A Phase I/IIA, Multi-Centre, Open-Label, Dose-Escalation Study with Expansion Arms to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of CB-103 Administered Orally in Adult Patients with Advanced or Metastatic Solid Tumours and Haematological Malignancies Characterised by Alterations of the NOTCH Signalling Pathway

NOTCH signalling plays a key role in many cellular processes during
develop-ment. NOTCH is a developmental pathway characterized by cell to cell
commu-nication and activation via ligand-receptor interaction. The pathway is
known to play critical roles during embryonic development as well as for the
regulation of self-renewing tissues. Aberrant activation of NOTCH signalling
leads to deregu-lation of the self-renewal process resulting in sustained
proliferation, evasion of cell death, loss of differentiation capacity,
invasion and metastasis, and re-sistance to chemotherapy, all of which are
hallmarks of cancer. Over-activation of the NOTCH signalling pathway can lead
to cancer development, or, if it occurs during the course of the disease, it
may contribute to the de-differentiation of can¬cer, promoting progression,
development of metastasis, escaping apoptosis or to even cause resistance
against chemotherapy or other targeted therapies.
Aberrant or over-activation of the NOTCH signalling pathway, in particular the
constitutive activation of NOTCH signalling (independent of ligand/receptor
ex-pression) can be found in many solid tumour indications and various
haematological malignancies. The level of oncogenic activation of NOTCH
signalling is correlated with a more aggressive course of disease, resulting in
poorer survival rates with a more rapid disease progression compared to the
overall survival seen in patients with the same tumours not hav¬ing any
aberration or dysregulation of the NOTCH pathway.
Altogether, the correlation and dependency of the patient*s life expectancy
with the NOTCH status in their tumours confirms the important role of NOTCH
signal¬ling in human malignancies indicating that a strong rationale exists for
the devel¬opment of NOTCH-tailored therapies.
(Ref. see Investigators Brochure section 2 (introduction) for more information)

This Phase I/IIA study is a first-in-human (FIH), open-label study
investigating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics
(PD) and preliminary efficacy of the pan-NOTCH inhibitor CB-103 in adult
patients with advanced or metastatic solid tumours and haematological
malignancies. CB-103 is an orally administered, small molecule targeting the
NOTCH signalling pathway by a novel mode of action (protein-protein interaction
inhibition) with binding to the NOTCH-specific transcription complex located at
the nucleus of tumour cells. The study is divided into two parts with Part A
(the Phase I component of the study) being the dose escalation part of the
study to determine the maximum tolerated dose (MTD) or recommended Phase II
dose (RP2D). Part B (the Phase IIA component of the study) is the expansion
part of the study with several expansion arms to confirm MTD/RP2D of CB-103 in
patients with selected tumour indications and to explore preliminary clinical
efficacy and PD of CB-103 in these indications. While in Part A no patient
enrichment for NOTCH will be implemented, in Part B the patients in all
expansion arms must have tumours characterised by a functionally over-activated
NOTCH signalling pathway determined by molecular and/or biochemical biomarkers
in their tumours. (Ref. see Protocol section 1 (Introduction) for more
information)

Primary Objectives
The primary objectives of this study are:
Phase I, Part A - Dose Escalation:
• To determine the maximum tolerated dose (MTD) or recommended phase 2 dose
(RP2D) of CB-103 as a single agent when administered orally and with repeat
dosing to adult patients with advanced or metastatic solid tumours and
haematological malignancies, who have progressed despite curative therapy or
for whom no curative therapy exists.
Phase IIA, Part B - Expansion:
• To assess preliminary anti-tumour, anti-lymphoma and anti-myeloma activity of
single agent CB-103 when administered orally and with repeat dosing in the
different expansion arms across the different indications.

Secondary Objectives
The secondary objectives for parts A and B of this study are:
• To characterise the pharmacokinetic (PK) characteristics of CB-103 in
patients after single and repeated administration at various dose levels.
• Part A only:
o To characterise safety and tolerability of the MTD/RP2D of CB-103 in patients
with selected solid tumours and haematological malignancies
o To assess preliminary anti-tumour, anti-lymphoma and anti-myeloma activity of
single agent CB-103 when administered orally and with repeat dosing.
• Part B only:
o To characterise safety and tolerability of the MTD/RP2D of CB-103 in patients
with selected solid tumours and haematological malignancies, stratified into
separate expansion arms for the respective indications and with tumours
characterised by genetic alterations and activation of the NOTCH pathway.
Exploratory Objectives
The exploratory objectives for parts A and B of this study are:
• To explore potential correlations between PK and parameters of efficacy (e.g.
tumour response, tumour shrinkage), pharmacodynamic (PD) markers (genes and
proteins) and safety (e.g. occurrence of adverse events, relationship of CB 103
concentration versus electrocardiogram [ECG] change from baseline QT interval
corrected for heart rate using the Fridericia*s correction factor [QTcF], heart
rate [HR], PR interval [PR] and QRS complex [QRS]).
• To investigate plasma levels of metabolite(s) when feasible.
• To assess changes in NOTCH target and downstream PD markers (genes, proteins)
in pre- and post- CB-103 dosing in tumour tissue biopsies (where available and
accessible) as a measure of NOTCH pathway inhibition.
• To assess changes in NOTCH target genes and downstream PD markers (genes,
proteins) in pre- and post- CB-103 dosing in whole blood, plasma samples and
hair follicles as a surrogate model to measure NOTCH pathway inhibition.
• To explore the potential influence of certain genotypes (e.g. cytochrome P450
[CYP] enzymes or N-acetyltransferases [NAT]) on the PK of CB-103.
• Exploratory genomic studies may be performed on tumour tissue samples as a
part of this study to identify gene aberrations and protein expression patterns
that are associated with treatment response to CB-103, disease progression,
and/or adverse events. The decision to perform such analyses would be dependent
on the outcome data and sample availability.
• Optional exploratory pharmacogenetic assessments may be performed (for
consenting patients) on DNA derived from blood samples (liquid biopsy with
circulating tumour DNA and/or blood cell-derived DNA) with the objectives of
examining whether individual genetic variations in genes relating to drug
metabolism, to specific cancer indications, and/or the drug target pathway
confer differential response to CB-103. The decision to perform such analyses
would be dependent on the outcome data and sample availability.
• To evaluate the potential role of biomarkers and genetic markers for safety,
PD, and anti-tumour activity of CB-103.
• To evaluate the biomarkers planned to be assessed in this study for their use
to define the optimal biological dose of CB-103.
• To measure possible immune modulatory effects of NOTCH inhibition by CB-103
by monitoring immune cell subsets from whole blood samples (especially CD8+
T-cells, NK cells and gdT-cells).

This study is designed as an open label, non-randomised, uncontrolled Phase
I/IIA dose escalation study with expansion cohorts of CB-103 administered
orally on a once-daily schedule, based on a 28-day treatment cycle. The
administration schedule may be adapted during dose escalation (e.g.
twice-daily, intermittent dosing schedule) depending on the PK and safety
signals that occur.
There will be two parts to this study. The aim of the Phase I part of the study
(Part A) with the dose escalation is to determine the MTD/RP2D. An adaptive
2-parameter Bayesian logistic regression model (BLRM) for dose escalation with
overdose control (EWOC) will be used in Part A to guide determination of the
MTD or the RP2D in patients with advanced or metastatic solid tumours and
haematological malignancies (i.e.,non- Hodgkin lymphomas).
Part A will be followed by the expansion Phase IIA, Part B of the study to
determine preliminary evidence of anti-tumour activity and to confirm the
safety of the CB-103 MTD/RP2D in different expansion arms consisting of
patients stratified into various pre selected cancer indications at an advanced
or metastatic stage of the disease. All patients in Part B will be required to
have evidence of NOTCH signalling pathway activation in their tumour tissues
through the presence of either mutations, amplifications/translocations or
gene/protein expression alterations related to the NOTCH signalling pathway.
Part A - dose escalation (Phase I)
Part A will be a dose-finding study based on a 2-parameter BLRM to investigate
the safety and tolerability of sequentially enrolled dose cohorts of at least
3, up to 6 patients per dose cohort. Depending on the BLRM, additional patients
may be enrolled in some dose cohorts. If possible, a patient with a
haematological malignancy should be included in each dose cohort with the
exception of the first 2 dose cohorts for which this rule is not applicable.
The first two patients of each dose level will be enrolled in a staggered
approach with at least 1 day apart between first dosing of these patients.
Subsequent patients may be enrolled concurrently, whereby a dose cohort must be
completed with regards to the dose-limiting toxicity (DLT) assessment period
and be reviewed by the Cohort Review Committee (CRC) established for this study
before further recruitment into the next dose cohort. The BLRM will be assessed
for those patients satisfying the requirements for inclusion in the
dose-determining set (DDS). After completion of a given dose cohort, or at any
time the BLRM is updated, the decision to dose escalate and the actual dose and
schedule chosen will depend on the recommendation of the BLRM about the highest
admissible dose according to the EWOC principle and medical review of available
clinical, pharmacokinetic and laboratory data. The outcome of these analyses
and the respective datasets will be reviewed by a CRC consisting of the
Investigators, Sponsor Chief Medical Officer (CMO) and representatives and
independent functional experts as required. The CRC will make the decision to
determine the next dose and schedule for continuation of enrolment into the
next higher dose cohort.
Part B - dose expansion (Phase IIA)
Part B will be the expansion phase following the determination of MTD/RP2D in
Part A. Patients will be enrolled into one or several expansion arm(s). These
arms will consist of patients with pre-selected cancer indications with tumour
cells characterised by NOTCH signalling pathway over-activation to confirm
safety of the MTD/RP2D of CB-103 and to assess its anti-tumour activity in each
of the pre-selected indications. For the expansion arms a Bayesian hierarchical
design will be applied for the preliminary efficacy analyses.
Enrolment into Part B of the study will start once the MTD or RP2D in Part A
has been determined.

The following assessments/procedures will be performed:
• Oral intake of the study drug CB-103: once-daily schedule, based on a 28-day
treatment cycle.
• Hospital visits: In Cycle 1 visit the hospital on Days 1, 2, 3, 8, 9, 15 and
22. Afterward you will be asked to visit the hospital at Day 1 and 15 of Cycle
2, 3, 4 and subsequent.
• Keeping record of intake of the study drug in Patient Diary
• Blood collection: Approximately 2.5 to 40 ml of blood will be taken each
time.
• Urine Sampling: Every month for pregnancy testing for woman with childbearing
potential.
• Vital signs and physical examination during the visits: pulse, blood
pressure, height, weight, temperature and respiratory rate will be measured.
• Heart tracing (ECG, Holter or MUGA scan)
• CT, MRI or PET-CT scan after cycle 2, every 8 weeks and after cycle 6 every
12 weeks until End of Treatment or disease progression/overall survival.
• Hair Sampling
• Archival tumour biopsy

Optional Assessments and Sub-studies
• Liquid Biopsy
• Fresh Tumour Biopsy
• Sub-study about influence of food intake or acid reducing agents

This is the first clinical study where CB-103 is given to patients; thus, its
risks and side effects in humans are not known. Based on what has been observed
so far in studies in animals and on the side effects from other similar drugs,
the human subject will be monitored closely to detect any potential serious
side effects, including the following: :
• Changes to your heart beat and frequency
• High blood pressure
• Cardiac dysfunction including congestive heart failure with signs and
symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough,
pulmonary oedema, abnormal heart sound, or reduced cardiac pump function.
• Increased extramedullary haematopoesis (e.g. production of blood cells
outside of the bone marrow)
• Enlarged spleen (Splenomegaly)
• Diarrhoea, nausea, vomiting, abdominal pain
• Dilated pupils (Mydriasis)
• Skin rash and redness
• Decreased physical activity and fatigue
• Decreased body weight
• Convulsions
• Oedema

CT scans
CT scans give higher radiation doses than ordinary x-rays do. The main risk of
exposure to radiation is that another cancer may occur many years after the
exposure. The risk of a cancer forming from the amount of radiation patient
receive during these diagnostic tests is considered to be low to moderate for
an individual in good health. However, for a patient with cancer condition, the
risk of inducing such a cancer from these exposures can be considered to be
negligible compared to the benefit of monitoring the benefit/risk to treatment
and so patient are very unlikely to experience any health problems due to
radiation exposure as a result of these tests.

MRI scan
An MRI scan is a painless and safe procedure. Patients may find it
uncomfortable if a patient has claustrophobia (fear of enclosed spaces), but
with support from the radiographer, most people find this manageable. Sometimes
going into the scanner feet first may be easier, although this is not always
possible. However, not everyone can have an MRI scan such as people who have
certain types of implants fitted, such as a pacemaker (a battery operated
device that helps control an irregular heartbeat).

PET scan
A PET-CT scan is a safe test for most people. But like all medical tests it has
some risks. The radiation in the radioactive tracer is very small. Drinking
plenty of fluids after scan will help to flush the drug out of system.

X-Ray
The risk of the radiation causing any problems in the future is very small. The
ovaries and testicles are particularly sensitive to radiation and may have lead
blocks to shield them if they are in the x-ray field.

Bone Marrow Biopsy and Aspirate
For lymphoma indication, bone marrow biopsy at baseline is needed only if
clinically indicated, at the discretion of study doctor.
It is likely that patient will experience some discomfort or pain, redness,
swelling and bruising at the site of the needle insertion. There is a very
small chance (approximately less than 1/100) of developing a significant
infection from this procedure or bleeding from site of the needle insertion. An
allergic reaction to the anaesthetic may occur.


Risks associated with fresh tumour biopsy
The risk of a tumour biopsy depends on the size, type and location of your
cancer. The risks include discomfort and bruising at the place where the biopsy
needle is inserted. Significant bleeding and infection can occur but are
uncommon (less than 2 in 100 patients).

Risks associated with drawing blood
Risks associated with drawing blood from your arm include pain and/or bruising,
infection, nerve damage excess bleeding, clotting or fainting are also
possible. There may be other risks that are unknown and we cannot predict.

Pregnancy risk
It is not known whether or not the treatment would harm an unborn child if
given to a pregnant woman.