primary system organ class, preferred term and reported term. 
A frequency table of the number and percentage of subjects with at least one prior 
surgical procedure for studied disease will be provided by primary system organ 
class and preferred term for each treatment group and overall for the included 
population. 
3.2.12 
Studied disease 
A frequency table of the number and percentage of subjects in each type of disease 
will be provided by treatment group and overall on the included population. 
Moreover, the following tumour characteristics will also be described by type of 
studied disease, by treatment group and overall on the included population: 
• For PDAC: 
- Time since diagnosis (in months), 
- Time since first relapse after last treatment (in months), 
- Histological grade, 
- Mutation status, 
- TNM staging at first diagnosis and at last relapse. 
• For CRC: 
- Time since diagnosis (in months), 
- Time since first relapse after last treatment (in months), 
- Location of the primary tumour, 
- Histological grade, 
- Mutation status, 
- TNM staging. 
• For GC: 
- Time since diagnosis (in months), 


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- Time since first relapse after last treatment (in months), 
- Location of the primary tumour, 
- Type of tumour, 
- Histological grade, 
- Helicobacter pylori infection status, 
- Mutation status, 
- TNM staging. 
• For GIST: 
- Time since diagnosis (in months), 
- Time since first relapse after last treatment (in months), 
- Location of the primary tumour, 
- Type of tumour, 
- Histological grade, 
- Helicobacter pylori infection status, 
- TNM staging. 
• For SCCHN: 
- Time since diagnosis (in months), 
- Time since first relapse after last treatment (in months), 
- Location of the primary tumour, 
- Histological grade, 
- Viral infection status, 
- Mutation status, 
- TNM staging. 
• For ES: 
- Time since diagnosis (in months), 
- Time since first relapse after last treatment (in months), 
- Location of the primary tumour (axial skeleton/appendicular skeleton), 
- Histological grade, 
- Mutation status, 
- TNM staging. 
All information on the studied disease will be listed by treatment group and subject. 
3.2.13 
Subject compliance 
All treatment administration information will be listed by treatment group and 
subject, for core trial and additional cycles separately. 
Number of cycles and cumulative therapeutic dose as well as overall cumulative dose 
(including the screening dose) will be also described by treatment group, for core 
trial and additional cycles separately. 
Duration of each cycle as well as duration of study drug exposure in core trial and 
additional cycles will be also summarised. 
All protocol deviations, defined prior to database freeze, will be listed by treatment 
group and subject, for core trial, additional cycles and long-term follow-up 
separately.  


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Major protocol violations will be summarised on the included population, for core 
trial, additional cycles and long-term follow-up separately. 
Additionally, protocol deviations due to COVID-19 (minor and major separately) 
will be summarised on the included population, by pooling core trial, additional 
cycles and long-term follow-up. 
3.2.14 
Prior and concomitant medications 
Prior and concomitant medications will be coded using WHO-DD with the latest 
version at Ipsen coding department at the time of database lock. The therapeutic class 
will correspond to the second level of Anatomic Therapeutic Class (ATC) code, 
which corresponds to the first three digits. 
The date and time of first study drug administration will be used as the cut-off date 
for the definition of prior and concomitant medications. A medication that started 
before study drug administration and is continuing at time of study drug 
administration will be considered as both, prior and concomitant. Prior, concomitant 
and both prior and concomitant medications will be flagged P, C and PC 
respectively, in all listings. 
In the event of incomplete start date and/or stop date which will not allow the 
categorisation of medication, it will be considered as concomitant. 
Listing will be presented for the therapeutic class, preferred name and reported name. 
The listing will be sorted by treatment group, subject, chronological start date, 
therapeutic class, preferred name and reported name, for core trial, additional cycles 
and long-term follow-up separately. 
A frequency table of the number and percentage of subjects with at least one prior 
medication will be provided by therapeutic class and preferred name for each 
treatment group and overall. 
A frequency table of the number and percentage of subjects with at least one 
concomitant medication will be provided by therapeutic class and preferred name for 
each treatment group and overall on the included population, for core trial, additional 
cycles and long-term follow-up separately. 
3.2.15 
Concomitant medications for studied disease 
Concomitant medications for studied disease will be coded using WHO-DD with the 
latest version at Ipsen coding department at the time of database lock. The 
therapeutic class will correspond to the second level of Anatomic Therapeutic 
Class (ATC) code, which corresponds to the first three digits. 
Listing will be presented for the therapeutic class, preferred name and reported name. 
The listing will be sorted by treatment group, subject, chronological start date, 
therapeutic class, preferred name and reported name, for core trial, additional cycles 
and long-term follow-up separately. 
A frequency table of the number and percentage of subjects with at least one 
concomitant medication for studied disease will be provided by therapeutic class and 
preferred name for each treatment group and overall on the included population, for 
core trial, additional cycles and long-term follow-up separately. 
3.2.16 
Prior and concomitant non-drug therapies  
Prior and concomitant non-drug therapies will be coded using MedDRA Dictionary 
with the latest version at Ipsen coding department at the time of database lock.  


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The date and time of first study drug administration will be used as the cut-off date 
for the definition of prior and concomitant therapies. A therapy that started before 
study drug administration and is continuing at time of study drug administration will 
be considered as both, prior and concomitant. Prior, concomitant and both prior and 
concomitant therapies will be flagged P, C and PC respectively, in all listings. 
In the event of incomplete start date and/or stop date which will not allow the 
categorisation of therapy, it will be considered as concomitant. 
Listing will present the primary system organ class, the preferred term and the 
reported term. The listing will be sorted by treatment group, subject, start date, 
primary system organ class, preferred term and reported term, for core trial, 
additional cycles and long-term follow-up separately. 
A frequency table of the number and percentage of subjects with at least one prior 
non-drug therapy will be provided by therapeutic class and preferred name for each 
treatment group and overall. 
A frequency table of the number and percentage of subjects with at least one 
concomitant non-drug therapy will be provided by primary system organ class and 
preferred term for each treatment group and overall for the included population, for 
core trial, additional cycles and long-term follow-up separately. 
3.2.17 
Concomitant surgical procedures 
Concomitant surgical procedures will be coded using MedDRA Dictionary with the 
latest version at Ipsen coding department at the time of database lock.  
Listing will present the primary system organ class, the preferred term and the 
reported term. The listing will be sorted by treatment group, subject, start date, 
primary system organ class, preferred term and reported term, for core trial, 
additional cycles and long-term follow-up separately. 
A frequency table of the number and percentage of subjects with at least one 
concomitant surgical procedure will be provided by primary system organ class and 
preferred term for each treatment group and overall for the included population, for 
core trial, additional cycles and long-term follow-up separately. 
3.2.18 
Pharmacodynamics/efficacy analyses 
All information related to tumour assessment according to RECIST criteria v1.1 will 
be listed by treatment group and subject, for core trial, additional cycles and long-
term follow-up separately. 
3.2.18.1 Best Overall Response 
The BOR will be presented by treatment group at the end of the core trial, at the end 
of the additional cycles and at the end of the long-term follow-up. 
BOR will be derived as the highest objective response achieved by the subject based 
on measurable lesions ((i.e. target, non-target and new lesions) from the time of first 
treatment until disease progression or the end of period and will be classified as: CR 
> PR > Non-CR/Non-PD (NCR/NPD) > SD> PD > NE.  
If SD is believed to the best response, it must also meet the minimum time from 
baseline of 56 days. If the minimum time is not met, the subject’s best response will 
be based on the subsequent assessments. 
According to RECIST guideline, any response CR or PR must be confirmed at least 
4 weeks later, or as close to this timepoint as possible. 


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3.2.18.2 Objective Response Rate  
The proportion of subjects with a BOR characterised as either CR or PR according to 
RECIST criteria v1.1 relative to the total number of evaluable patients will be also 
presented by treatment group.  
3.2.18.3 Disease Control Rate  
The proportion of subjects with a BOR characterised as either CR, PR or SD 
according to RECIST criteria v1.1 relative to the total number of evaluable patients 
will be presented by treatment group.  
3.2.18.4 Progression-Free Survival 
The PFS according to local review will include investigator assessed PD and deaths. 
Other data will be censored. PFS will be assessed at the end of the core trial, at the 
end of the additional cycles and at the end of the long-term follow-up. 
Definition of progression date: 
The PD date is assigned to the first time at which PD can be declared. 
Definition of censoring date: 
Censoring dates are defined in subjects with no PD or death before end of period or 
withdrawal. In these subjects, the censoring date is defined as the last date on which 
progression status was ‘adequately’ assessed. This is taken to be the date of the last 
radiological assessment at which the target lesions were evaluated by local 
investigator review.  
If no PD is documented, patient will be censored at the last available overall tumour 
assessment before start of the new anticancer therapy. 
Definition of PFS time: 
The PFS time will be calculated as the time from first treatment administration to 
either locally assessed PD or death. 
PFS time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
The distribution of PFS times will be estimated using the Kaplan-Meier (KM) 
product limit method.  
The Kaplan Meier method will provide hazard curves, life tables, median as well as 
corresponding 95% Confidence Interval (CI). These statistics will be presented for 
each treatment group.  
3.2.18.5 Overall Survival 
OS will be defined as the time from date of first treatment administration until death 
or last known alive. Any patient not known to have died at the time of analysis will 
be censored based at the last recorded date on which the patient was known to be 
alive (i.e. their status must be known at the censored date and should not be lost to 
follow up or unknown). OS will be assessed at the end of the core trial, at the end of 
the additional cycles and at the end of the long-term follow-up. 
Definition of OS time: 
The OS time will be calculated as the time from first treatment administration to 
death. 
OS time = [(Date of death or last date known to be alive – date of first treatment 
administration) + 1] / 7 (weeks) 
OS will be analyzed using the same methodology (Kaplan-Meier) as described for 
the PFS. 


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3.2.18.6 Metabolic tumour response  
Evaluation of metabolic tumour response using PERCIST will be summarised at 
each scheduled assessment by treatment group, for core trial and additional cycles 
separately. Corresponding information will be listed at each assessment by treatment 
group and subject, for core trial and additional cycles separately. 
3.2.18.7 Tumour markers in serum 
Tumour markers in serum will be listed at each assessment by treatment group and 
subject, for core trial and additional cycles separately.  
The baseline will be defined as the last available (and reliable if applicable) 
assessment collected prior to first IMP administration. 
Summary statistics by treatment group will be presented at each scheduled 
assessment for actual values and changes from baseline, for core trial and additional 
cycles separately. 
3.2.19 Pharmacokinetics, biodistribution and dosimetry analyses 
3.2.19.1 Analysis methods 
3.2.19.1.1 
Descriptive statistics and listings 
The Ipsen requirements for “Clinical PK and Pharmacometrics” instruction 
 will be followed. 
Listings of all parameters will be sorted by treatment group, subject, cycle (if 
applicable) and measurement time during core trial and additional cycles separately. 
Descriptive summaries by treatment group and by cycle (if applicable), during core 
trial and additional cycles separately, will include arithmetic means, Standard 
Deviation (SD), Coefficient of Variation (CV%), geometric mean, geometric CV%, 
median, minimum, maximum, n and missing. Descriptive statistics should be 
displayed only if at least 2/3 of the data are available (not missing) and only if at 
least 2/3 of the parameters are accurately determined (unflagged); otherwise, only 
minimum and maximum are reported. 
 
Of note, all BLQ (Below the Limit of Quantification) values must be replaced by 
missing/zero to compute descriptive statistics according to the rule set below:  
• For plasma 3BP-227 concentrations, BLQ data must be substituted by 0 for 
concentrations measured before the first quantifiable concentration. Any embedded 
BLQ value (i.e. single BLQ value occurring between 2 quantifiable concentrations) 
and BLQ values following the last quantifiable concentration in a profile will be set 
to missing for the purposes of PK analysis. BLQ values substituted by 0 are included 
in the NCA calculation whereas missing values are ignored. In any case, when all 
concentrations from a concentration-time profile are BLQ, they must be substituted 
by 0 and included in the PK analysis dataset. 
• For urine 3BP-227 concentrations, BLQ data have to be set as 0.  
• No BLQ values are expected for 177Lu-3BP-227 blood and urine total activity 
concentrations. 
• For biodistribution, the following nomenclature will be used: 
• 
“NA” (not applicable) for regions that are outside of the field of view 
(FOV) or for sex-specific organs: to be considered as missing.
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• 
 “NC” (not calculable) for regions inside the FOV, but where 
quantification is not possible or regions without segmentation: to be 
considered as missing. 
• 
“AU” (absent uptake) for regions inside the FOV, but with no 
radiopharmaceutical uptake: to be considered as zero. 
All BLQ concentrations or missing data will be labelled as such in the concentration 
data listings. 
BLQ values substituted by 0 are included in the calculation of descriptive statistics 
whereas missing values are ignored.  
3.2.19.1.2 
Graphical representations 
All BLQ values for 3BP-227 concentrations must be replaced by missing/zero for 
graphical representation according to the rule set below:  
• For plasma 3BP-227 concentrations, BLQ data must be substituted by 0 for 
concentrations measured before the first quantifiable concentration, and 
missing for BLQ concentrations after the last quantifiable concentration. Any 
embedded BLQ value (i.e. single BLQ value occurring between 2 quantifiable 
concentrations) and BLQ values following the last quantifiable concentration 
in a profile will be set to missing; 
• For urine 3BP-227 concentrations, BLQ data have to be set as missing.  
Nominal times are to be used to display the concentration plots. 
The graphic representation of PK parameters will be made only if at least 2/3 of the 
parameters are accurately determined. 
3.2.19.2 Analyses on blood pharmacokinetics of 177Lu-3BP-227 
Blood total activity concentrations (including PK blood sampling dates and times) 
and blood PK parameters will be listed and summarised as described in section 
3.2.19.1.1. A summary will be also planned for both cycles of core trial. 
The individual blood total activity concentration-time profiles of 177Lu-3BP-227 will 
be presented graphically on linear and log/linear coordinates with both cycles on the 
same graph, during core trial only. Spaghetti plots (overlay of individual 
concentration-time profile) will also be reported by treatment group, with both cycles 
on the same graph, during core trial only. 
Graph of arithmetic mean (±SD) on linear and log/linear coordinates will be 
presented by cycle, with all treatment groups on the same graph, during core trial 
only.   
Scatter plots will be also presented for the AUC0-tlast and t1/2 with all treatment groups 
on the same graph for cycle 1 and for both cycles. 
3.2.19.3 Analyses on urine pharmacokinetics of 177Lu-3BP-227 
Urine total activity concentrations (including PK urine sampling dates and times) 
will be listed, amount of drug excreted in urine will be summarised by time interval 
and overall and urine PK parameters will be listed and summarised at cycle 1 as 
described in section 3.2.19.1.1. 
Individual cumulative urine recovered activity versus time profiles of 177Lu-3BP-227 
will be presented graphically at cycle 1 for each treatment group with all subjects on 
the same graph. 


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The graph of cumulative recovered activity in urine over time will be provided for 
urine total activity concentration of 177Lu-3BP-227 at cycle 1 with all treatment 
groups on the same graph. 
3.2.19.4 Analyses on plasma pharmacokinetics of 3BP-227 
Plasma concentrations (including PK plasma sampling dates and times) and plasma 
PK parameters will be listed and summarised at cycle 1 as described in section 
3.2.19.1.1. 
The individual plasma concentration-time profiles of 3BP-227 will be presented at 
cycle 1 graphically on linear and log/linear coordinates. Spaghetti plots (overlay of 
individual concentration-time profile) will also be reported by treatment group. 
Graph of arithmetic mean (±SD) on linear and log/linear coordinates will be 
presented at cycle 1 with all treatment groups on the same graph.   
Scatter plots will be also presented for AUC0-tlast and AUC0-inf with all treatment 
groups on the same graph for cycle 1 and for both cycles. 
3.2.19.5 Analyses on urine pharmacokinetics of 3BP-227 
Urine total activity concentrations (including PK urine sampling dates and times) 
will be listed, cumulative amount of drug excreted in urine will be summarised by 
time interval and overall and urine PK parameters will be listed and summarised at 
cycle 1 as described in section 3.2.19.1.1. 
Individual urine cumulative recovered amount versus time profiles of 3BP-227 will 
be presented graphically at cycle 1 for each treatment group with all subjects on the 
same graph. 
The graph of urine cumulative recovered amount (Ae) over time will be provided for 
urine concentration of 3BP-227 at cycle 1 with all treatment groups on the same 
graph. 
3.2.19.6 Biodistribution analysis for 177Lu-3BP-227 
Uptake activity (including assessment dates and times) and PK parameters for organs 
of interest (healthy liver, bone marrow, left kidney, right kidney, spleen and body)  
will be listed and summarised as described in section 3.2.19.1.1. PK parameters for 
target lesions will be summarised similarly. A summary will be also planned for both 
cycles of core trial for organs. 
3.2.19.7 Radiation dosimetry analysis of 177Lu-3BP-227 
A frequency table on the organ receiving the highest absorbed dose will be provided 
by cycle and treatment group, for core trial and additional cycles separately, using 
the results from image-based analysis. 
The specific absorbed dose per organ will be summarised by cycle and overall (only 
for core trial), by treatment group and overall, for core trial and additional cycles 
separately, using the results from image-based analysis and model-based analysis. 
The specific absorbed dose to the target lesions will be summarised for core trial and 
additional cycles separately using the results from image-based analysis, by 
treatment group and overall as follows: 
• by localisation and overall and by cycle (only for core trial) and on overall 
cycles, 
• by localisation and overall and by study disease, on overall cycles only. 


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The absorbed organ dose per organ and to the target lesions on cycle 1 and 
cumulative absorbed dose on cycles 1 and 2 will be analysed by treatment group for 
core trial using the results from image-based analysis. 
The effective dose and specific effective dose will be summarised by cycle and 
overall (only for core trial) and by treatment group, for core trial and additional 
cycles separately, using the results from model-based analysis. 
Both image-based and model-based analyses will be listed by treatment group, 
subject and cycle, for core trial and additional cycles separately. 
Timing of planar scintigraphy and SPECT/CT assessments will be also listed by 
treatment group, subject and cycle, for core trial and additional cycles separately. 
3.2.20 
Exploratory analyses  
Exploratory analyses will be described in a dedicated SAP. 
3.2.21 
Derived data 
The derived data are variables which are calculated from the raw data in the eCRF 
and not included in the database and will be included in the listings (see Appendix 
1). 
3.2.22 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the 
number of decimal places used does not imply undue precision). Raw data will be 
presented with the number of decimal places collected, and derived data will be 
presented to an appropriate number of decimal places. The appropriate number of 
decimal places will be determined by general practice, mathematical rationale or 
scientific rationale (e.g. age should be presented in whole numbers).  
For PK/dosimetry data, all values will be reported with 3 significant digits for 
numbers < 1000, otherwise values will not be rounded. 
For summary statistics, the following will be presented: n, arithmetic mean, standard 
deviation, median and the range (minimum, maximum).  
Mean, median and standard deviation values will be reported with one decimal place 
greater than the raw/derived data that they summarise. Minimum and maximum 
values will be reported with the same precision as the raw data. 
Percentages will be reported with 1 decimal place and 0% will not be presented. 
Percentages will be calculated using a denominator of all subjects in a specified 
population and by treatment group. The denominator will be specified in a footnote 
to the tables for clarification if necessary.  
All values below or above a limit of quantification (e.g. < 0.1 or > 100) will be listed 
as such. For each safety parameter for which it is possible to have values below or 
above LOQ, the rule to be used in the statistical tables is to replace values below or 
above a limit of quantification by LOQ.  
All text fields must be left justified and numeric or numeric with some text 
specification (e.g. not done, unknown, < 4.5, …) must be decimal justified. Dates 
will be presented in the format [yyyy-mm-dd] and times in the format [hh:mm]. 
3.2.23 
Pooling of Centres 
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3.2.24 
Interim analysis 
An interim analysis of the escalation cohort data will be done at the end of the core 
trial. In addition, tables of safety and efficacy data from cohort 2 (4 GBqx2) will be 
used to support the rationale for the starting dose of 177Lu-IPN01087 in phase I study 
combination with Chemotherapy (Gemcitabine-Nab paclitaxel). 
3.2.25 
Role of Safety Review Committee (SRC) 
During the dose escalation part and before each decision on further dose escalation, 
safety and dose limit organ exposure data will be summarised and presented to the 
SRC. This SRC will be set up for the dose escalation decisions (after the end of the 
third subject’s Cycle 1) and second dosing cycle (after the end of the third subject’s 
Cycle 2).  
At the time of SRC meeting, all cumulative available information will be reviewed.  
A continual reassessment method (CRM) in conjunction with a Bayesian approach 
modeling of DLT rates and radiation exposure to target organs may be performed 
during the planned review meetings to generate additional relevant information for 
the adaptive dose selection decisions. PK and pharmacodynamic data may be also 
incorporated in the model. The SRC will review all available data and make the final 
decision as to dose escalation, de-escalation, or cohort expansion during the adaptive 
dose-escalation phase. This group will also determine when to implement predefined 
stopping rules.  
A specific charter has been developed to define roles and responsibilities, as well as 
the data set to be reviewed by the SRC.  
3.2.26 
Covariates and analysis of subgroups 
It is not planned to perform an analysis of subgroups or use covariates. 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using Microsoft Windows 7 Enterprise. 
4.2 
Software 
All TFLs will be produced and statistical analysis performed using SAS version 9.4 
[2]. All outputs will be in Microsoft Word Format and compiled in bookmarked .pdf 
files as per ICH section (e.g. 14.1, 14.2 …). 
4.3 
Validation programs 
Biotrial Biometrics will provide a validation plan to Ipsen identifying the methods of 
validation. 
The study statistician is responsible for reviewing each output associated with the 
deliverable product. Program logs are checked by the statistical programmer for 
logical, syntax and fatal errors. The checks in SAS includes, but is not limited to, all 
ERRORS, 
WARNINGS, 
BY-VALUE 
merge 
messages, 
NOTES, 
and 
UNINITIALIZED variables. Program logs are also reviewed for accurate and 
consistent variable and observation counts following each procedure and data step. 
The study statistician is responsible for checking and reviewing the work produced 
using whatever method he/she feels is appropriate (e.g. SAS code review, hand 
calculation, etc.) to reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values 
or results and to check the consistency with the statistical analysis plan. Outputs are 


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cross-checked against each other for accuracy and consistency. For statistical tables, 
listings, appendix listings, and figures, this procedure includes comparison of subject 
group numbers, counts of subjects at each observation point, and consistency of 
results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible for 
making necessary changes. The programs will be retested after modifications. 
After final review, and when no further change is required to produce the deliverable, 
the statistical programmer and the study statistician have to complete and sign the 
quality control and statistical analysis results follow-up’s validation checklist, to 
indicate that they have successfully performed all of their responsibilities. Copies of 
the internal quality control forms produced for the validation process will be 
provided to the sponsor to support the validation. 
4.4 
Restitution of the programs 
All programs (including macros and analysis datasets) producing the tables, listings 
and statistical outputs along with associated logs should be given to the sponsor 
when the TFLs and statistical analyses have been finalised. 
5 
CHANGES FROM PROTOCOL 
Not applicable. 
6 
REFERENCES 
1. International Conference on Harmonisation (ICH) E9 and Federal register Vol. 63, 
No. 179 (September 1998). 
2. SAS, Version 9.4. SAS Institute Inc., Cary, NC, USA, 2012. 
3. Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1, 
Eisenhauer et al., European Journal of Cancer 45 (2009) 228 – 247. 
 


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7 
APPENDICES TO THE SAP 
Appendix 1: Derived Data 
The following derived data will be calculated: 
• Study day 
Study day will be defined as ‘-1’ for the day prior to first IMP administration during 
core trial and as ‘1’ for the day of first IMP administration during core trial (i.e. day 
0 does not exist). 
• BMI 
BMI (kg/m2) will be derived as Weight (kg)/[Height(cm)/100]2 and rounded to the 
nearest decimal. 
• Core trial duration 
Core trial duration (days) will be calculated as (date of last visit attended during core 
trial - date of informed consent form) + 1. 
• Long-term follow-up duration 
Long-term follow-up duration (days) will be calculated as (date of last visit attended 
during long-term follow-up - date of informed consent form) + 1. 
• Time since diagnosis 
Time since diagnosis in months will be calculated as (date of informed consent form 
- date of diagnosis) + 1] / 30.4375. 
• Time since first relapse after last treatment 
Time since first relapse after last treatment in months will be calculated as (date of 
informed consent form - date of first relapse after last treatment) + 1] / 30.4375. 
• Baseline 
Baseline will be derived as the last available (and reliable if applicable) assessment 
before first IMP administration. 
• Changes from baseline 
Changes from baseline will be calculated as the difference from baseline (e.g. 
assessment at the visit – assessment at baseline). 
• Duration of each cycle  
Duration of each cycle (days) will be calculated as (date of infusion of the next cycle 
- date of infusion of the cycle) + 1. 
For last cycle, duration will be calculated as (date of Day 29 of last cycle - date of 
infusion of the cycle) + 1. 
• Study drug exposure during core trial 
Study drug exposure (days) = (date of infusion of last cycle during core trial - date of 
infusion of cycle 1) + 29 days. 
• Study drug exposure during additional cycles 
Study drug exposure (days) = (date of infusion of last cycle during additional cycles - 
date of infusion of first cycle during additional cycles) + 29 days. 
• Progression-Free Survival 
PFS time (weeks) = [(Date of event – date of first treatment administration) + 1] / 7. 


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Event 
Decision 
Date of event or censoring to 
consider for the analysis 
Progression Disease Not censored 
Date of progression 
No event 
Censored 
Last date of tumour assessment 
Death  
Not Censored 
Date of death 
• Overall survival 
OS time (weeks) = [(Date of death or last date know to be alive – date of first 
treatment administration) + 1] / 7. 
Event 
Decision 
Date of event or censoring to 
consider for the analysis 
Death 
Not censored 
Date of death  
No event 
Censored 
Date last known to be alive 
• Therapeutic Class 
The therapeutic class will correspond to the first three digits of the ATC code. The 
decoding of the therapeutic class will be done from the WHO-DD (latest version at 
the time of database lock). 
• Prior and concomitant flags 
The date and time of baseline (study day 1) is used as the cut-off date for the 
definition of prior and concomitant medications. A medication started before study 
day 1 and continuing at time of Day 1 is considered as both, prior and concomitant. 
Prior, concomitant and both prior and concomitant will be coded as P, C and PC 
respectively. 
In the event of incomplete start date and/or stop date which will not allow the 
categorisation of medication, it will be considered as concomitant. 
• Medical and surgical history 
The duration of medical and surgical history will be calculated as (end date – start 
date) + 1. If the recorded end date is CONT. (for continuing), the end date will be 
listed as “ongoing” and the duration will be approximated as “≥ (screening visit date 
– start date) + 1” day(s). If the start date or the end date are partial, the duration will 
be presented as a superior inequality “≥ xx”day(s) [i.e. ≥2 where start 
date=31JAN2004 and end date=FEB2004 or start date=JAN2004 and end 
date=01FEB2004] but if both are partial or one is missing the duration will not be 
presented. 
• Prior and concomitant medication/Concomitant medications for studied disease 
/prior and concomitant non-drug therapies duration 
If the start and end dates of the medication are identical then “<1” day will be 
presented with the duration in hh:mm recorded in the eCRF if it is available. If times 
are available, the duration of treatments will be calculated as (end date/time - start 
date/time). If at least one time is missing, the duration of concomitant treatments will 
be calculated as (end date - start date) + 1. If the recorded end date is continuing at 
the end of the study then the end date will be listed as “ongoing” and the duration 
will be approximated as “≥(last attended visit date – start date) + 1” day(s). If the 
start date or the end date are partial, the duration will be presented as an inequality 
“≥xx” day(s) [i.e. ≥2 where start date=31JAN2004 and end date=FEB2004 or start 
date=JAN2004 and end date=01FEB2004] but if both are partial or one is missing 
the duration will not be presented. 


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• AE duration 
If the start and end dates of the AE are identical then “<1” day will be presented with 
the duration in hh:mm recorded in the eCRF if it is available. If times are available, 
the duration will be calculated as (end date/time – start date/time) and presented in 
days hh:mm. If at least one time is missing and if the duration is greater than 
24 hours then it will be calculated as (end date - start date) + 1 and presented in days. 
If the recorded end date is continuing at the end of the study, the end date will be 
listed as “ongoing” and the duration will be approximated as “≥(last attended visit 
date – start date) + 1” day(s). If the start date or the end date are partial the duration 
will be presented as a superior inequality “≥xx” day(s) [i.e. ≥2 where start 
date=31JAN2004 and end date=FEB2004 or start date=JAN2004 and end 
date=01FEB2004]. 
• Time since last dose for adverse event 
If the start date of the adverse event is identical to the date of last administration, 
then”<1” day will be presented with the duration in hh:mm recorded in the eCRF if 
it is available. Otherwise, it will be calculated as (start date/time - last 
administration date/time) and presented in days days hh:mm. If at least one time is 
missing and if the duration is greater than 24 hours then it will be calculated as 
(start date – last administration date) + 1 and presented in days. If the start date and 
the associated information do not allow to state about the last dose received (partial 
start date or start at administration day without knowing if it started before or after 
the drug intake), all the possible time since last dose will be presented [i.e.: if a 
subject received a daily administration and reported an AE at second administration 
day but without indication about before or after the drug intake the time since last 
dose will be as “2 / <1”]. If the start date is partial, the time since last dose will be 
presented as an superior inequality (i.e.: for an AE started in FEB2004 after the 
only administration performed on 31JAN2004, the time since last dose will be as 
“≥2” days). If the start date is missing the time since last dose will not be presented 
although the AE will be assigned to each dose received before its end date. 


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