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

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.

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.

This is a multicentre, open-label phase I/II study of 177Lu-3BP-227 in subjects
with metastatic or locally advanced solid tumour 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 advanced, recurrent and/or
metastatic tumours expressing NTSR1 originating from either the:
- Pancreas (pancreatic ductal adenocarcinoma, PDAC)
- Colon and rectum (Colorectal cancer, CRC)
- Stomach (gastric cancer, GC; adenocarcinoma or Gastrointestinal Stromal
Tumours, (GIST)) or
- Head and neck region (squamous-cell carcinoma of head and neck, SCCHN).
- Bone (Ewing Sarcoma, ES)

For the dose escalation part, it is anticipated that approximately 30 subjects
will be included, in up to six escalation steps. Three to five subjects will be
treated per activity level in order to yield a minimum of three subjects
treated at the full planned radioactivity amount fractionated into two
administrations. Once the dose escalation part has been completed, the maximum
tolerated cumulative activity (MTCA) level will 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, subjects may receive up
to four additional administrations of 177Lu-3BP-227 after the end of the core
trial (EOCT), if they have clinical benefit and acceptable tolerability profile
according to investigator's jugement, and if the organ dose limits are not
exceeded.

The MTCA is defined as the maximum 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 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:
- 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 more than seven 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 aspartate amino
transferase/alanine amino transferase (AST/ALT) with accompanying Grade 2 or
higher bilirubin (Hy*s law);
- any Grade 3 or higher renal injury/toxity (estimated glomerular filtration
rate (eGFR) <30 mL/min/1.73 m2);
- any Grade *3 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
selfcare activities of daily living) 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 to Grade <2 AE (with the
exception of alopecia and lymphopenia).

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 enroled 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 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 doses
followed by fractionated lower doses. 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.
At this time and based on available preclinical and clinical data, it is
anticipated that most likely two cohorts of subjects, one with PDAC and another
with CRC, will enrol approximately 125 subjects, using the administration
schedule and radioactivity/smallmolecule doses derived from phase I. 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.
- The PDAC cohort will enrol approximately 55 subjects and will investigate
whether 177Lu3BP-227 attains an ORR superior to a clinically accepted
historical threshold of current standard-of-care treatment for subjects with
metastatic or locally advanced disease.
- The CRC cohort will enrol approximately 70 subjects and will investigate
whether 177Lu3BP-227 attains an ORR superior to a clinically accepted
historical threshold of current standard-of-care for subjects with metastatic
or locally advanced 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.

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.


Please describe which intervention is given; e.g. one group receives a 10 mg
tablet of product X twice daily and the other group receives a placebo tablet
twice daily.

The duration of the study depends upon how many treatment cycles the subject
will receive and how long he/she will be followed during the long-term
follow-up. In case the subject has 2 treatment cycles and a long-term follow-up
of 24 months, his/her participation will last for about 28 months and will
includes 26 study visits. It consists of a screening visit, 8 visits per
administration cycle, 1 follow-up visit and 8 visits during the long-term
follow-up.
During the study the subject will undergo 3 to 4 MRI/CT scans, 1 PET scan, 1 or
2 tumor biopsies. At 9 visits a physical examination will be performed, at 14
visits blood will be collected and at 9 visits a urine sample will be taken. At
6 visits a ECG will be made and at day 1 of each cycle a hotter recording will
be made.

Safety measures have been taken into consideration to minimise the risk. Each
subject recruited across the sites will be hospitalised for 24 hours following
administration for observation. The level of radioactivity will be monitored
until it has fallen to safe levels for discharge.
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.

Even though promising safety data were collected from the treatment attempt,
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. 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.

Subject-specific dosimetry will be performed on a regular basis for up to 48
hours, and optionally up to 72 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 can be reduced or
the cycle can be delayed.

The risks associated with this study are controlled well by planned cautionary
measures in the study design and the target population as well as with the
potential benefit of the treatment.