Clinical trial NCT03422679
Conditions: Breast Cancer Colorectal Cancer Adenoid Cystic Carcinoma Non-hodgkin Lymphoma Glomus Tumor, Malignant Hepatocellular Carcinoma Osteosarcoma T-ALL
Keywords: advanced solid tumours haematological malignancies phase I/II NOTCH pathway pan-NOTCH inhibitor
Sponsor: Cellestia Biotech AG
Start date: 2017-12-05; Completion date: 2022-11-11
Enrollment: 79 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase I/II, non randomized, open-label, dose escalation study to investigate the safety, tolerability and preliminary efficacy of CB-103.

Detailed description:
This Phase I/IIA, open label, multicenter, dose escalation study of CB-103 in patients with Locally Advanced or Metastatic Solid Tumours and Haematological Malignancies. After providing signed informed consent, patients will be screened for entry into the study. The study will be conducted in 2 stages: dose escalation in Part A of the study (Phase I) followed by dose expansion in Part B (Phase IIA).

Escalation cohorts will receive repeat doses of CB-103 to determine the MTD and RP2D.

CB-103 will be administered orally in treatment cycles of 28-days each. Aim of the expansion Phase IIA, Part B of the study will be to collect preliminary evidence of anti-tumour activity.

Arms: arm 1: CB-103 capsules will be administered orally in treatment cycles of 28-days each.
Interventions: intervention 1: CB-103
Intervention descriptions: intervention 1: Hard gelatine capsules taken orally during treatment period. Treatment cycle is 28 days.

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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Protocol Reference: CB103-C-101 
 
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Statistical Analysis Plan 
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 LOCALLY ADVANCED OR METASTATIC 
SOLID TUMOURS AND HAEMATOLOGICAL MALIGNANCIES CHARACTERISED 
BY ALTERATIONS OF THE NOTCH SIGNALLING PATHWAY 
 
Statistical Analysis Plan: Final 
Statistical Analysis Plan: 2.0 
Statistical Analysis Plan Date: 29Apr2022 
Investigational Product: CB-103 
Protocol Reference: CB103-C-101 
Labcorp Drug Development Study ID: 000000186267 
Sponsor: Cellestia Biotech AG 
 
 
 
Author: Yann Amistani, Principal Biostatistician 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 


Statistical Analysis Plan 
 
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Table of Contents 
GLOSSARY OF ABBREVIATIONS ............................................................................................................... 4 
1. 
SOURCE DOCUMENTS ............................................................................................................................... 7 
2. 
PROTOCOL DETAILS ................................................................................................................................... 8 
2.1 
OVERALL STUDY DESIGN ........................................................................................................................................ 8 
2.1.1 
Description of Study ............................................................................................................................... 8 
2.1.2 
Study Treatment .................................................................................................................................... 9 
2.1.3 
Planned Dose‐Cohorts for Dose Escalation .......................................................................................... 10 
2.1.4 
Dose Modifications, Dose Delays and Treatment Discontinuation ...................................................... 10 
2.1.5 
Study Schedule ..................................................................................................................................... 10 
2.2 
STUDY OBJECTIVES ............................................................................................................................................. 11 
2.2.1 
Primary Objective(s) ............................................................................................................................. 11 
2.2.2 
Secondary Objective(s) ......................................................................................................................... 11 
2.2.3 
Exploratory Objective(s) ....................................................................................................................... 11 
2.3 
SAMPLE SIZE AND POWER .................................................................................................................................... 13 
2.4 
INTERIM ANALYSES ............................................................................................................................................. 13 
2.5 
PRIMARY VARIABLE(S) ......................................................................................................................................... 13 
2.6 
SECONDARY VARIABLE(S) ..................................................................................................................................... 13 
2.7 
EXPLORATORY VARIABLE(S) .................................................................................................................................. 14 
2.8 
SAFETY VARIABLE(S) ........................................................................................................................................... 15 
3. 
ANALYSIS POPULATIONS .......................................................................................................................... 16 
3.1 
SAFETY SET ....................................................................................................................................................... 16 
3.2 
DOSE‐DETERMINING SET ..................................................................................................................................... 16 
3.3 
PK SET ............................................................................................................................................................. 16 
4. 
DATA HANDLING ...................................................................................................................................... 17 
4.1 
TIME POINTS AND VISIT WINDOWS ....................................................................................................................... 17 
4.1.1 
General Definitions .............................................................................................................................. 17 
4.1.2 
Baseline Period ..................................................................................................................................... 17 
4.1.3 
Treatment Period ................................................................................................................................. 17 
4.1.4 
Visit Windows ...................................................................................................................................... 17 
4.2 
HANDLING OF DROPOUTS, MISSING DATA, AND OUTLIERS ......................................................................................... 17 
5. 
STATISTICAL METHODS ............................................................................................................................ 18 
5.1 
GENERAL PRINCIPLES .......................................................................................................................................... 18 
5.2 
SUBJECT DISPOSITION AND DATA SETS ANALYZED ..................................................................................................... 19 
5.3 
PROTOCOL DEVIATIONS OR VIOLATIONS ................................................................................................................. 19 
5.3.1 
Violation criteria .................................................................................................................................. 19 
5.3.2 
Protocol deviations .............................................................................................................................. 19 
5.4 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................................................................ 19 
5.4.1 
Demographic Characteristics ............................................................................................................... 19 
5.4.2 
Prior and Concomitant Medications .................................................................................................... 20 
5.5 
MEASUREMENTS OF TREATMENT COMPLIANCE AND EXPOSURE .................................................................................. 21 


Statistical Analysis Plan 
 
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5.6 
PRIMARY ANALYSIS ............................................................................................................................................. 21 
5.6.1 
Dose Escalation .................................................................................................................................... 21 
5.6.2 
Efficacy Analysis ................................................................................................................................... 26 
5.7 
SAFETY ............................................................................................................................................................. 29 
5.7.1 
Adverse Events ..................................................................................................................................... 30 
5.7.2 
Laboratory Evaluations ........................................................................................................................ 30 
5.7.3 
Vital Signs ............................................................................................................................................ 32 
5.7.4 
Electrocardiograms .............................................................................................................................. 33 
5.7.5 
Physical Examination and ECOG status ............................................................................................... 34 
5.8 
PHARMACOKINETIC ASSESSMENTS ......................................................................................................................... 34 
5.8.1 
Pharmacokinetic Analysis .................................................................................................................... 34 
5.8.2 
Below Limit of Quantification (BLQ)..................................................................................................... 37 
5.8.3 
PK assessments in CSF in T‐ALL/T‐LBL patient ..................................................................................... 38 
5.9 
BIOMARKER ANALYSIS ......................................................................................................................................... 38 
6. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS .......................................................... 39 
7. 
APPENDICES ............................................................................................................................................. 40 
8. 
REFERENCES ............................................................................................................................................. 50 
 
 
 


Statistical Analysis Plan 
 
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Reviewers 
The following reviews of the Statistical Analysis Plan (SAP) were conducted: 
 
Glossary of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase  
aPTT 
activated Partial Thromboplastin Time 
AR 
Accumulation ratio 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
BID 
twice daily 
BL 
Baseline 
BLRM 
Bayesian logistic regression model 
BLQ 
Below Limit of Quantification 
BMI 
Body mass index 
BNP 
Brain natriuretic peptide 
BOR 
Best overall response 
Bpm 
Beats per minute 
BPM 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBR 
Clinical benefit rate 
CCC 
Cholangiocellular carcinoma 
CI 
Confidence Interval 
CL/F 
Clearance of drug after administration  
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
CR 
Complete response 
CNS 
Central nervous system 
CRC 
Cohort Review Committee 
CRP 
C-reactive Protein 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDS 
Dose-determining Set 
Name and Title  
 Role 
Version Last 
Reviewed 
Company / 
Organization 
Ravi Gondaliya 
Biostatistician II 
Peer Review Statistician 
 
Labcorp Drug 
Development 
Reddy Raghavendra Muriki 
Nagaraja 
Programming Lead 
Lead Programmer 
 
Labcorp Drug 
Development 
Oliver Schoenborn-
Kellenberger 
Biostatistician 
Consultant Statistician 
 
Cogitars GmbH 
Florian Vogl 
Chief Medical Officer 
Chief Medical Officer and Medical 
Responsible 
 
Cellestia Biotech AG 


Statistical Analysis Plan 
 
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DLT 
Dose-limiting toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case-report form 
ER 
Estrogen receptor 
EOS 
End-of-Study 
EWOC 
Escalation with overdose control  
FU 
Follow-up 
GBM 
Glioblastoma multiforme malignancies 
GI 
Gastrointestinal 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
IA 
Interim analysis 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
LVEF 
Left ventricular ejection fraction 
kg 
Kilogram 
KM 
Kaplan-Meier 
MTD 
Maximum tolerated dose 
LLOQ 
Lower Limit of Quantification 
LVEF 
Left ventricular ejection fraction 
Max 
Maximum 
MedDRA  
Medical Dictionary for Regulatory Activities  
mg 
milligram 
Min 
Minimum 
mL 
millilitre 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition 
NAT 
N-acetyltransferases 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non-small-cell Lung Cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PP 
Per protocol 
PR 
Partial response 
PT 
Preferred Term 
QRS 
QRS complex 
QD 
Once daily 
QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcF 
QT corrected for heart rate using the Fridericia’s correction factor 
RBC 
Red Blood Cell 
RP2D 
Recommended phase 2 dose 


Statistical Analysis Plan 
 
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RECIST 
Response evaluation criteria in solid tumours 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SS 
Safety Set 
SD 
Standard Deviation 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma concentration  
TNBC 
Triple negative breast cancer 
TTR 
Time to Response 
ULN 
Upper limit of normal 
Vd/F 
Volume of distribution during terminal phase 
Vss/F 
Volume of distribution at steady-state 
WBC 
White Blood Cell 
WHO 
World Health Organization  
 
 


Statistical Analysis Plan 
 
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1. Source Documents 
The SAP is based on the following documentation and is for the Part A of the study. 
Document 
Date 
Version 
Protocol 
03 August 2020 
4.1 
eCRF 
17 May 2021 
4.0-4.2 


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2. Protocol Details 
2.1 
Overall Study Design 
2.1.1 
Description of Study 
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 a dose 
escalation phase and the MTD/RP2D confirmatory cohort 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. 
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. 
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. 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, with at 
least 1 day apart from the second patient, whereby a dose cohort must be completed with regards 
to the DLT assessment period and be reviewed by the Cohort Review Committee (CRC) 
established for this study before further patients are dosed in 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 the CRC consisting of the Investigators, Sponsor and CRO 
representatives, and independent functional experts as required. The CRC will make the decision 
to determine the next dose level and schedule for the next dose cohort.  
Any dose level cohort that has been declared safe after the DLT period, may be expanded by 
individual patients in order to collect additional pharmacodynamic (PD) and pharmacokinetic (PK) 
information to support and/or confirm the mechanism of action and explore doses at the currently 
tolerated dose level or below. These patients will be counted for the respective cohort at the future 
CRC meetings and will contribute towards the overall safety, PK, PD and clinical efficacy 
evaluation. 
When the MTD/RP2D is defined, based on the decision of the CRC, approximately 45 additional 
NOTCH-positive patients with recurrent/metastatic ACC, breast cancer, r/r T-ALL/T-LBL, or any 
other solid tumour with proven Notch pathway activation will receive the MTD/RP2D dose to 


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ascertain that optimal safety related to efficacy and pharmacodynamics in the tumour and in 
peripheral blood are achieved. 
Part B - Expansion (Phase IIA) 
Part B will be the expansion phase following the determination of MTD/RP2D in Part A. Patients 
will be enrolled into several expansion arms. These arms will consist of patients with pre-selected 
cancer indications with tumour cells characterised by NOTCH over-activation to confirm safety 
of the MTD/RP2D of CB-103 and to explore 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 study design is illustrated below. 
 
Abbreviations: ACC, adenoid cystic carcinoma; DG, dose group; MTD, maximum tolerated dose; RP2D, 
recommended phase 2 dose; pts, patients; ER, estrogen receptor; CRC, colorectal cancer; HCC, hepatocellular 
carcinoma; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; r/r, relapsed/refractory; 
RP2D, recommended phase 2 dose; TNBC, triple negative breast cancer. 
 
2.1.2 
Study Treatment 
CB-103 will be administered orally as a continuous once daily (QD) dosing during the treatment 
period of both Part A and Part B until disease progression, unacceptable toxicity or until the 
Investigator’s decision or the patient’s refusal. As soon as clinical safety and PK data become 
available, it is possible that an alternate dosing (e.g. twice daily [BID], intermittent) may be 
implemented. 
For scheduling and evaluations, a treatment cycle is defined as 28 days throughout the whole study.  


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2.1.3 
Planned Dose-Cohorts for Dose Escalation 
For Part A, the DLT period is defined as the 1st cycle of CB-103 dosing with a duration of 28 
days. Eight provisional dose levels are defined for the dose escalation as well as one dose level 
with a 30% lower dose than the 1st dose level if the first dose level is not well tolerated. 
2.1.4 
Dose Modifications, Dose Delays and Treatment Discontinuation 
Every effort should be made to administer CB-103 at the planned dose and schedule. In the event 
of treatment-related toxicities and DLT with CB-103, dose adjustments are permitted if it is 
considered by the Investigator in the best interest of the patient to continue therapy. In the event 
of multiple toxicities, the dose modification should be based on the worst toxicity observed 
(according to the NCI CTCAE, v4.03). Any adjustment to the CB 103 dose should be documented 
in the eCRF. 
Patients whose CB-103 treatment is delayed or discontinued should have at least weekly follow-
ups that include a physical examination, vital signs including weight, performance status, ECGs, 
and assessment of adverse events and concomitant medication. Following a DLT or toxicity, 
haematology, renal and liver function tests should be performed as appropriate.  
Guidance on dose reductions and resumption of treatment if found in protocol section 7.4.5.  
2.1.5 
Study Schedule 
Please, find complete schedules of assessments for part A in Appendix 3. 
 
 
 


Statistical Analysis Plan 
 
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2.2 
Study Objectives 
2.2.1 
Primary Objective(s) 
Phase I, Part A - Dose Escalation: 
 To determine the MTD or RP2D of CB-103 as a single agent in adult patients.  
Phase I, Part A – Confirmatory Cohort: 
 To confirm safety of the RP2D of CB-103 as a single agent in adult patients.  
2.2.2 
Secondary Objective(s) 
The secondary objectives for parts A and B of this study are: 
 
To characterise the PK characteristics of CB-103 in patients after single and repeated 
administration at various dose levels. 
 
To characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected 
solid tumours and hematological malignancies. 
 
To assess preliminary anti-tumour activity of single agent CB-103. 
2.2.3 
Exploratory Objective(s) 
The exploratory objectives for part A of this study are: 
 
To characterise the pharmacokinetic (PK) characteristics of CB-103 in subgroups of patients 
(e.g., by indication or ethnicity) after single and repeated administration at various dose levels. 
 
To explore potential correlations between PK and parameters of efficacy (e.g. tumour 
response, tumour shrinkage, tumour metabolic activity), PD markers (genes and proteins) and 
safety (e.g. occurrence of adverse events, relationship of CB-103 concentration versus 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]). 
 
Positron Emission Tomography (PET) in selected tumours: baseline and on-treatment, 
18Fluoro-deoxyglucose positron emission tomography (FDG-PET) in combination with CT 
(PET-CT) will be collected to determine changes in glucose metabolism of the tumour lesions 
in tumour types exhibiting FDG-uptake. 
 
To investigate plasma levels of metabolite(s) when feasible. 
 
To explore the CB-103 metabolic profile in biological matrices such as urine and/or stool 
samples. 
 
To assess changes in NOTCH target and downstream PD markers (genes, proteins) in solid 
tumours:  
‒ in pre- and post- CB-103 dosing in tumour tissue biopsies as a measure of 
NOTCH pathway inhibition; 
‒ in pre- and post- CB-103 dosing in whole blood, plasma samples and hair 
follicles as a surrogate model to measure NOTCH pathway inhibition. 


Statistical Analysis Plan 
 
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 
To assess changes in NOTCH target genes and downstream PD markers (genes, proteins) in 
haematological malignancies: 
‒ in pre- and post- CB-103 dosing in T-lymphocytes from blood and/or bone 
marrow samples; 
‒ in pre- and post- CB-103 dosing in whole blood and plasma samples. 
 
To assess the changes in the percentage of mutated alleles in liquid biopsies pre- and post CB-
103 dosing to determine the effect of CB-103 treatment. 
 
To evaluate the cerebrospinal fluid (CSF) exposure of CB-103 in patients with haematological 
malignancies, in whom intra-thecal (IT) prophylaxis is planned by the treating physician. 
 
To explore the potential influence of certain genotypes (e.g. CYP enzymes or NAT) on the 
PK of CB-103. 
 
Exploratory genomic studies may be performed on tumour tissue samples or on blood 
and/or bone marrow 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. 
 
Exploratory CB-103 quantification analysis may be performed on tumour tissue samples. 
 
To evaluate the potential role of biomarkers and genetic markers for safety, PD, and anti-
tumour activity of CB-103 and to define the optimal biological dose of CB-103. 
 
To explore and assess changes in the immune system in pre- and post-CB-103 dosing whole 
blood and plasma. 
 
Additional exploratory analyses may be performed on available samples from the study, for 
example to establish a correlation of biomarkers across methods or types of tissue. 
 
 
 


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2.3 
Sample Size and Power 
For all dose levels, from starting dose to the respective dose escalation levels, 3-6 patients will be 
enrolled and treated with CB-103 according to a staggered inclusion scheme to ensure adequate 
time for safety observation between inclusions, and before dose escalation. During the study, a 
minimum of 3 patients evaluable for the DDS will be treated per dose cohort until determination 
of the MTD or RP2D. Depending on the BLRM, additional patients may be enrolled in some dose 
cohorts. Approximately 11 dose cohorts are considered for this study with at least 3 patients per 
dose cohort. It is estimated that approximately 55 patients will be enrolled, not taking into account 
the drop-outs and additional patients enrolled for some of the dose groups. Based on the decision 
of the CRC, approximately 45 patients may be enrolled in the MTD/RP2D confirmatory cohort to 
confirm safety before opening Part B. 
 
2.4 
Interim Analyses 
Each dose escalation step is considered to be an interim analysis. The BLRM will be updated with 
the respective number of patients treated and the number of DLTs observed in the last cohort. The 
updated model will then give a statistical recommendation for the next escalation step. However, 
a risk-benefit assessment that includes a comprehensive analysis of safety and available clinical 
information will be done to decide on the next escalation steps. 
 
2.5 
Primary Variable(s) 
The primary endpoint for Phase I, Part A (dose-escalation) of this study is as follows: 
- 
The number of patients experiencing dose-limiting toxicity (DLT) during the first 28-day 
cycle of CB-103 treatment 
The primary endpoint for Phase I, Part A (confirmatory) of this study is as follows: 
- 
The incidence rate, severity and relationship to CB-103 of adverse drug reactions and serious 
drug reactions according to common terminology criteria for adverse events (CTCAE) V4.03, 
safety laboratory, vital signs, ECG and ECHO/MUGA assessments. 
 
2.6 
Secondary Variable(s) 
The secondary endpoints for Part A of this study are as follows, unless otherwise specified: 
- 
The incidence rate, severity and relationship to CB-103 of adverse drug reactions and serious 
drug reactions according to common terminology criteria for adverse events (CTCAE) V4.03, 
safety laboratory, vital signs, ECG and ECHO/MUGA assessments in each dose group and 
expansion arm. 
- 
CB-103 plasma concentrations, PK parameters: Cmax, tmax, Cmin, Clast, tlast, area under the curve 
(AUC) during 8 and 24 hours (AUC0-8, AUC0-24), AUC from time 0 extrapolated to infinite 
time (AUC0-∞), apparent volume of distribution (Vd/F), apparent volume of distribution at 
steady (Vss/F), apparent clearance after oral administration (CL/F), t1/2 and AR. 
- 
To assess tumour response rates 


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‒ For solid tumour indications:  to assess best overall response rate (CR + PR), 
assessed by RECIST 1.1 (Eisenhauer et al., 2009). 
‒ For haematologic malignancies: to assess the best overall response rate (CR or CRi) 
per NCCN guidelines. 
- 
To assess clinical benefit rate 
‒ For solid tumour indications:  clinical benefit rate (CR + PR + SD), assessed by 
RECIST 1.1. (Eisenhauer et al., 2009). 
- 
Duration of response (DOR), time to response, progression-free survival (PFS), OS. 
2.7 
Exploratory Variable(s) 
The exploratory endpoints for Part A of this study are as follows: 
- To assess plasma levels and PK parameters (Cmax, tmax, Cmin, Clast, tlast, AUC0-8, AUC0-24, AUC0–
∞, t1/2 and AR) of metabolite(s) when feasible. 
- To evaluate the relationship between CB-103 plasma concentrations and/or PK parameters 
(e.g., Cmax and AUC0-24) and safety, efficacy and PD parameters. 
- To assess NOTCH and NOTCH target genes expression (NOTCH1-4 receptors, NOTCH 
ligands, NICD1-4 and NOTCH target genes) assessed by Nanostring expression analysis in pre- 
and post-treatment tumour tissue samples, whole blood / plasma samples and hair follicles in 
solid tumours and in T-lymphocytes from blood and/or bone marrow samples, whole blood and 
plasma in T-ALL/T-LBL, and assess their relation to clinical activity of CB-103. 
- To assess the cerebrospinal fluid (CSF) exposure of CB-103 in haematological malignancies, 
in patients in whom IT prophylaxis is planned by the treating physician. 
- To assess certain genotypes (e.g. cytochrome P450 enzymes or NAT) and assess relation to PK 
outcome data. 
- To assess NOTCH genetic aberrations in pre- and post-treatment tumour tissue samples, whole 
blood and hair follicles in solid tumours and in T-lymphocytes from blood and/or bone marrow 
samples, whole blood and plasma in T-ALL/T-LBL, and assess their relation to clinical activity 
of CB-103. 
- To assess NOTCH1-4 NICD expression assessed by IHC staining or by Western Blot in pre- 
and post-treatment in solid tumour tissue samples and to assess their relation to clinical activity 
of CB-103. 
- To assess NOTCH mutations by genomic mutation analysis in tumour tissue samples in solid 
tumours and in T-lymphocytes from blood and/or bone marrow samples, whole blood and 
plasma in T-ALL/T-LBL, and to assess their relation to clinical activity of CB-103 treatment. 
- To evaluate the intra-tumoral quantification of CB-103 in solid tumour tissue samples.  
- To profile tumour tissue samples in solid tumours and T-lymphocytes from blood and/or bone 
marrow samples in T-ALL/T-LBL by single cell RNA-seq and/or other gene expression and 
genetic profiling techniques.  
- To explore and assess changes in the immune system in pre- and post-CB-103 dosing whole 
blood and plasma (e.g., measure expression of cytokines/chemokines by RNA expression 


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analysis, quantify pro-inflammatory and anti-inflammatory cytokines and chemokines, 
phenotype different types of immune cells (T cells, B cells, dendritic cells and macrophages, 
etc.) using flow cytometry). 
- To assess change from baseline cardiac intervals versus increasing plasma CB-103 
concentrations. 
- To assess the metabolic profile of CB-103 in biological matrices such as urine and/or stool 
samples based on metabolic expressions of CB-103 in urine and/or stool samples 
2.8 
Safety Variable(s) 
The safety variables of this study are as follows: 
- Adverse events 
- Laboratory findings 
- Vital signs 
- Physical examination and ECOG status 
- Cardiac function 
 


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3. Analysis Populations 
In accordance with ICH E31 and E92, the following analysis sets will be used for the analyses. 
 
3.1 
Safety Set 
The safety set will consist of all patients who received at least one dose of CB-103 and had at least 
one post-baseline safety assessment (where the statement that a patient had no adverse event on 
the Adverse Events eCRF constitutes a safety assessment). The safety set will be the primary 
population for all efficacy and safety related endpoints except determination of the dose-DLT 
relationship. 
 
3.2 
Dose-Determining Set 
The dose-determining set (DDS), which is the analysis set used for determination of the MTD, 
will consist of all patients in the safety set, who have (a) experienced DLT at any time during 
Cycle 1, and/or (b) met the minimum treatment and safety evaluation requirements without 
experiencing DLT within Cycle 1, as described below.  
For all dose levels, from starting dose to the respective dose escalation levels, 3-6 patients will be 
enrolled and treated with CB-103 according to a staggered inclusion scheme to ensure adequate 
time for safety observation between inclusions, and before dose escalation. Depending on the 
BLRM, additional patients may be enrolled in some dose cohorts. The minimum treatment and 
safety evaluation requirements will have been met if, in Cycle 1, the patient has been treated with 
the planned dose of CB-103 for ≥ 21 days (75% of the planned dose; minimum exposure criterion), 
was observed for ≥ 28 days following the Cycle 1 Day 1 dose, and has completed the required 
safety evaluations for Cycle 1. Patients who do not meet these minimum treatment and safety 
evaluation requirements will be regarded as ineligible for inclusion in the DDS. Unless they 
experienced a DLT, patients will be replaced until the minimum number of 3 patients required for 
evaluation is reached. 
The DDS will be used in the BLRM to estimate the dose-DLT relationship. 
 
3.3 
PK Set 
The PK set consists of all patients who have at least received one dose of study drug and have at 
least one post-dose PK measurement. 
 
Note: Patients who were screened and have signed the informed consent but did not receive any 
treatment will be listed including reason for screen failure and any serious adverse event that is 
related to study procedure. These patients will not be part of any summary table except for 
summarizing disposition. 
 


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4. Data Handling 
4.1 
Time Points and Visit Windows 
4.1.1 
General Definitions 
All assessment days will be related to the first day of first dose of treatment. 
Day 1 is defined as first dose of treatment at Cycle 1 Day 1. Relative days after Day 1 are calculated 
as (assessment date – Day 1 date) + 1. Relative days prior to Day 1 are calculated as (assessment 
date – Day 1 date). The day prior to Day 1 is Day -1. Day 0 is not defined. 
The date of the first dose of treatment for each subject will be taken from the PK sampling eCRF 
page. 
The date of the last dose of treatment for each subject will be taken from the End of  Treatment 
eCRF page. If the date in this eCRF page is missing, alternatively the date of End of Study will be 
used. If the date is missing because the subject was lost to follow-up, the date of the last visit will 
be imputed, if appropriate. 
4.1.2 
Baseline Period 
For all subjects, the baseline period is defined as the period from informed consent to the first dose 
of treatment. For some variables, data from more than one assessment within the baseline Period 
can be collected prior to the first dose of treatment. 
The baseline value for a variable is therefore defined as the last non-missing value collected before 
the first dose of treatment in the baseline period. 
4.1.3 
Treatment Period 
The Treatment Period is defined as the period from the date / time of the first dose of treatment up 
to and including the date / time of the last dose of treatment. 
4.1.4 
Visit Windows 
All data will be analyzed using nominal study visit as defined in the Study Schedule and eCRF. 
No visit windows will be applied for summary and analysis. 
 
4.2 
Handling of Dropouts, Missing Data, and Outliers 
Missing, unused and spurious data will be dealt with as such.  
Due to the dose escalation design of Part A of the study no missing imputation of missing values 
will be done for any analysis.  
Currently no drop-outs are foreseen. However, if patients in the escalation phase (Part A) do not 
fulfil the minimum treatment and safety evaluation requirements and discontinue for a reason other 
than DLT they will be replaced. 


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5. Statistical Methods 
5.1 
General Principles 
All data processing, summarization and analyses will be performed using Labcorp Drug 
Development’s SAS Environment / Version 9.4 (or later) of the SAS statistical software package.   
Baseline, safety and tolerability as well as efficacy analyses will be based on the SS.  
Pharmacokinetic evaluation will be done for the PK set.  
The dose-determining analyses, i.e. those to determine MTD or RP2D, will be done for the DDS. 
Results will be listed and summarized using descriptive statistics overall and by cohort: 
 All patients 
 Cohort 1 (dosing level 1, e.g. 15mg) 
 Cohort 2 (dosing level 2, e.g. 30mg) 
 Etc. 
 Cohort with RP2D 
 
All summary statistics will be rounded (using the SAS® function ROUND) and presented to one 
more decimal place than the raw value, except for the minimum and maximum values that will be 
presented with the same decimal precision as the raw value. 
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing data per 
category will be the default summary presentation, and where appropriate and present, the number 
of missing values as a “Missing” category. Number of subjects in the analysis population will be 
used as denominator for percentages calculation, unless stated otherwise in TFLs mock shell(s). 
When appropriate, considering number of patients within groups, Clopper-Pearson confidence 
intervals (CI) will be provided for rates. 
For time to event type data, Kaplan-Meier estimates will be presented for dose groups with 
sufficiently high patient numbers. 
Due to being of non-comparative nature, no inferential statistical analysis will be applied in either 
the escalation or the expansion part of this study to compare dose groups or arms.  
The final statistical analysis will occur after all patients have discontinued treatment for any reason 
and completed safety FU.  
All additional data collected during long-term survival FU will be separately reported in a 
combined FU analysis. 
Notes: 
 Any duration [days] = end date – onset date + 1 
 All data will be listed 
 All unscheduled visits will be summarized into one visit as the final visit in summary 
tables. In case of multiple unscheduled assessments, the first one will be considered in the 
summary table but will all be listed. 


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5.2 
Subject Disposition and Data Sets Analyzed 
The number and percentage of patients who were screened and have signed informed content, but 
did not receive any treatment, as well as patients receiving study treatment, in each analysis 
population, those who are ongoing on study treatment and those who discontinued study treatment 
together with primary reason for discontinuing treatment, those who completed and discontinued 
the study as well as the reasons for any premature discontinuation from the study will be 
summarized by cohort i.e. by dose groups in dose escalation part A. Data will be listed accordingly. 
Inclusion and exclusion criteria will be listed. 
 
5.3 
Protocol Deviations or Violations 
5.3.1 
Violation criteria 
Patients who meet any of the following criteria will be listed and presented in the study report: 
 Non-compliance with inclusion criteria. 
 Non-compliance with exclusion criteria. 
5.3.2 
Protocol deviations 
All important protocol deviations occurring during the study will be reviewed, classified (as 
major/minor) and approved by sponsor in data review meeting prior to database lock. Minor 
deviation (e.g. Deviation in visit windows or time slots) may not justify exclusion of the patient. 
Should additional important protocol deviations, not anticipated at the time of preparing this SAP, 
be identified during the study, they will be documented in a separate document and included in all 
relevant protocol deviation reviews and approvals. 
 
5.4 
Demographic and Other Baseline Characteristics 
5.4.1 
Demographic Characteristics 
All demographic and baseline characteristics will be summarized by cohort for both SS and PK 
populations and listed accordingly. The summary will include age, gender, race, height, baseline 
bodyweight, baseline BMI and screening and baseline ECOG. If two populations are identical, the 
table will be appropriately identified as representing both populations and will not be duplicated. 
Demographic characteristics will be also provided by subtype of cancer (solid tumours except T-
ALL/T-LBL, Adenoid Cystic Carcinoma, T-ALL or T-LBL).  
Patients’ initial cancer history will be summarized, including tumour type (for breast cancer 
including ER, PR and HER2 status), Notch status as well as histological tumour grade of initial 
cancer, also whether or not previous systemic anti-cancer treatments, previous radiotherapies or 
previous surgeries had been applied and if cancer is recurrent or metastatic; the full information 
on primary cancer will be provided in Listings. 
Active medical history (i.e. histories marked as ongoing at time of screening) will be summarized 
by number of active disease events, number and percentage of patients with at least one active 


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disease and number and percentage of patients with each disease displayed by System Organ Class 
(SOC) and preferred term (PT). 
Prior systemic anti-cancer (AC) therapies will be summarized by number and percentage of 
patients previously treated with at least one systemic agent, by line of prior therapy, best response 
to and reason for discontinuation of prior therapy as well as number and percentage of patients 
who progressed under the prior therapy. These will also be summarized by number of systemic 
therapies, number and percentage of patients previously treated with at least one systemic agent 
and number and percentage of patients treated with each systemic agent displayed by type of 
cancer and preferred drug name and listed. Prior radiotherapy will be summarized by number and 
percentage of patients who received any prior radiotherapy, by body location of, setting of and 
best response to prior radiotherapy as well as number and percentage of patients who progressed 
after prior radiotherapy. Prior surgery will be summarized by number and percentage of patients 
with any prior surgery, by type, body location and outcome of prior surgery as well as number and 
percentage of patients who progressed after prior surgery. 
Substance use at screening will be summarized for smoking status, alcohol use and drug abuse.  
Vital signs and ECOG status at baseline will be summarized and listed. 
Physical examination at baseline will be listed. 
Fresh tumour biopsies collected at baseline will be listed only. 
Notes: 
 Age will be derived in eCRF from entered year of birth. 
 Medical history will be coded according to MedDRA version will be noted in the footnote 
of the Tables. 
 Active medical history is defined as marked as ongoing at time of screening. 
 Prior systemic AC therapies will be coded according to WHO-Drug Dictionary version 
will be noted in the footnote of the Tables. 
5.4.2 
Prior and Concomitant Medications 
Incidence of prior and concomitant medication will be presented by cohort, ATC class and 
preferred drug name and listed.  
Prior medications are those that started and stopped before exposure to study medication; 
concomitant medications are all medications taken during the study period, including those started 
before but on going at first dose. 
Where a medication start date is partially or fully missing, and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that it is concomitant. 
Medications within 24 hours prior to PK sampling will be listed only. 
Note: 


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Medications are coded using WHO Drug dictionary version will be stated in the footnote of the 
tables. 
 
5.5 
Measurements of Treatment Compliance and Exposure 
Exposure to study drug will be summarized overall and by cohort as well as by cycle for the SS 
for following parameters: 
 Cumulative dose (in g) 
 Duration of study treatment (in months)  
 Actual exposure (in months)  
 Actual dose intensity (in mg/d)  
 Planned dose intensity (in mg/d)  
 Relative dose intensity (in %)  
 Treatment compliance (in %) 
All information recorded concerning study drug modifications will be listed.  
Notes:      
Duration of study treatment (months) is defined as: 
 
(date of last dose of study treatment – date of first dose + 1) / 30.4375. 
Actual exposure (months) is defined as: 
 
number of days when patients actually took study medication/ 30.4375. 
Actual dose intensity (mg/d) is defined as:  
 
total actual dose taken (mg)/actual exposure (d). 
Planned dose intensity (mg/d) is defined as:  
 
total planned dose taken (mg)/planned exposure, i.e. planned days on treatment (d) 
Relative dose intensity is defined as: 
 
actual dose intensity / planned dose intensity x 100% 
Treatment compliance (in %) is defined as:  
 
total actual dose taken/ total planned dose*100 
  
5.6 
Primary Analysis 
5.6.1 
Dose Escalation 
Each dose escalation step is considered an IA.  
An adaptive BLRM guided by the EWOC principle will be used in the dose escalation. 


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The BLRM will be updated with the respective number of patients treated and the number of DLTs 
observed in the last cohort. The updated model will then give a statistical recommendation for the 
next escalation step. However, a risk-benefit assessment that includes a comprehensive analysis of 
safety and available clinical information will be done to decide on the next escalation steps. 
5.6.1.1 Dose-Finding of Single Agent CB-103 
A 2-parameter BLRM (Neuenschwander et al 2008) will be used for dose escalation. Standardised 
doses will be used such that one of the doses (d*) equals 1, e.g., doses are rescaled as d/d*. As a 
consequence, α is equal to the odds of the probability of toxicity at d*. All information currently 
available about the dose-DLT relationship of CB-103 is summarised in a prior distribution. For 
this study, this includes pre-clinical data about the starting dose and predicted MTD of CB-103 
within different animal species. This prior distribution is then updated after each cohort of patients 
with all the DLT data available in the DDS from the current trial. Once updated, the distribution 
summarises the probability that the true rate of DLT for each dose lies in the following categories: 
 [0,16%] under-dosing 
 [16%,33%] targeted toxicity 
 [33%,100%] excessive toxicity 
The EWOC principle (Babb et al 1998, Neuenschwander, et al 2008) mandates that any dose of 
CB-103 that has more than a 25% chance of being in the excessive toxicity category is not 
considered for the next dose cohort.  
In case that another regimen is evaluated during the study, a separate 2-parameter logistic 
regression will be used for the assessment of the respective DLT rates. However, all data that are 
available from the other regimen (or regimens) before “First Patient First Visit” (FPFV) for the 
new regimen has happened will be incorporated into an informative, meta-analytic predictive 
(Neuenschwander et al 2015) prior distribution. This prior distribution will be mixed with a weakly 
informative prior distribution to hedge against a potential prior-data conflict. 
The frequency of DLTs will be tabulated by dose for patients in the dose escalation phase and 
information about the DLTs will be listed by dose.  
5.6.1.2 Bayesian Logistic Regression Model to Determination of MTD 
The objective of the design is to determine the MTD defined as the highest dose with less than 
25% risk of the true DLT rate being above 33%. The Part A dose-finding will be guided by a 
Bayesian 2-parameter logistic regression model with overdose control.  
The model is formulated as follows: 
logit(p(d)) = log(α) + β*log(d/d*) 
where logit(p) = log(p/(1-p)).  


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p(d) represents the probability of having a DLT in the first cycle at dose d, d* = 150 mg is the 
reference dose, allowing for the interpretation of α as the odds of a DLT at dose d*, and θ = (log(α), 
log(β)) with α, β > 0 is the parameter vector of the model. 
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter vector 
θ needs to be specified. This prior distribution will be specified as a mixture of two multivariate 
normal distribution, i.e. 
π(θ) = φ1π1(θ) + φ2π2(θ)  
with φi, i = 1, 2 the prior mixture weights (φ1+ φ2 = 1) and πi(θ) = MVN(μi, Σi) the multivariate 
normal distribution of the i-th component with mean vector μi and covariance matrix Σi, with 
 
Mixture prior distributions have the advantage that they allow for specification of different logistic 
dose-toxicity curves, therefore making the prior more robust.  
Prior derivation 
For the current study, data from the pre-clinical animal studies were available. Therefore, the 
following prior will be used: A combination of the observed toxicity data from a study in rats 
further supported by data from a study in dogs.  
Prior from rat data: 
Based on the IMPD, the starting dose of CB-103 will be 15 mg, which is expected to achieve an 
exposure (AUC0-24) in humans of approximately 600 µg*h/mL. This exposure is comparable with 
1/10th of the exposure at the highest non-severely toxic dose (HNSTD) (30 mg/kg/day) in male 
rats. It is therefore highly unlikely that a DLT would occur at this dose, leading to the prior 
assumption that the median DLT rate at 15mg is 0.1%. On the other hand, assuming dose-
proportionality in humans, a dose of 150 mg would approximately have an exposure of 6000 
µg*h/mL, i.e., the same as the exposure at the HNSTD in rats. Using a cautious approach, the 
median DLT rate at d*= 150 mg was therefore assumed 25%. 
Prior from dog data: 
Based on the IMPD, the exposure at 1/10th of the HNSTD (8.6 mg/kg/day) in (male) dogs is 
approximately 9000 µg*h/mL, which we would correspond to a human dose of 15*9000/600 = 
225 mg, with a prior median DLT rate of 0.1%. A cautious approach was chosen again, using a 
median 25% DLT rate at d = 225 mg. 

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Table 4 
Summary of prior distribution 
Prior 
Component 
Mixture 
Weight 
Mean vector 
SD vector 
Correlation 
1: Rat 
0.500 
-1.122, 0.299 
1.98476, 0.9906 
-0.0004715777 
2: Dog 
0.500 
-1.682, -0.101 
1.9847620, 0.9906 
-0.0004715777 
A summary of the prior probabilities of DLT at different doses, as well as the corresponding 
probability of under-, targeted and overdosing, are shown in Table 5. The prior medians of the 
DLT probabilities are in line with the prior medians derived from the two animal studies, and the 
uncertainty around the medians is large, showing the low amount of in-men information this prior 
provides. 


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Table 5 
Prior probabilities of DLT at selected doses 
Dose 
Probability of true DLT rate in 
 
 
Quantiles 
 
[0–0.16) 
[0.16–0.33) 
[0.33–1] 
Mean 
SD 
2.5% 
50% 
97.5% 
10 mg 
0.857 
0.069 
0.075 
0.077 
0.162 
0 
0.008 
0.647 
15 mg 
0.832 
0.079 
0.089 
0.089 
0.173 
0 
0.012 
0.685 
30 mg 
0.775 
0.101 
0.123 
0.118 
0.197 
0 
0.025 
0.757 
60 mg 
0.688 
0.129 
0.182 
0.165 
0.228 
0 
0.057 
0.828 
120 mg 
0.524 
0.178 
0.298 
0.253 
0.266 
0.003 
0.144 
0.898 
180 mg 
0.384 
0.186 
0.429 
0.347 
0.3 
0.006 
0.256 
0.954 
240 mg 
0.31 
0.171 
0.519 
0.418 
0.324 
0.008 
0.352 
0.986 
320 mg 
0.26 
0.153 
0.588 
0.479 
0.339 
0.011 
0.449 
0.998 
400 mg 
0.229 
0.141 
0.63 
0.52 
0.345 
0.013 
0.525 
0.999 
Doses printed in bold type meet the overdose criterion, P(overdose) < 0.25.  
The MTD may be considered reached if one of the following criteria is fulfilled: 
1. The posterior probability of the true DLT rate in the target interval (16%-33%) of the MTD is 
above 50%  
OR 
2. 
 At least 6 patients have been treated at MTD, including the confirmatory cohort. 
Statistical model assessment 
The single agent model was assessed using two different metrics: 
1. Hypothetical data scenarios: for various potential data constellations as they could occur in the 
actual trial, the maximal next doses as allowed by the model and by the 100% escalation limit 
are investigated. Data scenarios thus provide a way to assess the “on-study” behaviour of the 
model. 


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2. Simulated operating characteristics: these illustrate for different assumed true dose-toxicity 
relationships, how often a correct dose would be declared as MTD by the model. They are a 
way to assess the “long-run” behaviour of the model. 
In summary, the model showed very good behaviour as assessed by these metrics.  
More details of the model for Part A can be found in Appendix 2.  
5.6.2 
Efficacy Analysis 
All efficacy endpoints will be summarized within cohort by descriptive statistics based on SS. 
Tumour assessments (via CT, MRI or PET-CT, bone marrow, respectively, pending on tumour 
type) are scheduled for following time-points: 
 At baseline  
 During Cycle 2, 4, 6, etc.: on Day 15 (i.e. every 8 weeks) 
 At EOT visit 
Progression-free Survival (PFS) is assessed explicitly at week 24 and at EOT visit, though disease 
progression can be detected and recorded at any time-point. 
Efficacy parameters are:  
  Overall Response Rate (ORR) 
  Best Overall Response (BOR) 
  Time to Response (TTR) 
  Duration of Response (DOR) 
  Clinical Benefit Rate (CBR) at 3 months, at 6 months and at 9 months 
  Progression-free Survival (PFS)  
  Overall Survival (OS)  
No formal hypothesis testing is planned. 
All lesion and other tumour assessments will be included in the assessment of efficacy parameters.  
All efficacy parameters from either the eCRF or calculated as part of statistical analysis will be 
listed. 
In case of patients with solid tumour cancers, baseline lesion status as well as post-baseline 
assessments of target, non-target and new lesions will be provided. The overall response 
assessment as of RECIST1.1 are listed by individual cycles. 
In T-ALL/T-LBL patients, baseline lesion status, tissue sites involved at baseline, post-baseline 
lesion status and new lesions will be listed; and so will the overall response assessments by cycle 
based on NCCN Guidelines on Adult Acute Lymphoblastic Leukaemia. 
Patients who cannot be evaluated for response will be categorized as Not Evaluable (NE) or 
Unknown/Not Assessed (NA).  


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5.6.2.1 Best Overall Response (BOR) 
BOR is defined as the best response recorded from the first day of study treatment until disease 
progression/recurrence, death or end of study respectively data cut-off, whatever comes first. 
Patients with solid tumours are considered responders if they have a tumour assessment status of 
PR or CR according to RECIST, v1.1.  
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence. Best is defined as the first response when all a subject’s response 
assessments are sorted by CR, PR, SD, PD, NE/UNK. In general, the subject's best response 
assignment will depend on the achievement of the measurement criteria. For subjects without a 
post-baseline, a non-missing response assessment will have a BOR of NE assigned. Unknown 
(UNK) or patients with symptomatic deterioration but without any scan will also be mapped to 
NE. 
Patients with haematologic malignancies are considered responders if they have a haematologic 
malignancies status CR or CRi as per NCCN guidelines. 
Any response must be confirmed not less than 4 weeks after the criteria for response are first met.  
Patients without a post-baseline assessment will be considered NE. Additionally, after baseline, a 
change in methods will result in an assessment of not evaluable.   
Patients who were enrolled in study, but did not receive any study treatment will have a best overall 
response ‘Missing’ and will be included as non-responders in the analysis of BOR. 
BOR for different cancer types will be summarized by cohort for patients with Solid Tumour and 
for those with haematologic malignancies. The BOR information will be provided in Listing. 
5.6.2.2 Overall Response Rate (ORR) 
Overall response rate (ORR), i.e. rate of patients with response (CR+PR for RECIST V1.1), will 
be presented together with corresponding Clopper-Pearson 95% CI for each dose group with at 
least 6 patients. For changes in solid tumour size, waterfall plots will be presented. For all response 
assessments, swimmers plots will be presented. All response assessments will be listed. 
For T-ALL/T-LBL patients, the overall bone marrow response rate as per local assessment, the 
number (n) and percentage (%) of patients with progressive disease [PD], refractory and relapsed 
disease will be summarized by cycle and overall for each dose group and overall, with 95 % CI. 
In addition to bone marrow the mediastinal response, CNS and extramedullary responses will be 
presented in the same way but only for subset of patients with extramedullary involvement at 
baseline.  Swimmers plots will be generated for graphical display of response. Clopper-Pearson 
(exact) method will be used to derive the CI. 
5.6.2.3 Time to response (TTR) and Duration of response (DOR) 
TTR is defined as the time from the first day of study treatment to the first date the response criteria 
are met, given they were later confirmed. Patients who are not confirmed responders will be 
censored at the time of their last evaluable tumour assessment. Patients with no tumour assessment 
after the baseline visit will be censored at the time of the first day of study treatment plus 1 day. 


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For each dose group, estimates of the median TTR and the corresponding two-sided 95% CI will 
be presented along with the estimates for the 25th and 75th percentiles and the associated ranges 
(minimum, maximum) using the Kaplan-Meier (KM) approach. 
DOR is defined only for the patients with a confirmed response according to RECIST, v1.1 for 
patients with solid tumours, according to NCCN guidelines for patients with haematologic 
malignancies. 
By definition, DOR is the time interval between the date of the earliest qualifying response and 
the date of PD or death from any cause, whichever occurs first. For patients who are alive without 
progression following the qualifying response, DOR will be censored on the date of last evaluable 
tumour assessment or last FU for PD before the data cutoff date. Data for patients who are lost to 
FU prior to documented progression will be censored at the last tumour assessment date which the 
patient is known to be progression-free prior to the data cutoff date.  
For each cohort, estimates of the median DOR and the corresponding two-sided 95% CI will be 
presented along with the estimates for the 25th and 75th percentiles and the associated ranges 
(minimum, maximum) using the Kaplan-Meier (KM) approach. 
Both TTR and DOR will be provided in Listing. 
5.6.2.4 Clinical Benefit Rate (CBR) 
Patients with solid tumours are considered to have clinical benefit if they have a tumour assessment 
status of CR, PR or SD according to RECIST, v1.1. 
The CBR at 3 months, 6 months and 9 months after treatment start will be presented together with 
corresponding Clopper-Pearson 95% CI for each dose group with at least 6 patients. 
5.6.2.5 Progression Free Survival (PFS) and Overall Survival (OS) 
PFS, measured in days, is defined as the time from the first day of study treatment until the first 
documented progression of disease or death from any cause, whichever occurs first.  
PFS for patients who have neither progressed nor died will be censored on the date of last evaluable 
tumour assessment prior to the data cut-off date. For patients who have not died and have no 
recorded post-BL tumour assessment, PFS will be censored on the date of the first dose of study 
medication plus 1 day. Patients who die without any recorded post-baseline tumour assessment 
after receiving the first dose will be considered to have an event on the date of death.  Data for 
patients who are lost to FU prior to documented progression will be censored at the last evaluable 
tumour assessments date which the patient is known to be progression-free prior to the data cut-
off date.   
For each dose group with at least 6 patients, estimates of the median PFS and the corresponding 
two-sided 95% CI will be presented along with the estimates for the 25th and 75th percentiles and 
the associated ranges (minimum, maximum) using the Kaplan-Meier (KM) approach. 
OS is defined as time between the first day of study treatment and date of death of any cause. 
Patients for whom no death is captured on the clinical database are censored at the last date they 
were known to be alive. Patients with no post-BL information will be censored at the time of first 
study treatment plus 1 day.  


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For each dose group at least 6 patients, estimates of the median OS and the corresponding two-
sided 95% CI will be presented along with the estimates for the 25th and 75th percentiles and the 
associated ranges (minimum, maximum) using the Kaplan-Meier (KM) approach. 
Both PFS and OS details will be provided in Listing. 
Futher survival status information from long-term FU will be listed in Listing. 
 
5.7 
Safety 
The safety analysis is the primary analysis for this study. 
All safety and tolerability assessments will be based on the SS and will be summarized within 
cohort. 
The safety endpoints include the following: 
 
Incidence of treatment-emergent adverse events (TEAEs), including  
o 
All adverse events (AE) 
o 
Serious adverse events (SAEs) 
o 
Dose-limiting toxicities (DLT)  
 
Laboratory tests values, including 
o 
Biochemistry 
o 
Haematology 
o 
Urinalysis 
o 
Cardiac markers 
 
Vital signs, including 
o 
Systolic and diastolic arterial blood pressure (BP) 
o 
Weight and BMI 
o 
Pulse rate (PR) 
o 
Oral temperature 
 
Cardiac function testing, including 
o 
Electrocardiogram (ECG), including Heart Rate, PR Interval, RR Interval, QRS 
Interval, QT Interval, QTc Interval 
o 
Incidence of abnormal ECG findings 
o 
Left ventricular ejection fraction (LVEF) results 
o 
Incidence of abnormal echocardiography findings 
 
Physical examination, including  
o 
Incidence of abnormal findings 


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o 
Incidence of abnormal, clinically significant findings 
5.7.1 
Adverse Events 
AEs and SAEs will be summarized by cohort by presenting the number and percentage of patients 
having any event, number of events is also presented; summaries classifying events according to 
severity (CTCAE) grade, relationship to study drug, outcome and action taken with study drug 
will be presented. Missing severity, relationship or outcome will be classed as unknown. If a 
patient experiences the same AE at more than one severity, or with more than one relationship to 
investigational product, the most severe rating or the stronger causal relationship to investigational 
product will be given precedence.  
All AEs, related AEs, SAEs, related SAEs, AEs with CTCAE Grade ≥ 3, related AEs with CTCAE 
Grade ≥ 3 as well as AEs leading to premature discontinuation, interruption or discontinuation of 
study drug or to dose modification will be also summarized presenting the number and percentage 
of patients having an event in each MedDRA system organ class (SOC) and preferred term (PT) 
category. A patient with more than one occurrence of the same AE in a particular SOC will be 
counted only once in the total of those experiencing AEs in that SOC.  
All AE, and SAE information collected will be listed as appropriate. A separate summary table 
and a listing including only DLTs will be also provided. 
Only treatment emergent AEs, i.e. AEs occurring on or after day of first administration of study 
treatment, will be included in the event summaries. Non-treatment emergent events (starting prior 
to exposure to study treatment) will be included in the patient listings and flagged but not included 
in the summary tables. Where an AE start date is partially or fully missing, and it is unclear as to 
whether the AE is treatment emergent, it will be assumed that it is. 
All deaths overall will be summarized and listed. 
Notes: 
 AEs coded using MedDRA version will be noted in the footnote of the tables and listings. 
 CTCAE  
 
5.7.2 
Laboratory Evaluations 
Laboratory values will be graded by NCI CTCAE version 4.03 (or higher), if no grading exists 
values will be classified into low/normal/high based on laboratory normal ranges. Each parameter 
will be presented by descriptive statistics at each visit including change from baseline (screening). 
Shift tables for CTCAE grades and normal ranges will be presented. 
All values should be reported in SI units (if applicable), results reported in non-SI unit should be 
converted to SI unit. Missing values will be excluded. 
Only patients with non-missing change from baseline data at the visit will be included in the post-
baseline summary statistics at the visit. Baseline is defined as the last measurement prior to dosing. 
Results from the following laboratory parameters will be summarized by cohort and time point:  


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Haematology: Haemoglobin, haematocrit, erythrocytes (RBC), reticulocyte count, platelets, 
leukocytes (WBC), differentials (counts): neutrophils, eosinophils, lymphocytes, monocytes, 
basophils. 
Coagulation: Prothrombin time expressed as International normalized ratio (INR), activated 
partial thromboplastin time (aPTT). 
Biochemistry: Total protein, albumin, alkaline phosphatase, total bilirubin, calcium, cholesterol, 
chloride, creatine kinase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
lactate dehydrogenase, C-reactive protein (CRP), lipase, pancreatic amylase, glucose, inorganic 
phosphorus, magnesium, potassium, sodium, triglycerides, urea/blood urea nitrogen, uric acid, 
creatinine (creatinine clearance estimated according to the Cockcroft-Gault formula). 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and conjugated 
bilirubin, albumin, alkaline phosphatase (ALP), gamma-glutamyl-transferase (GGT), amylase, 
bicarbonate, calcium, chloride, total cholesterol, creatine phosphokinase (CPK), C-reactive protein 
(CRP), creatinine, blood urea nitrogen (BUN), glucose, phosphate, lactate dehydrogenase (LDH), 
lipase, magnesium, potassium, total protein, sodium, triglycerides, urate. 
Urine from dipstick: Protein, glucose, ketones, red (RBC) and white blood cells (WBC), pH, 
specific gravity. 
Detailed Urinalysis (if clinically significant positive results from the dipstick): bacteria, casts 
(RBC, haemoglobin, hyaline, WBC), RBC, WBC, mucus, oxalates, epithelial cells, renal and 
squamous epithelial cells, uric acid crystals, unspecified crystals, urate, yeast. 
Cardiac markers: Serum troponin, N-terminal pro-peptide BNP  
Laboratory parameters other than cardiac markers are assessed at following time points: 
 At screening 
 During Cycle 1 on Day 1, Day 3 (only Part A), Day 8, Day 15 and Day 22 
 During other Cycles on Day 1 and Day 15 
 At EOT visit 
 
Cardiac serum markers are to be collected:  
 At baseline  
 During Cycle 1: on Day 22 
 During other Cycles on Day 1 and Day 15 
 At EOT visit 
Absolute values and changes values from baseline for haematology, biochemistry and coagulation 
assessments will be summarized (cf. notes in section 4.1).  
Shift tables for Out of Normal Range Results for haematology, biochemistry and coagulation 
assessments will be summarized.  
Shift tables for CTCAE grades for haematology, biochemistry and coagulation assessments will 
be summarized.  
Local dipstick urinalysis () as well as results will be summarized according to being normal or 
abnormal. 


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All laboratory results will be listed.  
A separate listing for abnormal lab values (Grade 3 and higher, and low/high values) will be 
presented. 
Notes: 
 All results outside ranges will be flagged in the data listings as follows:  
o Out-of-reference-range values will be marked as high (H) or low (L).  
o Values falling outside the clinically significant reference range of the respective laboratory 
will be marked as clinically significant laboratory abnormalities (i.e., potentially clinically 
relevant) and labelled in addition by “CS”. Marked laboratory abnormalities will be labeled 
in the subject listings as “HH” for significantly high or “LL” for significantly low. 
 Repeat laboratory results within a visit will replace the original value.  
 Unscheduled results will be listed only. 
Any other laboratory results will be listed only. 
 
5.7.3 
Vital Signs 
Absolute as well as change from baseline results for systolic and diastolic blood pressure, pulse 
rate, Body Mass Index (BMI), weight and oral temperature will be summarized by cohort and visit, 
using standard descriptive statistics. All vital signs will be listed together with flags for outside of 
reference range. 
Only patients with non-missing change from baseline data at the visit will be included in the post-
baseline summary statistics at the visit. 
Frequency of patients with notably abnormal vital signs will be provided by cohort and visit and 
will be defined as follows: 
  - Systolic blood pressure [mmHg]:  >=180 mmHg or <=90 mmHg with increase or decrease from 
baseline of >=20 mmHg 
  - Diastolic blood pressure [mmHg]: >=105 mmHg or <=50 mmHg with increase or decrease from 
baseline of >=15 mmHg    
  - Pulse rate [bpm]: >=120 bpm or <=50 bpm with increase or decrease from baseline of >=15 
bpm       
Baseline is defined as the last measurement prior to dosing. 
Systolic and diastolic blood pressure as well as pulse rate is recorded at following time points: 
 At screening  
 During Cycle 1: on Days 1, 2 (only Part A), 3 (only Part A), 8, 15 and 22 
 During other Cycles on Day 1 and Day 15 
 At EOT visit 
 At unscheduled visits. 


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Oral temperature is taken at following time points: 
 At baseline  
 During Cycle 1: on Days 2 (only Part A), 3 (only Part A), 8, 15 and 22 
 During other Cycles on Day 1 
 At EOT visit 
 At unscheduled visits. 
Weight, and hence BMI, is assessed at following time points: 
 At baseline  
 During all Cycles other then 1: on Day 1 
 At EOT visit 
 At EOS visit 
 At unscheduled visits. 
Note: 
 All results outside ranges will be flagged in the data listings as follows: 
o Out-of-reference-range values will be flagged as high (H) or low (L) where reference 
ranges are as follows: 
 Weight: >=7% increase or decrease from baseline weight 
 Systolic blood pressure [mmHg]: >=180 mmHg/<=90 mmHg with increase/decrease 
from baseline of >=20 mmHg 
 Diastolic blood pressure [mmHg]: >=105 mmHg/<=50 mmHg with increase / decrease 
from baseline of >=15 mmHg 
 Pulse rate [bpm]: >=120bpm/<=50 bpm with increase / decrease from baseline of >=15 
bpm 
o Values falling outside the clinically significant reference range of the respective laboratory 
will be marked as clinically significant vital signs abnormalities (i.e., potentially clinically 
relevant). Marked abnormalities will be labelled in the subject listings as “HH” for 
significantly high or “LL” for significantly low. 
 
5.7.4 
Electrocardiograms 
Cardiac function testing includes 12-lead ECG, Holter ECG and LVEF assessment  
A 12-lead ECG is carried out:  
 At screening  
 During Cycle 1: on Days 1, 2 (only Part A), 3 (only Part A), 8, 15 and 22 
 During other Cycles on Day 1 and Day 15 


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 At EOT visit 
 At unscheduled visits. 
A Holter ECG is done: 
 At baseline  
Only for Part A: 
 During Cycle 1: on Days 1 and 8 
 During Cycle 2: on Day 1 
 At EOT visit 
Assessment of LVEF via MUGA or ECHO is done: 
 At baseline  
 During Cycle 1: on Day 8 
 During Cycle 3: on Day 1 
 At EOT visit 
 
Details of the ECG analyses will be covered by a separate SAP created by BMS.  
Results of LVEF assessments (not done, normal, abnormal not clinically significant and abnormal 
clinically significant) will be summarized by cohort and time point and listed. If either result is 
missing for any patient, then an ‘Unknown’ category will be presented. 
5.7.5 
Physical Examination and ECOG status 
A physical examination by body system (i.e. general appearance, eyes, ears and nose, skin, head, 
respiratory including throat, cardiovascular, renal and urinary, gastrointestinal, musculoskeletal, 
nervous system and other) is performed at following time points: 
 At screening  
 At baseline  
 During Cycle 1: on Days 2 (only Part A), 3 (only Part A), 8, 15 and 22 
 During other Cycles on Day 1 and Day 15 
 At EOT visit 
 At unscheduled visits. 
Abnormal, clinically significant findings will be summarized by cohort and time point. All 
physical examination results will be listed. 
ECOG performance status is assessed at screening, at baseline, during cycle 1 on days 2, 3, 8, 15 
and 22, during all other cycles on days 1 and 15 as well as at EOT, at safety FU and at unscheduled 
visits. It will be summarized by dose group and time point and listed. 
5.8 
Pharmacokinetic Assessments 
5.8.1 
Pharmacokinetic Analysis  
Samples for PK profiles is done at following timepoints: 


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In Part A: 
 During Cycle 1:  
o 
on Day 1: pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h post-dose 
o 
on Day 2: 24h post Day 1 dose, pre-dose 
o 
on Day 3: pre-dose 
o 
on Day 8: pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h 
o 
on Day 9: 24h post Day 1 dose, pre-dose 
o 
on Day 15: pre-dose, 1h post-dose 
o 
on Day 22: pre-dose, 1h post-dose 
In case an oral BID dosing regimen of CB-103 is implemented, the PK sampling scheme 
during cycle 1 will be adjusted as follows: 
o 
on Day 1: pre-dose, 1st intake, 0.5h, 1h, 2h, 4h post-dose 
o 
on Day 1: pre-dose, 2nd intake, 0.5h, 1h, 2h, 4h post-dose 
o 
on Day 2: pre-dose, 1st intake 
o 
on Day 8: pre-dose, 1st intake, 0.5h, 1h, 2h, 4h post-dose 
o 
on Day 8: pre-dose, 2nd intake, 0.5h, 1h, 2h, 4h post-dose 
o 
on Day 9: pre-dose, 1st intake 
o 
on Day 15: pre-dose, 1st intake 
 During Cycle 2:  
o 
on Day 1: pre-dose, 0.5h, 1h, 2h, 4h, 6h and 8h post-dose 
o 
on Day 15: pre-dose 
 All further Cycles:  
o 
Each visit: one sample, any time 
The following PK parameters will be calculated using non-compartmental methods as data permit 
for each dose:  
 Maximum observed plasma concentration (Cmax)  
 Minimum observed plasma concentration (Cmin)  
 Time to maximum plasma concentration (tmax) 
 Time to last measurable plasma concentration (tlast) 
 Concentration at last measurable plasma concentration (Clast) 
 Area under the plasma concentration-time curve up to 8h (AUC(0-8)) 
 Area under the plasma concentration-time curve up to 24h (AUC(0-24)) 


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 Total area under the plasma concentration-time curve from time zero to infinity 
(AUC(0-inf)) 
 Accumulation ratio (AR) 
 Terminal-phase elimination rate constant (z) 
 Elimination half-life (t1/2) 
 Apparent clearance of drug after oral administration (CL/F) 
 Apparent volume of distribution (Vd/F) 
 Apparent volume of distribution at steady state (Vss/F) 
Non-compartmental analysis will be performed using Phoenix WinNonlin version 6.3. 
For each PK parameter, individual and mean data, i.e. summary statistics (including number of 
patients, arithmetic mean together with SD, geometric mean and CV% [except for tmax and tlast], 
median, Min and Max) will be presented. 
Area under the plasma concentration-time curve to the last observable plasma concentration 
[AUC(0-t)] will be calculated from the observed data using the linear up logarithmic down 
trapezoidal method. Total area under the plasma concentration-time curve from time zero to 
infinity [AUC(0-inf)] will be then estimated by AUC(0-inf) = AUC(0-t) + Ct/z, where Ct will be the 
observed concentration at the last quantifiable time point.  
The accumulation ratio (AR) is defined as AR = AUC(0-24) Day 8 / AUC(0-24) Day 1. 
The terminal-phase elimination rate constant (z) will be estimated by log-linear regression of 
those data points visually assessed to be in the terminal phase of the profile. At least three terminal 
plasma concentrations after Cmax will be used for estimating z. Elimination, i.e. terminal-phase, 
half-life (t1/2) will be calculated as t1/2 = Ln2/z, apparent clearance of drug after oral administration 
as CL/F=Dose/AUC(0-inf), apparent volume of distribution as Vd/F=Dose/( AUC(0-inf)*z) and 
volume of distribution at steady state Vd /SS = Dose* AUMC(0-inf)/AUC(0-inf)2, where AUMC is the 
area under the first moment curve. 
Individual CB-103 plasma concentration-time data will be listed and graphically displayed for 
each patient both on linear as well as on semi-logarithmic (on concentration axis) scale for Cycle 
1 Day 1, Cycle 1 Day 8 and Cycle 2 Day 1, where C1D1, C1D8 and C2D1 profiles will be overlaid 
for all individuals by cohort and day. 
Summaries of plasma concentrations will be presented in tabular form by assessment time-point 
(Cycle, day within cycle and time post study drug intake). Also for Cycle 1 Day 1, Cycle 1 Day8 
and Cycle 2 Day1, the mean (+/-SD) plasma concentrations will be displayed graphically over 
time on linear as well as on semi-logarithmic (on concentration axis) scale for each cohort and for 
each visit across cohorts. A graph of the pre-dose mean (+/-SD) concentrations for all days where 
a PK plasma sample is drawn will be provided, with both individual curves by cohort and average 
curves across cohorts. 
Plots of key PK parameters (Cmax, AUC(0-inf)) vs dose including all visits in one plot figure will 
be provided. 


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All PK summaries are based on the PK Set and will also be provided by indication i.e, for solid 
tumours or T-ALL/T-LBL and by ethnicity. 
 
All derived PK parameters will be listed for all patients in PK set and summarized within cohort. 
5.8.2 Below Limit of Quantification (BLQ) 
5.8.2.1 During calculation of PK parameters: 
 Any BLQ (<LLOQ (Lower Limit of Quantification)) values that occur before the first 
quantifiable concentration will be replaced with zero.  
 If a BLQ (<LLOQ) value occurs after a quantifiable concentration in a profile and is 
followed by a value of LLOQ or above, then the BLQ (<LLOQ) will be replaced with 
LLOQ/2. 
 If two BLQ (<LLOQ) values occur in succession, the profile will be deemed to have 
terminated at the final quantifiable concentration and subsequent LLOQ or above values 
will be treated as 'missing'. 
5.8.2.2 For individual pharmacokinetic profiles 
 
A value of LLOQ/2 will be substituted for any <LLOQ irrespective of where they are in 
the profile and the plasma concentration-time data will be plotted as such.  
 
A line with a label of LLOQ in the concentration axis will be overlaid to show the level of 
LLOQ. 
5.8.2.3 Mean or median concentration profiles 
When estimating the mean or median value for the concentration at a given time point (descriptive 
mean or median curve), the following guidelines should be considered:  
 The mean/median value at a time with one or more BLQ (<LLOQ) values will be calculated 
by assigning LLOQ/2. If the calculated mean/median value is less than LLOQ of the assay, 
then that time point will be ignored for plotting the mean/median pharmacokinetic profiles.  
 It should be noted that since a high proportion of BLQ (<LLOQ) values may affect the SD; 
if more than 50% of values are imputed, then no mean/median be calculated for that time 
point.  
 A line with a label of LLOQ (Lower Limit of Quantification) in the concentration axis will 
be overlaid to show the level of LLOQ. 
5.8.2.4 Concentration summaries: 
 
Prior to calculation of summary statistics: 
o Any individual values less <LLOQ that occur before the first quantifiable 
concentration will be replaced with zero.  


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o If a <LLOQ value occurs after a quantifiable concentration in a profile and is 
followed by a value of LLOQ or above, then the <LLOQ will be replaced with 
LLOQ/2. 
o After the last value above LLOQ, individual patients with values below LLOQ at 
the end of the plasma curve will have these values replaced with zero. 
 
If the calculated mean value is less than LLOQ, then the summary statistics will be left 
blank, with <LLOQ presented only for the mean value.  
 
Within the summary statistics, any minimum, median, or lower confidence values that are 
calculated to be <LLOQ will be presented as <LLOQ within the summary presentation.  
 
In listings, <LLOQ will be presented for all values of <LLOQ and a value of LLOQ added 
to a footnote. 
Notes:  
 The lower limit of quantification (LLOQ) is 3ng/mL. 
Concentrations (Cmax) will be rounded to 3 significant figures. All times (tmax and t1/2) will be 
rounded to 2 decimal places. All AUCs, CL/F, Vd/F and Vss/F to 4 significant figures. Summary 
statistics will be reported to one more decimal place (or significant figure) than the data listings, 
except CV% which will be rounded to 2 decimal places in all instances, and minimum and 
maximum values which will be reported to the same precision used in the listings. 
5.8.3 PK assessments in CSF in T-ALL/T-LBL patient 
Summary statistics of the CB-103 concentration in CSF will be reported in selected patients with 
haematological malignancies. The concentrations in CSF will be compared with serum 
concentrations. 
 
5.9 
Biomarker Analysis 
Summary statistics of PD, mechanistic, and anti-tumour markers will be reported by dose group 
and examined for possible correlations with CT/MRI/PET-CT efficacy endpoints. Additional 
analyses include comparing PD modulation with exposure. Details of the biomarker analyses will 
be covered by a separate SAP. 
 
 
 


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6. Changes in the Conduct of the Study or Planned Analysis 
There were no changes in the analysis planned in the protocol of the study at the time of 
preparing this SAP. 
 
Any deviations from the approved SAP will be described and justified in the CSR.  


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7. Appendices 
Appendix 1: Document History 
Document Version, Status, Date 
Summary / Reason for Changes 
Version 2.0, Final, 29Apr2022 
New version following Protocol Amendment 
Version 1.0, Final, 28Aug2019 
Initial version 
 
Appendix 2: Statistical Details for Part A (Escalation) 
The model was assessed by two different metrics: hypothetical on-study data scenarios and long-run 
operating characteristics.  
Hypothetical data scenarios 
Hypothetical data scenarios are shown in Table 1. These scenarios reflect potential on-study data 
constellations and related escalation as allowed by the model and the 100% escalation limit. For each 
scenario, the probability of overdose for the current dose, as well as the next potential dose and related 
probabilities of under-dosing, target dose and over-dosing are shown.  
For example, scenario 1 represents the case that no DLT is observed in three patients at the starting dose of 
15 mg. In this case, the next dose permitted by the model and by the 100% escalation rule is 30 mg. 
Similarly, scenario 2 represents the case that one DLT is observed in the first cohort of three patients at 15 
mg, the model would than not allow to escalate to 30 mg and would require more patients enrolled on the 
dose level of 15 mg.  Scenario 6 represents the case that two DLTs are observed in the second cohort in 
three patients at 30 mg. The model then allows a de-escalation to 15 mg. Despite the fact that no DLTs 
were seen in the previous cohort (6 patients in total), the model reacts immediately to the data observed at 
30 mg and requires a de-escalation to 15 mg. This case illustrates the adaptive behaviour of the model even 
in extreme situations. 


Statistical Analysis Plan 
 
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Labcorp Drug Development Study: 000000186267 
 
Protocol Reference: CB103-C-101 
 
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Table 1 
Hypothetical data scenarios  
Scenario Dose 
#DLT #Pat 
Current Dose 
-P(OD) 
Next 
Dose 
Next Dose 
- P(UD) 
Next Dose 
- P(TD) 
Next Dose 
- P(OD) 
1 
15 
0 
3 
0.011 
30 
0.89 
0.079 
0.031 
2 
15 
1 
3 
0.239 
15 
0.467 
0.294 
0.239 
3 
15 
2 
3 
0.685 
 
 
 
 
4 
15 
0 
3 
 
 
 
 
 
 
30 
0 
3 
0.007 
60 
0.871 
0.094 
0.035 
5 
15 
0 
3 
 
 
 
 
 
 
30 
1 
3 
0.121 
30 
0.602 
0.277 
0.121 
6 
15 
0 
3 
 
 
 
 
 
 
30 
2 
3 
0.4 
15 
0.439 
0.356 
0.206 
7 
15 
0 
3 
 
 
 
 
 
 
30 
1 
6 
0.034 
60 
0.53 
0.308 
0.162 
8 
15 
0 
3 
 
30 
0 
3 
 
 
 
 
 
 
60 
1 
3 
0.102 
60 
0.61 
0.289 
0.102 
Operating characteristics 
Operating characteristics are a way to assess the long-run behaviour of a model. Under an assumed 
true dose-toxicity curve, metrics such as the probability of recommending a dose with true DLT 
rate in the target interval can be approximated via simulation. Table 2 describes 3 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. These 
scenarios reflect a wide range of possible cases as follows: 
 Scenario 1 (P):  aligned with prior means 
 Scenario 2 (H):  high-toxicity scenario 
 Scenario 3 (LH): low-toxicity followed by high-toxicity 
 
 
 


Statistical Analysis Plan 
 
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Table 2 
Assumed true dose-toxicity scenarios 
Scenario 
 
Dose 
 
 
10 
mg 
15 
mg 
30 
mg 
60 
mg 
120 
mg 
180 
mg 
240 
mg 
320 
mg 
400 
mg 
1 (P) 
P 
(DLT) 
0.08 
0.09 0.12 
0.17 0.25 
0.35 
0.42 
0.48 
0.52 
2 (H) 
0.12 
0.17 0.25 
0.42 0.55 
0.63 
0.7 
0.8 
0.9 
3 (LH) 
0.05 
0.08 0.12 
0.16 0.2 
0.4 
0.5 
0.65 
0.9 
Bold numbers indicate true DLT rates in the target interval [0.16-0.33). 
For each of these scenarios, 500 trials were simulated. It was then assessed how often a dose was 
declared as MTD with true DLT rate in the under-, targeted or over-dose range. Furthermore, the 
average, minimum and maximum number of patients per trial and the average number of DLTs 
per trial are reported. Results are shown in Table 3. 
Table 3 
Simulated operating characteristics 
Scenario 
% of trials declaring an MTD with true DLT rate in 
# Patients 
# DLT 
 
Underdose 
Target dose 
Overdose 
Stopped 
Mean 
(Min-Max) 
Mean 
(Min- Max) 
1 (P) 
23.6 
61.6 
9.4 
5.4 
19.13 (3-51) 3.09 (1-11) 
2 (H) 
1.8 
61.2 
16.2 
20.8 
15.30 (3-39) 3.68 (1-11) 
3 (LH) 
22.6 
67.4 
9.1 
3.6 
19.89 (3-52) 3.25 (1-12) 
 
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 61.6% 
of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose range. Since 
this reflects a low toxicity prior assumptions the highest currently planned dose of 150 mg was 
identified quite often as MTD, namely in 61.4% of the simulated cases.  
In Scenario 2 (high-toxicity scenario), the starting dose has already > 17% probability of observing 
at least 2 DLTs in the first cohort. This contributes to the high percentage (20.8%) of all simulated 
trials for which the trial is stopped since none of the doses is considered tolerable anymore. This 
is an expected situation for a high-toxicity scenario. 
In Scenario 3, more than 67.4% of the simulated trials declared a dose as MTD with true DLT rate 
in the targeted dose range. 
The mean patient numbers range from 15.30 patients (high-toxicity scenario) to 19.89 patients 
(low-high) and the maximum number of patients was 52. Therefore, the patient numbers are as 
expected and increase when moving away from the high-toxicity scenario.  


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In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination. 
 
 


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Appendix 3: Schedule of Assessments for Part A 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EO
T28 
Safety follow-
up29 
After Cycle 
6 
(28-day 
cycles, until 
PD or 
toxicity) 
Un-scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EO
T 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Overnight hospital stays 
 
  
 
X3 
 
 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent4 
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test6 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Vital Signs and body 
measurement 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body height (cm) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
ECOG perf. Status7 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination8 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Body temperature 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Respiratory rate 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
 
 
 
Cardiac Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Heart rate 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan 
 
 CONFIDENTIAL 
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 Protocol Reference: CB103-C-101 
 
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Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EO
T28 
Safety follow-
up29 
After Cycle 
6 
(28-day 
cycles, until 
PD or 
toxicity) 
Un-scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EO
T 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
12-lead ECG9 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
Holter monitoring9 
 
 
X9 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
ECHO or MUGA for LVEF 
assessment9 
 
 
X9 
 
 
 
X 
 
 
 
 
 
 
 
X9a 
 
X 
 
 
X 
Cardiac serum markers10 
 
 
X10 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X22 
X 
Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmological exams11  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X12 
 
 
Clinical chemistry13 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Hematology13 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Coagulation13 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
PK profile blood sampling14 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
PK sub-study  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Whole blood, plasma 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Stool sample15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 16 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessment (PFS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


Statistical Analysis Plan 
 
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 Protocol Reference: CB103-C-101 
 
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Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EO
T28 
Safety follow-
up29 
After Cycle 
6 
(28-day 
cycles, until 
PD or 
toxicity) 
Un-scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EO
T 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Survival follow-up 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Safety assessment incl. 
AE/SAEs 18 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Assessments  
(Solid Tumours only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumour biopsies19  
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumour biopsies 20 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Liquid biopsy 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
X 
Tumour assessment  
(CT/MRI/PET-CT) 21 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X22 
X 
 
X22 
X 
Hair follicles 23 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Other Assessments 
(T-ALL/T-LBL only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy and/or 
aspirate 24  
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Lumbar puncture25 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CSF sample 26 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Tumour assessment  
(PET-CT)27 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X  
 
X 
 
X  
X 
Whole blood and Saliva 
X* 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
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 Protocol Reference: CB103-C-101 
 
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Abbreviations: BL, baseline; CT, computed tomography; CSF, cerebrospinal fluid; DLT, Dose limiting toxicity; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOS-A, End of Study Part A; EOT, End of Treatment; F-up; Follow-up; ICF, Informed Consent Form; LVEV, left ventricular ejection fraction; MRI, magnetic 
resonance imaging; MUGA, multigated acquisition; PD, pharmacodynamics; PE, physical examination; PET-CT, positron emission tomography–computed tomography; PK, pharmacokinetic; 
SAE, serious adverse event; SCR, screening. 
* Pre-screening: it applies ONLY to the MTD/RP2D confirmatory cohort for patients whose Notch pathway activation status is not known; the patient must sign the pre-screening consent 
form. For solid tumour patients: if there is no sufficient archival tumour sample available or if older than 6 months prior to the pre-screening, a fresh pre-dose tumour biopsy is to be obtained. 
For T-ALL/T-LBL patients: when Notch status in unknown the whole blood and saliva will be collected at pre-screening, otherwise at BL to confirm the Notch status.  
1 
Visit windows: DLT treatment phase (first cycle): ± 0 day; cycles 2-6: ± 3 days. After cycle 6, visits are planned every 4 weeks (± 7 days) if no medical issue or complication occurred in 
the previous cycles. 
2 
Screening: may be performed in one or more visits.  
3 
Overnight stays at C1D1: it may not be required if reduced ECG&PK sampling is implemented. 
4 
Informed Consent: must be obtained prior to undergoing any study-related procedure. 
5 
Medical history (including relevant disease history) 
6 
Pregnancy test: for women of childbearing potential only. The serum pregnancy test must be performed within a maximum of 7 days of first CB-103 administration. The urine pregnancy 
test will also be done whenever one menstrual cycle is missed during the active treatment period (or when potential pregnancy is otherwise suspected) to confirm the patient has not become 
pregnant during the study. 
7 
ECOG: performance scale is available in Table 13 of the protocol. ECOG performance status will be assessed within 14 days prior to the first administration of CB-103, during the screening 
period. 
8 
Physical examination: will be performed at the screening, baseline and at the indicated patient visit, even if administration of study medication is being withheld. More frequent 
examinations may be performed at the Investigator’s discretion, if medically indicated. If the baseline examinations are performed within 72 hours prior to the first administration 
of CB-103, they need not be repeated on C1D1, except for patients with T-ALL/T-LBL who need to repeat the PE at C1D1. 
9  
12-lead ECG: at each time point, three consecutive high-quality (without artefacts/lead misplacement) 12-lead ECGs will be performed approx.1-2 minutes apart. Refer to Table 14 of the 
protocol for further details. ECG and PK blood samples need to be obtained at the same time-points and the ECG should be performed just prior to the drawing of the blood. A 15-minute 
window for ECG collection is allowed around each nominal ECG time point except for the 24 hour ECG time point, where a 1 hour window is allowed. 
9 
Holter monitoring: 3-lead Holter ECG monitoring with 24 hours ECG profiles. Refer to Table 14 of the protocol for the scheduling and further details. At BL allowed from Day -7. Holter 
recording should start 1 to 2 hours before the CB-103 intake. 
9 
ECHO/MUGA: allowed from Day -7. It may be repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity.  
9a  Between cycles 3 and 6 the ECHO/MUGA is only requested on C3D1. 
10  Cardiac markers: allowed from Day -7. They will be performed locally and may be repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
11  Ophthalmological exams: they will be performed by an ophthalmologist/eye doctor at screening, End of Treatment and when clinically indicated. Refer to Section 8.2.2.2 of the protocol. 
12  Ophthalmological exams: will be done at the safety follow-up if the patient had ocular symptoms during the treatment phase 
13  Clinical chemistry/Haematology/coagulation will be performed locally; at screening (within 14 days of C1D1), and at the indicated visits. Refer to Section of the protocol for the testing 
required. May be performed within a window of ± 24 hours during the DLT period and throughout all treatment cycles. 
14  PK time sampling: blood sampling will be collected as per the schedule and time window indicated in Section 8.4 of the protocol. Changes to the PK sampling scheme may be required 
based on emerging data. In case of twice daily intake of CB-103 the sampling schedule is slightly adjusted for cycle 1 (refer to Section 8.4.1 of the protocol) 


Statistical Analysis Plan 
 
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 Protocol Reference: CB103-C-101 
 
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15  Stool specimen collection: only one sample is to be possibly collected during cycle 2 and 3. 
16  Chest X-ray: a baseline chest x-ray should be performed and be repeated if clinically indicated. If a chest CT is performed at baseline to assess tumour lesions, then a chest X-ray may not 
be required. 
17  Survival follow-up: it is planned for one year, every three months, after the End-of-Study visit or after the last treatment cycle (if outside of the 6 cycles period). 
18  Between the signature of the ICF and the initiation of CB-103, only the SAEs caused by study-related procedures will be reported; any other AEs will be only recorded on the Medical 
History in the eCRF. After initiation of CB-103, all AEs/SAEs will be reported until four weeks after the last dose of CB-103. 
19  Archival tumour biopsy tissue (Solid Tumour): for the patients enrolled in Part A (dose-escalation) it should be not older than 6 months prior to screening and if not available a pre-dose 
fresh tumour biopsy must be taken. If the lesion is not accessible for a fresh tumour biopsy, a liquid biopsy may be used after confirmation with the Sponsor. 
20  Fresh tumour biopsy (Solid Tumour): mandatory in the MTD/RP2D confirmatory cohort of Part A of the study, is to be collected pre-dose during the screening/BL period, then on-treatment 
at C2D15 ± 3 days and at disease progression or when clinically indicated. The pre-dose fresh biopsy is not required if already obtained during the pre-screening. In individual cases, where 
the lesion is not accessible for a fresh tumour biopsy, a liquid biopsy may be used after confirmation with the Sponsor 
21 
Tumour assessments (Solid Tumours): will be performed at baseline, then 6 weeks after the first administration of CB-103 (i.e., day 15 of cycle 2) then see note 22. For breast cancer 
patients  enrolled in the MTD/RP2D confirmatory cohort (refer to Appendix 9 of the protocol) the CT scan will be replaced with PET-CT (or add PET) at baseline (and if positive, also at 
C2D15, before tumour biopsy).  A time window of ± 3 days is allowed for the tumour assessments. A wider time window is allowed only at baseline however assessments should be 
performed as close as possible to the 1st drug administration and if feasible, not later than 2 weeks prior to the 1st drug administration. 
22 
Tumour assessments (Solid Tumours): after cycle 2 will be performed, every 8 weeks and after cycle 6 every 12 weeks until EOT or disease progression/overall survival. The response 
will be determined as per the RECIST 1.1 and, if applicable, with confirmation as per RECIST.  
23  Hair follicles (Solid Tumour): samples will be collected for solid tumour indications only as per the schedule and time window indicated in Section 8.5.2 of the protocol. In the MTD/RP2D 
confirmatory cohort they will be collected only on selected patient groups. 
24  Bone marrow biopsy and/or aspirate (T-ALL/T-LBL): a bone marrow biopsy and/or aspirate will be obtained to assess bone marrow cellularity and to determine the percentage of leukemic 
blasts, including assessment of minimal residual disease (MRD) to confirm remission status. At the baseline assessment, bone marrow biopsy and/or aspirate is within 2 weeks and no less 
than 1 day before the first dose of CB-103. Then patients are assessed for disease response by bone marrow biopsy and/or aspirate on day 29. If the blasts in bone marrow are <5% but 
marrow is hypocellular (cellularity ≤15%) on day 29 (±3 days), then a repeat bone marrow biopsy and/or aspirate is obtained 1 week later to assess response; if residual leukaemia is 
present, repeated bone marrow biopsy and/or aspirate will be obtained per 28 days until CR or CRi. A response (CR or CRi) must be confirmed no less than 28 days from the first evidence 
of response by bone marrow core biopsy as indicated. In case of CR or CRi confirmed by bone marrow biopsy and/or aspirate on 2 bone marrow biopsy and/or aspirate assessments no less 
than 28 days apart (the interval between assessments), bone marrow biopsy and/or aspirate assessment may be increased to every 8 weeks until to PD or EOS (whichever is earlier). 
25  Lumbar puncture (T-ALL/T-LBL) for prophylactic intrathecal therapy: if prophylactic intrathecal therapy is foreseen by the treating physician, a lumbar puncture may be performed up to 
3 days before the first dose of CB-103, and, depending on the response of the patient, may be repeated at the discretion of the treating physician at the end of the first cycle of treatment 
with CB-103, and at the end of any subsequent cycle of treatment with CB-103, if more than one is warranted. 
26  CSF sample (T-ALL/T-LBL): in patients in whom a lumbar puncture is done (e.g., for intrathecal prophylaxis) a CSF sample should be taken on or around cycle 1 day 28, if clinically 
feasible, to determine the exposure of CB-103 in the CSF. 
27  Tumour assessments (T-ALL/T-LBL): only for patients with extramedullary disease or as clinically indicated a PET-CT will be performed at baseline and if positive, also at C2D1, C3D1 
and thereafter as clinically indicated. A time window of ± 3 days is allowed for the tumour assessments. A wider time window is allowed only at baseline; however assessments should be 
performed as close as possible to the 1st drug administration and if feasible, not later than 2 weeks prior to the 1st drug administration.   
28  EOT: within 14 days after the last administration of CB-103 (within the 12 cycles period or completion of the treatment period in T-ALL/T-LBL patients). All participating patients must 
complete this visit even if they have had to prematurely discontinue treatment with CB-103. 


Statistical Analysis Plan 
 
 CONFIDENTIAL 
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 Protocol Reference: CB103-C-101 
 
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29  Safety Follow-up: within 28 days after the last dose of CB-103 (within the 6 cycles period or completion of the treatment period in T-ALL/T-LBL patients). All patients must have this 
visit, even if they have prematurely discontinued CB-103 treatment. 
 
 


Statistical Analysis Plan 
 
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Protocol Reference: CB103-C-101 
 
Final, Version 2.0, 29Apr2022 
 
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8. References 
 
1ICH. Structure and Content of Clinical Study Reports, Guideline E3, 1995. Available at  
https://database.ich.org/sites/default/files/E3_Guideline.pdf 
 
2ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
https://database.ich.org/sites/default/files/E9_Guideline.pdf 
 

Prot_000.pdf: 
CONFIDENTIAL 
This document contains information that is the property of Cellestia Biotech AG, Switzerland and 
therefore is provided to you in confidence for review by you, your staff, an applicable ethics 
committee or institutional review board, and regulatory authorities. It is understood that this 
information will not be disclosed to others without written approval from Cellestia Biotech AG except 
to the extent necessary to obtain informed consent from patients (or their legal guardians) to whom 
the study treatment may be administered. 
 
 
 
 
 
 CLINICAL STUDY PROTOCOL 
 
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 LOCALLY 
ADVANCED OR METASTATIC SOLID TUMOURS AND HAEMATOLOGICAL 
MALIGNANCIES CHARACTERISED BY ALTERATIONS OF THE NOTCH 
SIGNALLING PATHWAY 
 
PROTOCOL NUMBER: CB103-C-101 
VERSION: 
4.3 
DATE FINAL: 
28 May 2021 
STUDY PHASE 
I/IIA 
EUDRACT NUMBER: 
CLINICALTRIAL.GOV:  
IND NUMBER: 
2017‐001491‐35 
NCT03422679 
141987 
 
 
TEST COMPOUND: 
CB-103 
SPONSOR: 
Cellestia Biotech AG 
Hochbergerstrasse 60C 
4057 Basel, Switzerland 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
Page 2/222 
Final Version 
Version 4.3, 28 May 2021 
 
 
CONFIDENTIAL 
May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
SPONSOR CONTACT DETAILS 
SPONSOR  
 
Cellestia Biotech AG 
Hochbergerstrasse 60C 
4057 Basel 
Switzerland 
 +41 61 633 2980 
Chief Medical Officer and 
Medical Responsible 
 
Florian Vogl, MD, PhD 
Cellestia Biotech AG 
 +41 61 633 2957  
Email: florian.vogl@cellestia.com  
Head of Clinical Operations  
 
Laura Beni, PhD 
Cellestia Biotech AG 
 +41 79 952 8696 
Email: laura.beni@cellestia.com 
Biostatistician 
 
Oliver Schoenborn-Kellenberger 
Cogitars GmbH, Heidelberg, Germany 
 +49 6221 7283362 / +49 173 6235314 
Email: oliver.schoenborn-kellenberger@cogitars.com 
MEDICAL HOTLINE 
 
Site-specific toll and toll-free telephone numbers for the 
Medical Hotline can be found in the Investigator Site File 
 
 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
Elena Garralda, MD 
Executive Director of the Early Drug 
Development Unit (UITM) 
 
Vall d' Hebron Institute of Oncology (VHIO) 
Vall d'Hebron University Hospital 
P. Vall d'Hebron 119-129 
08035 Barcelona, Spain  
 +34 93 274 60 00 
E-mail: egarralda@vhio.net 
 
 


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CLINICAL RESEARCH ORGANISATIONS (CRO) AND CENTRAL 
LABORATORY INFORMATION 
CRO 
 
Covance Clinical and Periapproval Services 
Limited 
Osprey House 
Westacott Way 
Maidenhead, SL6 3QH 
United Kingdom 
CRO (Asian countries) 
dMed Biopharmaceutical Co., Ltd. 
Room 301 building 1, 298 Xiangke Road, China 
(Shanghai) Pilot Free Trade Zone  
 
Bioanalytical Analysis of PK 
samples 
SYNLAB Analytics & Services Switzerland AG 
Sternenfeldstrasse 14 
4127 Birsfelden 
Switzerland 
ECG and Holter ECG 
ERT (Cardiac safety and imaging) 
Waversesteenweg 1945 
Chaussée de Wavre 
1160 Brussels 
Belgium 
Medical Imaging 
ERT (Cardiac safety and imaging) 
Waversesteenweg 1945 
Chaussée de Wavre 
1160 Brussels 
Belgium 
For the biomarker analyses refer to the related laboratory manuals listing the labs involved with 
all contacts details.   
  
 


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SPONSOR APPROVAL 
SIGNATURE PAGE 
 
Compound Name:  
CB-103 
Protocol Number:  
CB103-C-101 
Protocol Title:  
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 Locally Advanced or Metastatic Solid Tumours 
and Haematological Malignancies Characterised by Alterations of the NOTCH Signalling 
Pathway 
 
NAME 
TITLE 
DATE 
 
SIGNATURE 
Florian Vogl, MD, 
PhD 
Chief Medical Officer / 
Protocol Author  
 
 
 
 
Oliver Schoenborn-
Kellenberger 
Statistician, Cogitars 
GmbH, Germany 
 
 
 
 
 
 
 
 
 


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CLINICAL RESEARCH ORGANISATION APPROVAL 
SIGNATURE PAGE 
 
Compound Name:  
CB-103 
Protocol Number:  
CB103-C-101 
Protocol Title:  
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 Locally Advanced or Metastatic Solid Tumours 
and Haematological Malignancies Characterised by Alterations of the NOTCH Signalling 
Pathway 
 
NAME 
TITLE 
DATE 
 
SIGNATURE 
 
 
Victor Angélico  
 
Medical Monitor, 
Covance 
 
 
 
 
 
 
 
 


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COORDINATING INVESTIGATOR  
SIGNATURE PAGE 
 
Compound Name:  
CB-103 
Protocol Number:  
CB103-C-101 
Protocol Title:  
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 Locally Advanced or 
Metastatic Solid Tumours and Haematological Malignancies Characterised by 
Alterations of the NOTCH Signalling Pathway 
 
I agree to the terms and conditions relating to this study as defined in this protocol, 
Investigator’s Brochure, the Case Report Form (CRF), and any other protocol-related 
documents. I am aware of my responsibilities as a coordinating investigator under the 
International Council of Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and 
all applicable regulations, laws and the study protocol. I agree to conduct the study 
according to these guidelines and to appropriately direct and assist the staff under my 
control, who will be involved in the study. 
 
NAME 
DATE 
 
SIGNATURE 
Elena Garralda, MD 
Hospital Vall d'Hebron 
 
 
 
 
 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
Compound Name:  
CB-103 
Protocol Number:  
CB103-C-101 
Protocol Title:  
 
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 Locally Advanced or 
Metastatic Solid Tumours and Haematological Malignancies Characterised by 
Alterations of the NOTCH Signalling Pathway 
I agree to the terms and conditions relating to this study as defined in this protocol, 
Investigator’s Brochure, the Case Report Form (CRF), and any other protocol-related 
documents. I fully understand that any changes instituted by the Investigator(s) without 
previous agreement with the Sponsor would constitute a violation of the protocol, including 
any ancillary studies or procedures performed on the patients in this study (other than 
those procedures necessary for the well-being of the patients). 
I agree to conduct this study in accordance with the Declaration of Helsinki and its 
amendments, International Council of Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, and all applicable regulations and laws. In particular, I will obtain approval by 
an Independent Ethics Committee or Institutional Review Board (IEC/IRB) prior to study 
start and signed informed consent from all patients included in this study. In case an 
amendment to the protocol is necessary, I will obtain approval by an IEC/IRB and ensure 
approval by regulatory authorities (if applicable) has been obtained before the 
implementation of changes described in the amendment. In addition, I will allow direct 
access to source documents and study facilities to Sponsor representative(s), particularly 
monitor(s) and auditor(s),and agree to inspection by regulatory authorities or IEC/IRB 
representative(s). I will ensure that the study treatment(s) supplied by the Sponsor are 
being used only as described in this protocol. Furthermore, I confirm herewith that the 
Sponsor is allowed to enter and utilise my professional contact details and function in an 
electronic database for internal purposes and for submission to Health Authorities 
worldwide. 
Principal Investigator  
 
Date 
 
Signature 
 
Name, title 
 
 
 
 


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STUDY PROTOCOL SYNOPSIS 
TITLE: 
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 locally 
advanced or metastatic solid tumours and haematological 
malignancies characterised by alterations of the NOTCH 
signalling pathway 
 
PROTOCOL NUMBER: CB103-C-101 
VERSION: 
DATE FINAL: 
4.3  
28 May 2021  
EUDRACT NUMBER: 
CLINICALTRIAL.GOV: 
IND NUMBER: 
2017‐001491‐35 
NCT03422679 
141987 
TEST COMPOUND: 
CB-103 
STUDY PHASE: 
I/IIA 
SPONSOR: 
Cellestia Biotech AG 


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OBJECTIVES  
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 in adult patients.  
Phase I, Part A – Confirmatory Cohort: 
• 
To confirm safety of the RP2D of CB-103 as a single agent in adult patients.  
Phase IIA, Part B - Expansion: 
• 
To assess preliminary anti-tumour activity of single agent CB-103 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 activity of single agent CB-103  
• 
Part B only: 
o To further characterise safety and tolerability of the MTD/RP2D of CB-
103 in patients with selected solid tumours and haematological 
malignancies, stratified by disease into separate expansion arms. 
Exploratory Objectives 
The exploratory objectives for parts A and B of this study are: 
• 
To characterise the pharmacokinetic (PK) characteristics of CB-103 in subgroups 
of patients (e.g., by indication or ethnicity) after single and repeated administration 
at various dose levels. 
• 
To explore potential correlations between PK and parameters of efficacy (e.g. 
tumour 
response, 
tumour 
shrinkage, 
tumour 
metabolic 
activity), 
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]). 
• 
Positron Emission Tomography (PET) in selected tumours: baseline and on-
treatment, 18Fluoro-deoxyglucose positron emission tomography (FDG-PET) in 


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combination with CT (PET-CT) will be collected to determine changes in glucose 
metabolism of the tumour lesions in tumour types exhibiting FDG-uptake.  
• 
To investigate plasma levels of metabolite(s) when feasible. 
• 
To explore the CB-103 metabolic profile in biological matrices such as urine 
and/or stool samples. 
• 
To assess changes in NOTCH target and downstream PD markers (genes, 
proteins) in solid tumours:  
o pre- and post- CB-103 dosing in tumour tissue biopsies as a measure 
of NOTCH pathway inhibition; 
o pre- and post- CB-103 dosing in whole blood, plasma samples and hair 
follicles (if the appropriate laboratory is available) as a surrogate model 
to measure NOTCH pathway inhibition.  
• 
To assess changes in NOTCH target genes and downstream PD markers 
(genes, proteins) in haematological malignancies: 
o pre- and post- CB-103 dosing in T-lymphocytes from blood and/or 
bone marrow samples; 
o pre- and post- CB-103 dosing in whole blood and plasma samples (if 
the appropriate laboratory is available). 
• 
To assess the changes in the percentage of mutated alleles in liquid biopsies pre- 
and post CB-103 dosing and their relation to the effect of CB-103 treatment. 
• 
To evaluate the cerebrospinal fluid (CSF) exposure of CB-103 in patients with 
haematological malignancies in whom intra-thecal (IT) prophylaxis is planned by 
the treating physician. 
• 
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 analysis may be performed on tumour tissue samples or on blood 
and/or bone marrow samples as a part of this study to identify gene 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. 
• 
Exploratory CB-103 quantification analysis may be performed on tumour tissue 
samples.  
• 
To evaluate the potential role of biomarkers and genetic markers for safety, 
pharmacodynamic, and anti-tumour activity of CB-103 and to define the optimal 
biological dose of CB-103. 
• 
To explore and assess changes in the immune system in pre- and post-CB-103 
dosing whole blood and plasma. 
• 
Additional exploratory analyses may be performed on available samples from the 
study, for example to establish a correlation of biomarkers across methods or 
types of tissue. 


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Note: during the course of the study, sample collection for and analysis of any of the 
above-mentioned exploratory objectives may be stopped for all patients or in selected 
patients’ groups depending on the emerging preliminary data; the decision will be 
documented in a Note to File. 
STUDY DESIGN 
Description of Study 
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 a dose escalation phase and the MTD/RP2D confirmatory cohort 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. 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.  
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. 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, with at least 1 day apart from the second patient, 
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 patients are dosed in 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 the CRC consisting of the Investigators, Sponsor and CRO 
representatives, and independent functional experts as required. The CRC will make the 
decision to determine the next dose level and schedule for the next dose cohort.  
Any dose level cohort that has been declared safe after the DLT period, may be 
expanded by individual patients in order to collect additional pharmacodynamic (PD) and 
pharmacokinetic (PK) information to support and/or confirm the mechanism of action and 
explore doses at the currently tolerated dose level or below. These patients will be 


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counted for the respective cohort at the future CRC meetings and will contribute towards 
the overall safety, PK, PD and clinical efficacy evaluation. 
When the MTD/RP2D is defined, based on decision of the CRC, approximately 45  
additional 
NOTCH-positive 
patients 
(MTD/RP2D 
confirmatory 
cohort) 
with 
recurrent/metastatic 
adenoid 
cystic 
carcinomas 
(ACC), 
breast 
cancer, 
relapsed/refractory (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoma (T-
LBL), or any other solid tumour with proven Notch pathway activation will receive the 
MTD/RP2D dose to ascertain that optimal safety related to efficacy and 
pharmacodynamics in the tumour and in peripheral blood are achieved.  
Part B - 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 and confirmed. 
NUMBER OF PATIENTS 
Part A: approximately 55 patients; depending on the BLRM, additional patients may be 
enrolled in some dose cohorts. Based on the decision of the CRC approximately 45 
patients in total may be enrolled in the MTD/RP2D confirmatory cohort to confirm safety 
before opening Part B. 
Part B: 100-140 patients plus the eligible patients from the MTD/RP2D confirmatory 
cohort, resulting in 145-185 patients dosed at the RP2D.  
Total study population: 200-240 patients. 
TARGET POPULATION 
Adult patients with histologically confirmed locally advanced and/or metastatic solid 
tumours and with r/r T-ALL or T-LBL for whom no standard-of-care therapy exists. 


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INCLUSION/EXCLUSION CRITERIA 
Inclusion criteria 
Patients must meet the following criteria for study entry: 
1. Disease 
a. Histologically or cytologically confirmed solid tumours that are surgically 
unresectable, locally advanced, or metastatic which have progressed on at 
least one line of systemic therapy (with the exception of adenoid cystic 
carcinoma [ACC] patients who are allowed to be systemic treatment-naïve) 
and for which no established therapeutic alternatives exist. 
or 
b. Relapsed or refractory (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or 
lymphoma (T-LBL). Refractory patients are defined as T-ALL/T-LBL patients 
with ≥ 5% bone marrow blasts and/or concomitant extramedullary 
involvement, 
who 
have 
not 
achieved 
a 
CR 
after 
standard 
induction/consolidation therapy attempt. Relapsed patients are defined as T-
ALL/T-LBL patients who have recurrent disease, i.e. ≥ 5% bone marrow 
blasts and/or concomitant extramedullary relapse, after having achieved a 
prior CR. 
c. For Part A (dose-escalation) solid tumour indications based on known 
frequent involvement of the NOTCH pathway activation in these indications, 
and tumours with an a priori known NOTCH1-4 pathway activation are 
eligible, as defined below: 
• Breast cancer (triple negative breast cancer [TNBC], ER+/-, HER2+/-), 
gastrointestinal (GI) cancers (resistant to oxaliplatin or irinotecan-based 
therapy colorectal cancer [CRC], hepatocellular carcinoma [HCC]), 
osteosarcoma, ACC and malignant glomus tumour.  
• Any other solid cancer (including lymphoma) with a confirmed NOTCH1-
4 activating mutation or genetic lesion. 
d. For Part A (MTD/RP2D confirmatory cohort) and Part B expansion 
cohorts, solid and haematological tumour indications with confirmed Notch 
pathway activation as follows:  
 
• ACC  
• Metastatic breast cancer (regardless of receptor status of ER/PR, HER2) 
• r/r T-ALL/T-LBL  
• Any other cancer (haematologic or solid) with a confirmed NOTCH 
pathway activation, after approval by the Sponsor  
Notes:  
- Patients are eligible if Notch pathway activation was determined in the 
past. If the Notch status is unknown, it will be determined on fresh bodily 
material.  


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- The pathogenic character of the detected mutation/genetic alteration 
needs to be confirmed before the patient can be enrolled. Patients whose 
tumour mutations/alterations are not unambiguously pathogenic will be 
included at the Sponsor’s discretion. Details on molecular alterations as 
signs of Notch pathway activation and the specific test method can be 
found in the laboratory manual. 
e. Patients with solid tumours must have at least one measurable lesion (at 
least 1.0 cm in diameter) according to Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.1 guideline for solid tumours (irradiated lesions are 
only measurable if unequivocal disease progression is demonstrated). 
f. Patients with solid tumour indications in Part A (dose-escalation):  
• Sufficient archival tumour tissue samples. If the archival tissue is older 
than 6 months at screening – or, if not available – a fresh pre-dose 
tumour biopsy is required. If the lesion is not accessible for a fresh 
tumour biopsy, a liquid biopsy may be used after confirmation with the 
Sponsor.  
g. Patients with solid tumours in the MTD/RP2D confirmatory cohort of 
Part A and in Part B:  
• If Notch status is unknown, patients with solid tumours should have 
sufficient archival biopsy tissue not older than 6 months prior to pre-
screening (or, if not available, a fresh tumour biopsy must be taken) in 
order to enable the selection of the patients.  
• All solid tumour patients: tumour lesions accessible to biopsy and patient 
willing to provide a fresh tumour biopsy at pre-dose, one during 
treatment, and one at disease progression or when clinically indicated. 
In individual cases where the lesion is not accessible for a fresh tumour 
biopsy, a liquid biopsy may be used after confirmation with the Sponsor.  
h. Life expectancy of at least 3 months in the opinion of the investigator.  
2. Demography 
a. Men and women ≥ 18 years old on the day of signing informed consent. 
b. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
c. Patients able and willing to swallow capsules. 
3. Organ function and laboratory results 
Patients must have the following laboratory values (obtained within 14 days of 
enrolment): 
a. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) 
b. Alkaline phosphatase (ALP) ≤ 2.5 x ULN; if liver function abnormalities are 
due to the underlying malignancy and known bone metastases, then ALP 
must be ≤ 5 x ULN  


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c. Serum 
aspartate 
aminotransferase 
(AST/SGOT) 
and 
alanine 
aminotransferase (ALT/SGPT) ≤ 2.5 x ULN; if liver function abnormalities 
are due to the underlying malignancy and known hepatic metastases or 
bone metastases, then AST and ALT must be ≤ 5 x ULN  
d. Serum creatinine ≤ 1.5 x ULN; or if serum creatinine > 1.5 x ULN, then 
serum creatinine clearance (CrCl) ≥ 50 mL/min (estimated by Cockcroft-
Gault formula) 
e. Potassium levels within normal limits or correctable with supplements 
f. Total calcium levels (corrected for serum albumin) within normal limits or 
correctable with supplements 
g. Magnesium levels within normal limits or correctable with supplements 
h. Phosphorus levels within normal limits or correctable with supplements 
i. 
Serum albumin concentration ≥ 30 g/L 
j. 
Patients with solid tumours must have: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L  
• Haemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L) 
• Platelet count ≥ 75 x 109/L (without platelet transfusion or growth factor 
support in the preceding 7 days) 
• Partial thromboplastin time (PTT) ≤ 1.5 x ULN and international 
normalised ratio (INR) ≤ 1.3 (unless the patient is receiving therapeutic 
anticoagulants) 
4. Contraceptive measures 
a. Women of childbearing potential (WOCBP, for definition see protocol 
Section 6.2) must have a serum pregnancy test performed within a 
maximum of 7 days before start of study treatment, and a negative result 
must be documented before start of study treatment. 
b. Women of childbearing potential and men must agree to use at least two 
highly effective forms of contraception (i.e., two of the following – oral 
contraception, injectable contraceptives, mechanical contraception 
including a condom for the partner, or an intrauterine coil) and must 
continue using them throughout the entire clinical trial period and for 90 
days post-treatment completion (duration of 3 ovulatory cycles). 
Contraception must start from the day of 1st administration of CB-103. 
c. Men whose partners could be of childbearing potential must routinely use 
a condom throughout the entire clinical trial period and for 90 days post-
treatment completion (duration of sperm turnover). The partner should also 
use a reliable form of contraception such as the oral contraceptive pill or 
an intrauterine device. 
d. Azoospermic males and females with sterilisation (e.g. tubal ligation) are 
exempt from contraceptive requirements. 


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e. Women capable of becoming pregnant who are continuously not 
heterosexually active are exempt from contraceptive requirements. 
However, they must still undergo pregnancy testing as described in 
inclusion criterion “4a”. 
5. Informed consent 
a. Ability to understand the patient information and informed consent form 
(ICF) and comply with the protocol-related procedures. 
b. Signed and dated written informed consent obtained prior to performing 
any study-related procedure, including pre-screening (part A - MTD/RP2D 
confirmatory cohort - and part B) and screening. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from participation in the 
study: 
1. Medical History 
a. Patients with symptomatic CNS metastases who are neurologically unstable or 
require increasing doses of steroids to control their CNS disease. 
Note: Patients with controlled CNS metastases may participate in this study. 
The patient must have completed radiotherapy or surgery for CNS 
metastases > 2 weeks prior to study entry. Patients must be neurologically 
stable, having no new neurologic deficits on clinical examination, and no new 
findings on recent CNS imaging. If patients require steroids for management of 
CNS metastases, they must have been on a stable dose of steroids for two 
weeks preceding study entry. 
Note: Patients without clinical signs or symptoms of brain involvement are not 
required to have a computed tomography (CT)/magnetic resonance imaging 
(MRI) scan of the brain. 
Note: T-ALL/T-LBL patients with active CNS disease defined as the presence 
of CNS disease at diagnosis, and/or presence of CNS involvement-related 
symptoms, e.g. related to cranial nerve involvement, may not be included. 
b. Hypersensitivity to any of the excipients of the finished drug CB-103. 
c. Patients with unresolved nausea, vomiting, or diarrhoea of common 
terminology criteria for adverse events (CTCAE) grade ˃ 1 
d. Impairment of GI function or presence of GI disease that may significantly alter 
the absorption of CB-103 (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhoea, malabsorption syndrome, or small bowel resection) 
e. History of second or other primary cancer with the exception of: 
• Curatively treated non-melanomatous skin cancer 
• Curatively treated cervical cancer or breast carcinoma in situ 


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• Other primary solid tumour treated with curative intent and no known active 
disease present and no treatment administered during the last 2 years 
2. Exclusionary concurrent medical conditions 
a. Impaired cardiac function or clinically significant cardiac diseases, including 
any one of the following: 
1. Clinically significant cardiac disease including congestive heart failure (New 
York Heart Association [NYHA] class III or IV), arrhythmia or conduction 
abnormality requiring medication, or cardiomyopathy  
2. Clinically uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg 
or diastolic blood pressure ≥ 100 mmHg) 
3. Complete left bundle branch block 
4. Right bundle branch block + left anterior hemiblock  
5. Mandatory use of a cardiac pacemaker 
6. Congenital long QT syndrome 
7. History or presence of sustained or symptomatic ventricular tachyarrhythmia 
8. Presence of atrial fibrillation  
9. Clinically significant resting bradycardia (< 50 bpm) 
10. Corrected QT interval using Fridericia formula (QTcF) > 450 ms for males 
and > 470 ms for females at the screening ECG 
11. QRS ≥ 110 ms 
12. History of symptomatic congestive heart failure 
13. Left ventricular ejection fraction (LVEF) < 50%. History of absolute decrease 
in LVEF of ≥ 15 absolute percentage points, or ≥ 10 absolute percentage 
points and crossing from > lower limits of normal (LLN) to < LLN on prior 
anti-cancer therapy (e.g., anti-HER2 therapy, anthracyclines), even if 
asymptomatic 
14. Angina pectoris ≤ 6 months prior to starting study drug 
15. Acute myocardial infarction (MI) ≤ 6 months prior to starting study drug 
b. General conditions or other clinically significant diseases, including any one of the 
following: 
1. Haemorrhagic, embolic, or thrombotic stroke within 6 months prior to the 
first planned CB-103 treatment 
2. For patients with solid tumours: prior bone marrow/haematopoietic stem 
cell transplant. 
Note: For T-ALL patients prior allogenic bone marrow/haematopoietic 
stem cell transplant is allowed if they have no current GvHD and patients 
are off immunosuppressive therapy. 


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3. Known infection with human immunodeficiency virus (HIV); or hepatitis B 
or C requiring treatment 
4. Any active infection requiring the use of parenteral anti-microbial agents 
or that is > Grade 2 
5. Non-malignant interstitial lung disease or pneumonitis 
6. Dyspnoea of any cause requiring supplemental oxygen therapy and 
dyspnoea at rest due to complications of advanced malignancy and co-
morbidities. 
7. Significant traumatic injury or major surgery (major surgery means opening 
of a body cavity, e.g., thoracotomy, laparotomy, laparoscopic organ 
resection, and major orthopaedic procedures, e.g. joint replacement, open 
reduction and internal fixation) within 14 days of scheduled dosing day 1. 
8. Other concurrent severe and/or uncontrolled medical conditions (e.g. 
uncontrolled diabetes, active or uncontrolled infection) that could cause 
unacceptable safety risks or compromise compliance with the protocol. 
3. Prior Therapy 
a. In patients with solid tumours, cytotoxic chemotherapy within 3 weeks (6 weeks 
for nitrosoureas and mitomycin C) of the scheduled first dose of CB-103 on day 
1.  
b. In T-ALL/T-LBL patients, prior anticancer therapy less than 2 weeks prior to 
starting therapy or 5 half-lives (whichever is longer) with the following 
exceptions: 
1. Up to 5 days of glucocorticoids (10 mg/m2 dexamethasone or 
equivalent/day) in combination with up to 3 doses of cyclophosphamide 
(200 mg/m2/day) are allowed as standard prephase treatment up to 1 day 
before start of study treatment 
2. Mercaptopurine may be dosed up to 5 days prior to first dose of CB103 
3. Vinca alkaloids may be dosed up to 5 days prior to first dose of CB103 
4. Prophylactic intrathecal (IT) chemotherapy may be dosed up to 3 days 
prior to first dose of CB103. 
c. Prior cumulative doxorubicin exposure of ≥ 500 mg/m2 
d. Prior cumulative epirubicin exposure of ≥ 900 mg/m2 
e. Any investigational treatment (including NOTCH signalling inhibitors and prior 
treatments with CB-103) within 4 weeks of scheduled CB-103 dosing day 1.    
f. Concurrent enrolment in another therapeutic clinical trial involving ongoing 
therapy with any investigational or marketed product or placebo. 
g. Radiation therapy within 2 weeks of scheduled CB-103 dosing day 1, unless 
the radiation comprised a limited field to non-visceral structures (e.g. a limb 
bone metastasis). 


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h. Immunotherapy (including interferons, interleukins, immune-conjugates, 
immune checkpoint inhibitors), biological therapies (including monoclonal 
antibodies, antibody drug conjugates or other engineered proteins), targeted 
small molecules (including but not limited to kinase inhibitors), hormonal 
therapies within 3 weeks of scheduled CB-103 dosing day 1. 
i. 
Unresolved toxicity CTCAE grade > 1 from previous anti-cancer therapy or 
radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia, or 
other adverse event associated with leukemic involvement), or incomplete 
recovery from previous surgery, unless agreed by Sponsor and the Principal 
Investigator and documented. 
4. Concomitant medications 
a. Drugs which prolong QT interval, either with a known or a conditional/ possible 
risk to induce Torsades de Pointes (a list of drugs is given in Appendix 4 of the 
protocol). However, in case of a life-threatening infection, in the best interest of 
the patient, concomitant treatment with the study drug and the relevant anti-
infectious drug, though this may be included in the list given in Appendix 4, 
can be continued with closer monitoring. 
b. Patients receiving warfarin and phenytoin that cannot be discontinued at least 
one week prior to start of treatment with CB-103 and for the duration of the 
study. 
c. Anticoagulants: Patients receiving coumarin-type anticoagulants who cannot 
discontinue at least one week prior to start of treatment and for the duration of 
the study. Low molecular weight heparin and direct oral anticoagulants are 
permitted. 
5. Demography 
a. Patients who are pregnant or breast feeding. 
6. Others 
a. Patients who are unable or unwilling to comply with all study requirements for 
clinical visits, examinations, tests, and procedures. 
DURATION OF STUDY 
The study will be completed 28 days after the last patient in Part B of the study received 
the last treatment. 
END OF STUDY 
The end-of-study is reached when the last patient in Part B of the study has been on 
study treatment for up to 12 cycles plus the safety follow-up period of 28 days after the 
last dose of CB-103. In case the study is stopped before any patient was treated for 
12 months, the end-of-study is reached 28 days after the last patient in Part B of the 
study has received his/her last dose of CB-103. 
 


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DOSE-LIMITING TOXICITY (DLT) 
DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated 
to disease progression, inter-current illness, or concomitant medications, that occurs 
≤ 28 days following the first dose of CB-103 (Cycle 1) and that meets any of the following 
criteria shown in the table below.  
Note: For T-ALL/T-LBL patients enrolled into the confirmatory cohort of Part A or 
expansion cohort of Part B of the study, haematological toxicity in non-responding 
patients, or death after progression should not be considered as DLT. 
Toxicity 
Any of the following criteria 
Haematology 
≥ CTCAE grade 3 neutropenia (ANC < 1.0 x 109/L) lasting for > 7 days1 
≥ CTCAE grade 4 neutropenia (ANC < 0.5 x 109/L)1 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 38.3°C) 1 
CTCAE grade 3 thrombocytopenia (platelets < 50-25 x 109/L) lasting for 
≥ 7 days and/or with signs of bleeding1 
CTCAE grade 4 thrombocytopenia (platelets < 25 x 109/L)1 
≥ CTCAE grade 4 anaemia1 
Cardiac 
≥ CTCAE grade 3 
≥ CTCAE grade 3 hypertension for > 14 consecutive days despite optimal 
anti-hypertension therapy 
Renal 
Serum creatinine > 2 x ULN 
Hepatic 
≥ CTCAE grade 3 total bilirubin (>3 x ULN) 
CTCAE grade 2 total bilirubin lasting for ≥ 7 days. 
≥ CTCAE grade 2 total bilirubin and ≥ CTCAE grade 2 ALT or AST 
CTCAE grade 3 ALT or AST lasting for > 7 days 
CTCAE grade 4 ALT or AST  
Hepatic lab parameters fulfilling Hy’s Law: AST/ALT 3 x ULN and 
concomitant 2 x ULN for bilirubin2 
Pancreatic 
≥ CTCAE grade 3 pancreatitis 
CTCAE grade 3 asymptomatic serum lipase lasting for ≥ 7 days 
CTCAE grade 3 symptomatic serum lipase  
CTCAE grade 4 serum lipase  
Other 
adverse 
events 
Any CTCAE grade 5 toxicity 
≥ CTCAE grade 3 blurred vision or any other eye disorder 
≥ CTCAE grade 3 vomiting or nausea for ≥ 72 hours despite optimal anti-
emetic therapy3 
≥ CTCAE grade 3 diarrhoea for ≥ 72 hours despite optimal anti-diarrhoea 
treatment3 


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Any other ≥ CTCAE grade 3 adverse event, except for the exclusions noted 
below 
Inability to administer CB-103 on ≥ 75% of scheduled treatment days during 
cycle 1 (i.e., ≥ 21 days for a 28-day daily dosing schedule) due to 
unresolved adverse event of any grade related to CB-103. 
Delay in 2nd cycle administration due to failure of recovery from a possibly, 
probably or definitely related adverse event to grade ≤ 1 or baseline by Day 
43 (D28 of cycle 1 + 15 days), except for alopecia. 
Exceptions 
to 
DLT criteria 
CTCAE grade 3 or 4 elevations in alkaline phosphatase 
< 96 hours of CTCAE grade 3 fatigue 
Investigations (e.g., laboratory values) CTCAE grade ≥ 3 which are judged 
not clinically significant by the Investigator4 
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate 
aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-
limiting toxicity; PRBC, packed red blood cells; ULN, upper limit of normal. 
NCI CTCAE v4.03 will be used for all grading. 
1 Patients may receive supportive care (e.g. use of granulocyte-colony stimulating factor 
[G-CSF], packed red blood cells (PRBCs), platelets) as per local institutional guidelines. 
However, during the DLT period it is not allowed to administer these supportive measures 
prophylactically. 
2 Patients fulfilling the criteria for Hy`s law will need to be immediately discontinued from 
treatment 
3 Optimal therapy for vomiting or diarrhoea will be based on institutional guidelines and based 
on Section 7.4.7, with consideration of the prohibited medications listed in the protocol. 
4 An abnormal lab value / investigation should be deemed clinically significant (assessed by 
the Investigator) if either of the following conditions is met:   
• 
The abnormality suggests a disease and/or organ toxicity that is new or has worsened 
from baseline 
• 
The abnormality is of a degree that requires additional active management, e.g., 
change of dose, discontinuation of the drug, close observation, more frequent follow-
up assessments, or further diagnostic investigation.  
Therefore, a clinically significant lab value is one that indicates a new disease process, an 
exacerbation or worsening of an existing condition, or requires further action(s) to be taken. 
 
During the MTD/RP2D confirmatory cohort of Part A of the study and during Part B, 
the study will use the CTCAE version 4.03 criteria to capture toxicities and these will 
be managed, and dose modified as described in Section 7.4.6. The CRC will review 
at least on a quarterly basis all CTCAEs ≥ grade 3, all SAEs, all clinically significant 
laboratory abnormalities and all available safety data to confirm the proposed dose for 
the expansion part is safe and well tolerated. The CRC will recommend, if necessary, 
to pause enrolment or implement additional safety monitoring while such a review is 
undertaken.  
All decisions made by the CRC will be captured in meeting minutes. 


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PRIMARY OUTCOME MEASURES 
The primary outcome measures for this study are as follows: 
Part A (Escalation):  
• 
Dose limiting toxicities (DLT) 
Part B (Expansion):  
• 
Best overall response according to the respective tumour assessment criteria for 
the different cancer indications 
SECONDARY OUTCOME MEASURES 
The secondary outcome measures for this study are as follows: 
• 
Safety 
a. Adverse events 
b. Safety laboratory 
c. Vital signs 
d. Electrocardiogram 
• 
Preliminary efficacy 
a. Overall response rate 
b. Clinical benefit rate at Month 3, 6, and 9 
c. Duration of response 
d. Progression free survival (PFS) and overall survival (OS) 
PHARMACOKINETIC OUTCOME MEASURES (SECONDARY) 
The PK outcome measures are: 
• 
Maximum plasma concentration (Cmax), time to Cmax (tmax), minimum plasma 
concentration (Cmin), last measurable plasma concentration (Clast), time to last 
measurable plasma concentration (tlast), area under the curve (AUC) during 8 and 
24 hours (AUC0-8, AUC0-24), AUC from time 0 extrapolated to infinite time (AUC0-∞
), apparent volume of distribution (Vd/F), apparent volume of distribution at steady 
state (Vss/F), apparent clearance after oral administration (CL/F), elimination 
half-life (t1/2) and accumulation ratio (AR). 
PHARMACOKINETIC/ PHARMACODYNAMIC OUTCOME MEASURES 
(EXPLORATORY) 
The PK/PD measures for this study are as follows: 
• 
Association of CB-103 plasma concentrations and/or PK parameters (e.g., AUC, 
Cmax) with signs of efficacy, PD parameters and safety. 
FURTHER EXPLORATORY OUTCOME MEASURES 
Further exploratory outcomes measures for this study are: 
• 
Additional PK, metabolite, PD markers, genomic, protein , and pharmacogenetics 
analyses (separate analysis plan and report). 


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BIOMARKER OUTCOME MEASURES (EXPLORATORY) 
The biomarker outcomes measures for this study are: 
• 
Summary statistics of PD, mechanistic and tumour profiling biomarkers will be 
reported by dose group and may be examined for possible correlations with 
CT/MRI/positron emission tomography (PET)-CT outcomes. 
BIOMARKER/GENOTYPING SAMPLE COLLECTION 
Remaining blood and/or tumour tissue samples may be used for DNA, RNA and/or 
protein-based analyses. Details regarding the biomarkers analysed will be provided in a 
separate Laboratory Manual. 
INVESTIGATIONAL MEDICINAL PRODUCT 
Test product: CB-103 
Placebo: Not applicable 
PROCEDURES 
Informed consent will be obtained prior to any study-specific procedures. Following 
eligibility at screening and the confirmation at baseline, patients will be enrolled into the 
study. The assessments and examinations will be conducted as described in the 
Schedules of Assessments for Part A (Escalation) and Part B (Expansion). 
Assessments as deemed necessary by the Investigator and/or Sponsor/its delegate 
clinical research organisation (CRO) Covance in particular for safety and any other 
additional examinations and assessments deemed necessary, can be performed at 
unscheduled visits at the discretion of the Investigator and Sponsor/delegate CRO 
Covance. 
Patients who complete the study will be followed-up for survival. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
Part A (Escalation):  
• 
Bayesian Logistic Regression Model for dose escalation to determine MTD or 
RP2D. 
Part B (Expansion):  
• 
Bayesian hierarchical partially exchangeable binomial design to determine 
preliminary efficacy. 
 
 


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SAFETY ANALYSES 
Adverse events, related adverse events, serious adverse events and related serious 
adverse events, adverse events with NCI CTCAE Grades ≥ 3, related adverse events 
with NCI CTCAE Grades ≥ 3, adverse events leading to premature discontinuation, 
interruptions or discontinuation of study drug or dose modification will be analysed 
descriptively utilising corresponding Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Classes (SOCs) and Preferred Terms (PTs). 
Safety laboratory results will be graded by NCI CTCAE version 4.03, if no grading exists 
values will be classified into low/normal/high based on laboratory normal ranges. Each 
parameter will be presented by descriptive statistics at each visit including change from 
baseline (screening). Shift tables for CTCAE grades and normal ranges will be 
presented. All laboratory values will be listed. A separate listing for abnormal lab values 
(Grade 3 and higher, and low/high values) will be presented. 
Vital signs will be summarised by descriptive statistics at each visit including change 
from baseline; these will be presented, and a listing will be provided.  
Centrally-read ECG data will be listed overall and a separate listing for any clinically 
significant finding in ECG values will be provided. Change from baseline in QT intervals 
by cohort will be summarised for each visit as well as change from baseline in all other 
ECG parameters. Also, the worst change from baseline will be summarised. The 
frequency and percentage of patients with notable ECGs and newly occurring qualitative 
ECG abnormalities will be tabulated by cohort. 


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EFFICACY ANALYSES 
Overall response rate as defined by achieving: 
• 
In solid tumours, confirmed complete response (CR) and/or partial response (PR) will 
be presented by percentage rates and 95% confidence intervals (CI). For changes in 
solid tumour size, waterfall plots will be presented. 
• 
In T-ALL/T-LBL patients, confirmed Complete Remission (CR) and/or Complete 
Remission with Incomplete Hematologic Recovery (CRi) will be presented by 
percentage rates and 95% CI. 
• 
For solid tumour indications: clinical benefit rate at Month 3, 6, and 9, as defined by 
achieving complete response (CR) and/or partial response (PR) and/or stable disease 
(SD) will be assessed by RECIST 1.1 and presented by percentage rates and 95% CI. 
Waterfall plots will be presented. 
• 
For T-ALL/T-LBL patients: the ORR is the sum of patients achieving a CR or a CRi 
divided by the total number of patients with T-ALL/T-LBL treated. Assessment of 
efficacy will be performed on results of bone marrow biopsies or aspirates, blood and 
CSF samples, and PET-CT in patients with extramedullary disease, based on the 
NCCN Guidelines on Adult Acute Lymphoblastic Leukemia (Version 1.2020). 
For all response assessments, swimmers plots will be presented. All response 
assessments will be listed. 
The duration of response defined as time from first assessment of PR or CR in solid 
tumours or CRi in T-ALL/T-LBL to follow-on first assessment of PD or relapse will be 
summarised by descriptive statistics including median duration of response and 
respective 95% CI. Duration of response will also be listed. 
Time from first treatment received until progressive disease (PD)/OS will be summarised 
by Kaplan-Meier estimates, median PFS/OS and respective 95% confidence intervals. 
Patients with no event will be censored at the last available tumour assessment for PFS 
and at the last timepoint known alive for OS. 
PHARMACOKINETIC ANALYSES 
CB-103 concentrations will be determined by a validated high-performance liquid 
chromatography (HPLC) tandem mass spectrometry (LC/MS/MS) method and the 
following PK parameters of CB-103 including:  Cmax, tmax, Cmin, Clast, tlast, AUC0-8, AUC0-
24, AUC0–∞, Vd/F, Vss/F, CL/F, t1/2 and AR.  All PK parameters will be calculated from the 
curves constructed from the individual patients. Non-compartmental analysis will be 
performed using Phoenix WinNonlin version 6.3 (Pharsight Corporation, Mountain View, 
CA, USA). 
No formal statistical analysis beyond descriptive statistics is planned. For each PK 
parameter, individual and mean data and summary statistics (including number of 
patients, arithmetic mean, geometric mean [for time to maximum plasma concentration 
(tmax) and time to last measurable plasma concentration (tlast) no geometric mean will be 


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calculated], standard deviation (StD), confidence value (CV), median, Min and Max) will 
be presented.  
EXPLORATORY ANALYSES 
Exploratory PK assessments, plasma levels of metabolite(s), PD markers (genes, 
proteins) in tumour tissue biopsies and in whole blood, plasma samples and hair follicles, 
genotypes, protein expression, and circulating tumour DNA in blood samples will be 
analysed post-hoc by Sponsor or by a delegated Laboratory or investigational site. With 
the PK timepoints collected, a population PK model will be built and then used to estimate 
individual AUCs or CL of CB-103. CB-103 AUC, as well as the observed Cmax, will then 
be tested for association with signs of efficacy and safety. A separate analysis plan and 
report for such assessments will be written.  
BIOMARKER ANALYSES 
Summary statistics of PD, mechanistic and tumour profiling biomarkers will be reported 
by dose group and may be examined for possible correlations with CT/MRI/PET-CT 
efficacy endpoints. Additional analyses include comparing PD modulation with exposure.  
SAMPLE SIZE JUSTIFICATION 
Part A (Escalation) 
For all dose levels, from starting dose to the respective dose escalation levels, 3-6 
patients will be enrolled and treated with CB-103 according to a staggered inclusion 
scheme to ensure adequate time for safety observation between inclusions, and before 
dose escalation. During the study, a minimum of 3 patients evaluable for the DDS will be 
treated per dose cohort until determination of the MTD or RP2D. Depending on the 
BLRM, additional patients may be enrolled in some dose cohorts. Approximately 11 dose 
cohorts are considered for this study with at least 3 patients per dose cohort. It is 
estimated that approximately 55 patients will be enrolled, not taking into account the 
drop-outs and additional patients enrolled for some of the dose groups. Based on the 
decision of the CRC, approximately 45 patients may be enrolled in the MTD/RP2D 
confirmatory cohort to confirm safety before opening Part B. 
Part B (Expansion) 
Part B of the study will consist of one or several expansion arm(s) with selected tumour 
indications. For the analysis of the expansion arms a Bayesian Hierarchical binomial-
design will be applied with enrolment of at least 10 patients into each arm. With 10-20 
patients enrolled into each expansion arm it is estimated that about 100-140 patients 
(pending of the number of arms) will need to be recruited. Patients from the MTD/RP2D 
confirmatory cohort of Part A that qualify for any of the expansion arms will be included 
into the analyses of Part B and will contribute to the total sample size per arm.  
20 patients per indication arm will give sufficient evidence to determine early signs of 
clinical benefit. Assuming a true response rate of 30% for exchangeable and partially-
exchangeable indications (based on response criteria) the lower limit of the credible band 
for the point estimate would be greater than or equal to 19%.  


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The following indications for patients with NOTCH activated pathways are considered 
and grouped into the respective expansion arms:  
1. Adenoid cystic carcinoma (ACC)  
2. Triple negative breast cancer (TNBC) 
3. Breast cancer (ER+/-, HER2+/-) 
4. Osteosarcoma, Malignant glomus tumour 
5. GI cancers (resistant to oxaliplatin or irinotecan-based therapy colorectal cancer, 
hepatocellular carcinoma) 
6. r/r T-cell Acute Lymphoblastic Leukaemia (T-ALL) or T-cell Lymphoblastic 
Lymphoma (T-LBL) 
7. Any other cancer (haematologic or solid) with confirmed Notch pathway activation 
(basket arm) 
The indications considered for the expansion arms in Part B might be adapted and/or 
additional arms added by a protocol amendment based on the outcome of Part A and 
further findings from non-clinical studies with CB-103 and the planned interim analysis; 
this might increase the planned sample size. 
Interim Analyses 
Part A (Escalation) 
Each dose escalation step is considered to be an interim analysis. The BLRM will be 
updated with the respective number of patients treated and the number of DLTs 
observed in the last cohort. The updated model will then give a statistical 
recommendation for the next escalation step. However, a risk-benefit assessment that 
includes a comprehensive analysis of safety and available clinical information will be 
done to decide on the next escalation steps. 
Part B (Expansion) 
Interim analyses will be triggered each time 10 patients in an arm have completed their 
first response assessment, this includes patients from the MTD/RP2D confirmatory 
cohort of Part A that qualify for any of the extension arms. An interim analysis will include 
all patients enrolled at, or prior to the cut-off (set by the completion of the 10th patient), 
and will be conducted once all patients have completed sufficient assessments to be 
categorised under the response endpoint, or have withdrawn from study. All arms that 
remain open to recruitment, and for which the minimum data efficacy requirements have 
been met, will be assessed for futility. For the interim and final analyses, a hierarchical 
model will be used. This model leads to more precise estimates of the indication-specific 
treatment effects as compared to those from stratified analyses. Details of the model can 
be found above, and further descriptions are given in Appendix 10 of the protocol. The 
results of the interim analyses will be non-binding. Safety criteria will also be evaluated 
to decide on the continuation of the study arms. Since this is a non-comparative multiple 
arm study, no adjustment for multiple testing is made. 


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LIST OF PROHIBITED MEDICATIONS 
The following medications are strictly prohibited in this study: 
Prior concomitant therapy 
Patients who have received any of the therapies and medications prior to study entry as 
outlined in the exclusion criteria under point 3, “Prior Therapy” are not allowed to be 
enrolled in this study. 
Concomitant medications 
• 
Drugs with a known risk to induce Torsades de Pointes: 
All QT-prolonging drugs (see Table 1 in Appendix 4) of the protocol) are prohibited 
for all patients from screening through permanent discontinuation of study treatment. 
• 
Drugs with a conditional risk to induce Torsades de Pointes: 
The concomitant use of any QT prolonging medication with a conditional risk of 
inducing Torsades de Pointes (see  Table 2  in Appendix 4) is allowed during the 
DLT period and throughout the treatment period, ONLY under the exceptions 
described in Section 7.4.7 for the management of diarrhoea and nausea. These 
exceptions will have to be discussed upfront with the Sponsor on a case-by-case 
basis.  
• 
Drugs with a possible risk to induce Torsades de Pointes: 
The concomitant use of any QT prolonging medication with a possible risk of 
inducing Torsades de Pointes (see Table 3 in Appendix 4) is not allowed during the 
DLT period and should be used with caution and under special attention throughout 
the treatment period before more safety information about CB-103 is collected.  
However, in case of a life-threatening infection, in the best interest of the patient, 
concomitant treatment with the study drug and the relevant anti-infectious drug, 
though this may be included in the list given in Appendix 4, can be continued with 
closer monitoring. 
List of drugs that should be used with caution: 
• 
Drugs that are metabolised by cytochrome p450 (CYP450) 
Caution should be exercised when CB-103 is combined with sensitive substrates of 
CYP enzymes and CYP substrates with a narrow therapeutic index (see examples 
in Table 1 of Appendix 5 of the protocol). 
• 
Drugs that are inhibitors or inducers of CYP450  
Strong inhibitors and inducers of CYP isoenzymes should be avoided during 
treatment with CB-103 (Table 1 in Appendix 6 of the protocol). 
• 
Drugs that affect serotonin levels 
Caution should be exercised when compounds that affect serotonin levels (e.g., 
SSRIs, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, 
tryptophan, dextromethorphan, meperidine) are combined with CB-103. 


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• 
Anticoagulants  
Patients receiving coumarin-type anticoagulants who cannot discontinue treatment 
at least one week prior to the start of treatment with CB-103 and for the duration of 
the study. Low molecular weight heparin and direct oral anticoagulants are 
permitted. 
 
 
 
 


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Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
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TABLE OF CONTENTS  
SPONSOR CONTACT DETAILS ..................................................................................... 2 
COORDINATING INVESTIGATOR ................................................................................. 2 
CLINICAL RESEARCH ORGANISATIONS (CRO) AND CENTRAL 
LABORATORY INFORMATION .............................................................................. 3 
STUDY PROTOCOL SYNOPSIS .................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 39 
1. 
INTRODUCTION ................................................................................................... 45 
2. 
BACKGROUND INFORMATION ........................................................................... 45 
2.1 
NOTCH Signalling Pathway ........................................................... 45 
2.2 
NOTCH Signalling in Cancer .......................................................... 47 
2.3.1 
Advanced and Metastatic Solid Tumours ....................................... 51 
2.3.2 
Acute Lymphoblastic Leukaemia / Lymphoma ................................ 52 
2.4 
NOTCH Targeting therapies ........................................................... 53 
2.5 
CB-103 – pan-NOTCH Targeting Drug Candidate .......................... 56 
2.5.1 
Mechanism of Action ...................................................................... 56 
2.5.2 
Non-Clinical Pharmacology ............................................................ 56 
2.5.2.1 Safety Pharmacology ..................................................................... 56 
2.5.3 
Pharmacokinetics ........................................................................... 58 
2.5.3.1 Animal Pharmacokinetics and Drug Metabolism ............................ 58 
2.5.3.2 Prediction of Human PK from Non-Clinical Studies 
(Allometric Scaling) ...................................................................................... 59 
2.5.4 
Animal Toxicology and Toxicokinetics ............................................ 60 
2.5.5 
Biomarker Development ................................................................. 61 
2.5.5.1 Patient Profiling Biomarkers ........................................................... 61 
2.5.5.2 Pharmacodynamic Markers of NOTCH Inhibition ........................... 62 
2.5.5.3 Pharmacodynamic Markers of Cellular Effects ............................... 63 
2.5.6 
Clinical Experience ......................................................................... 63 
2.5.6.1 Risk Mitigation Strategies............................................................... 65 
2.5.6.2 Drug-Drug Interaction Potential ...................................................... 65 
3. 
STUDY RATIONALE AND PURPOSE .................................................................. 67 
3.1 
STUDY RATIONALE ...................................................................... 67 
3.2 
Potential Risks and Benefits ........................................................... 67 


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3.3 
Conduct of Study ............................................................................ 70 
4. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 71 
4.1 
Study Objectives ............................................................................ 71 
4.1.1 
Primary Objectives ......................................................................... 71 
4.1.2 
Secondary Objectives .................................................................... 71 
4.1.3 
Exploratory Objectives ................................................................... 71 
4.2 
Study Endpoints ............................................................................. 73 
4.2.1 
Primary Endpoints .......................................................................... 73 
4.2.2 
Secondary Endpoints ..................................................................... 73 
4.2.3 
Exploratory Endpoints .................................................................... 74 
5. 
STUDY DESIGN ................................................................................................... 76 
5.1 
Description of Study ....................................................................... 76 
5.1.1 
Overview of Study Design .............................................................. 76 
5.1.1.1 Study Periods ................................................................................ 78 
5.1.2 
Study Duration ............................................................................... 81 
5.1.3 
End of Study ................................................................................... 81 
5.1.4 
Committees .................................................................................... 81 
5.1.4.1 Cohort Review Committee ............................................................. 81 
5.2 
Investigational Sites ....................................................................... 82 
6. 
STUDY POPULATION .......................................................................................... 83 
6.1 
Recruitment Procedures ................................................................. 84 
6.1.1 
Inclusion Criteria ............................................................................ 84 
6.1.2 
Exclusion Criteria ........................................................................... 88 
6.2 
Criteria for Women of Childbearing Potential .................................. 91 
6.3 
Numbering of Patients and Investigational Sites ............................. 91 
7. 
STUDY TREATMENT ........................................................................................... 93 
7.1 
Formulation .................................................................................... 93 
7.2 
Packaging, Labeling and Handling ................................................. 93 
7.3 
IMP Storage and Dispensing .......................................................... 93 
7.3.1 
IMP Accountability .......................................................................... 94 
7.4 
Dosage and Treatment Schedule ................................................... 95 
7.4.1 
Justification of Starting Dose in Dose Level 1 ................................. 96 


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7.4.2 
Dose Escalation and Maximum Exposure ...................................... 96 
7.4.3 
Criteria for Dose Escalation and Determination of the 
Maximum Tolerated Dose .................................................................................. 98 
7.4.4 
Dose-Limiting Toxicity (DLT) .......................................................... 99 
7.4.5 
Dose Modifications, Dose Delays and Treatment 
 
Discontinuation ............................................................................. 100 
7.4.6 
Follow-up for Dose-Limiting Toxicities .......................................... 101 
7.4.6.1 Follow-up Evaluations and Dosing Modifications for 
 
Toxicities ...................................................................................... 101 
7.4.6.1.1 Haematologic Toxicities for Solid Tumour 
 
Patients ............................................................................... 101 
7.4.6.1.2 Renal Toxicities ................................................................... 102 
7.4.6.1.3 Hepatic Toxicities ................................................................ 103 
7.4.6.1.4 Ocular/Vision-related Toxicities ........................................... 105 
7.4.6.1.5 Cardiac Toxicities ................................................................ 105 
7.4.6.1.6 Gastro-Intestinal Toxicities (Diarrhoea, Nausea) ................. 107 
7.4.6.1.7 Non-Laboratory Toxicities ................................................... 108 
7.4.7 
Diarrhoea and Nausea Management Plan .................................... 108 
7.4.7.1 First Report of Diarrhoea ............................................................. 110 
7.4.7.2 Management of Diarrhoea ........................................................... 110 
7.4.7.3 Treatment of Diarrhoea Grade 1 or 2 ........................................... 111 
7.4.7.4 Treatment of Diarrhoea Grade 3 or 4 ........................................... 112 
7.4.7.5 Diarrhoea Workup ........................................................................ 112 
7.4.8 
Sample Size in Part A and Part B ................................................. 113 
7.5 
Concomitant Therapy ................................................................... 114 
7.5.1 
Permitted Concomitant Therapy ................................................... 114 
7.5.2 
Prohibited Concomitant Therapy .................................................. 114 
8. 
VISIT SCHEDULE AND STUDY ASSESSMENTS .............................................. 115 
8.1 
Description of Study Assessments ............................................... 115 
8.1.1 
Eligibility Screening ...................................................................... 117 
8.1.2 
Information to be Collected on Screening Failures ....................... 117 
8.1.3 
Medical History and Demographic Data ....................................... 117 
8.1.4 
Disease History ............................................................................ 117 


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8.2 
Safety Assessments ..................................................................... 117 
8.2.1 
Adverse Events ............................................................................ 118 
8.2.2 
Physical Examination, Weight, Height and Vital Signs .................. 119 
8.2.2.1 Weight and Height ....................................................................... 120 
8.2.2.2 Physical Examinations ................................................................. 120 
8.2.2.3 Vital Signs .................................................................................... 121 
8.2.2.4 ECOG Performance Status .......................................................... 121 
8.2.3 
Cardiac Assessments ................................................................... 122 
8.2.3.1 Blood Pressure and Heart Rate ................................................... 122 
8.2.3.2 Electrocardiograms (ECG) and Holter Safety 
 
Monitoring .................................................................................... 122 
8.2.3.3 Cardiac Imaging – ECHO or MUGA ............................................. 127 
8.2.3.4 Cardiac Laboratory – Cardiac Markers......................................... 127 
8.2.4 
Laboratory Safety Assessments ................................................... 127 
8.3 
Efficacy Assessments .................................................................. 129 
8.4 
Pharmacokinetic Assessments ..................................................... 130 
8.4.1 
PK Sample Collection for BID Dosing Regimens of  .....................CB-
103 
131 
8.4.2 
PK Sub-study ............................................................................... 132 
8.4.3 
PK in CSF .................................................................................... 132 
8.5 
Pharmacodynamic/Biomarker Assessments ................................. 133 
8.5.1 
Tumour tissue in Patient with Solid Tumours ................................ 133 
8.5.2 
Hair follicles in patients with solid tumours ................................... 133 
8.5.3 
Whole blood plasma and saliva .................................................... 134 
8.6 
Positron Emission Tomography (PET) in Patients with 
Breast Cancer or T-ALL/T-LBL with Extramedullary 
Disease ........................................................................................ 134 
8.7 
Drug Metabolism and Genetics .................................................... 135 
8.8 
Optional Biomarker Studies on Additional or 
Remaining Samples ..................................................................... 135 
8.9 
Assays and Diagnostic Methods for Characterisation 
of the NOTCH Pathway ................................................................ 135 
8.10 
Timing of Study Assessments ...................................................... 136 
8.10.1 
Screening and Pre-treatment Assessments .................................. 136 


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8.10.2 
Assessments during Treatment .................................................... 136 
8.10.3 
Assessments at Study Completion ............................................... 136 
8.10.4 
Assessments at Unscheduled Visits ............................................. 136 
8.11 
Patient, Study, and Site Discontinuation ....................................... 137 
8.11.1 
Patient Discontinuation ................................................................. 137 
8.11.1.1 Discontinuation from Study Drug and Withdrawal 
from the Study ............................................................................................ 137 
8.11.2 
Study and Site Discontinuation ..................................................... 138 
9. 
ASSESSMENT OF SAFETY ............................................................................... 139 
9.1 
Safety Parameters and Definitions ............................................... 139 
9.1.1 
Adverse Events ............................................................................ 139 
9.1.2 
Serious Adverse Events ............................................................... 139 
9.1.3 
Non-Serious Adverse Events of Special Interest .......................... 140 
9.2 
Safety Plan ................................................................................... 140 
9.2.1 
Safety Precautions ....................................................................... 140 
9.2.2 
Dose-Limiting Toxicity (DLT) ........................................................ 141 
9.2.3 
Cardiac Monitoring ....................................................................... 141 
9.2.4 
Criteria for Withdrawal from the Study .......................................... 141 
9.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ........................................................................ 142 
9.3.1 
Adverse Event Reporting Period .................................................. 142 
9.3.2 
Eliciting Adverse Event Information .............................................. 142 
9.3.3 
Assessment of Severity of Adverse Events .................................. 142 
9.3.4 
Assessment of Causality of Adverse Events ................................. 143 
9.3.5 
Procedures for Recording Adverse Events ................................... 144 
9.3.5.1 Diagnosis versus Signs and Symptoms ....................................... 144 
9.3.5.2 Adverse Events Occurring Secondary to Other 
 
Events.......................................................................................... 144 
9.3.5.3 Reporting of Progression of Disease ............................................ 145 
9.3.5.4 Persistent or Recurrent Adverse Events ...................................... 145 
9.3.5.5 Abnormal Laboratory Values ........................................................ 145 
9.3.5.6 Abnormal Vital Sign Values .......................................................... 145 
9.3.5.7 Abnormal Liver Function Tests .................................................... 146 


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EudraCT No. 2017-001491-35 
 
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9.3.5.8 Deaths ......................................................................................... 146 
9.3.5.9 Pre-existing Medical Conditions ................................................... 146 
9.3.5.10 Hospitalisation or Prolonged Hospitalisation .............................. 147 
9.3.5.11 Overdose ................................................................................... 147 
9.4 
Immediate Reporting Requirements from Investigator 
to Sponsor .................................................................................... 148 
9.4.1 
Emergency Medical Contacts ....................................................... 148 
9.4.2 
Reporting Requirements for Serious Adverse Events 
and Non-Serious Adverse Events of Special Interest ....................................... 149 
9.4.3 
Reporting Requirements for Pregnancies ..................................... 149 
9.4.3.1 Pregnancies in Female Patients................................................... 149 
9.4.3.2 Pregnancies in Female Partners of Male Patients ........................ 150 
9.4.3.3 Abortions ..................................................................................... 150 
9.4.3.4 Congenital Anomalies/Birth Defects ............................................. 150 
9.5 
Follow-Up of Patients after Adverse Events.................................. 150 
9.5.1 
Investigator Follow-Up .................................................................. 150 
9.5.2 
Sponsor Follow-Up ....................................................................... 151 
9.6 
Post-Study Adverse Events .......................................................... 151 
9.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and Ethics 
Committees .................................................................................. 151 
10. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................ 153 
10.1 
Analysis Sets ................................................................................ 153 
10.1.1 
Missing Data/Discontinuation ....................................................... 154 
10.2 
Demographics, medical history, prior medication and 
other baseline characteristics ....................................................... 154 
10.3 
Study Treatment ........................................................................... 154 
10.4 
Concomitant Medication ............................................................... 154 
10.5 
Primary Analysis .......................................................................... 155 
10.5.1 
Part A (Escalation) ....................................................................... 155 
10.5.1.1 Bayesian Logistic Regression Model for Dose 
Escalation Determination ........................................................................... 155 
10.5.1.2 Dose-Finding of Single Agent CB-103........................................ 155 


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10.5.1.3 Bayesian Logistic Regression Model for MTD 
Determination ............................................................................................. 156 
10.5.2 
Part B (Expansion) ....................................................................... 158 
10.6 
Secondary Analyses ..................................................................... 159 
10.6.1 
Safety Analyses ........................................................................... 160 
10.6.1.1 Adverse Events .......................................................................... 160 
10.6.1.2 Safety Laboratory ...................................................................... 160 
10.6.1.3 Vital Signs .................................................................................. 160 
10.6.1.4 Electrocardiogram ...................................................................... 160 
10.6.2 
Efficacy Analyses ......................................................................... 160 
10.6.3 
Pharmacokinetic Analyses ........................................................... 161 
10.6.4 
Pharmacokinetic / Pharmacodynamic Analyses ........................... 162 
10.7 
Exploratory Analyses .................................................................... 162 
10.7.1 
Additional PK, metabolite, PD markers, Genomic, 
Pharmacogenetics, and Protein Analyses, CB-103 
metabolic expressions ................................................................. 162 
10.7.2 
Biomarker Analyses ..................................................................... 162 
10.7.3 
CSF Exposure of CB-103 in Haematological 
 
Malignancies ................................................................................ 162 
10.8 
Interim Analyses ........................................................................... 162 
10.8.1 
Part A (Escalation) ....................................................................... 162 
10.8.2 
Part B (Expansion) ....................................................................... 163 
10.9 
Sample Size ................................................................................. 163 
10.9.1 
Part A - Dose Escalation and Dose Confirmation ......................... 163 
10.9.2 
Part B - Dose Expansion, Stratified by Indication ......................... 163 
11. DATA COLLECTION AND MANAGEMENT ........................................................ 165 
11.1 
Data Quality Assurance ................................................................ 165 
11.2 
Electronic Case Report Forms...................................................... 165 
11.3 
Source Data Documentation ........................................................ 165 
11.4 
Retention of Records AND DOCUMENTS.................................... 166 
12. ETHICAL CONSIDERATIONS ............................................................................ 168 
12.1 
Compliance with Laws and Regulations ....................................... 168 
12.2 
Informed Consent ......................................................................... 168 


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12.2.1 
Patient Informed Consent Forms .................................................. 168 
12.2.2 
Exploratory Biomarker Sub-Study Consent Form ......................... 169 
12.3 
Ethics and Good Clinical Practice ................................................. 169 
12.4 
Institutional Review Board or Ethics Committee ........................... 170 
12.5 
Confidentiality ............................................................................... 170 
12.6 
Financial Disclosure ..................................................................... 171 
13. STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION .............................................................................................. 172 
13.1 
Study Documentation ................................................................... 172 
13.2 
Site Audit AND Inspections .......................................................... 172 
13.3 
Monitoring .................................................................................... 172 
13.4 
Publication of Data by Investigators and Protection of 
Trade Secrets ............................................................................... 173 
13.5 
Protocol Amendments .................................................................. 174 
13.5.1 
Substantial Amendments .............................................................. 174 
14. REFERENCES .................................................................................................... 175 
 
LIST OF TABLES 
Table 1 
Overview of the NOTCH pathway components and function ................ 46 
Table 2 
Pharmacokinetic parameters observed in mouse, rat and dog and 
predicted for humans using allometric scaling ...................................... 59 
Table 3 
Provisional dose escalation levels ........................................................ 97 
Table 4 
Dose modifications for haematologic toxicities ................................... 102 
Table 5 
Dose modifications for renal toxicities ................................................ 103 
Table 6 
Dose modifications for hepatic toxicities ............................................. 104 
Table 7 
Dose modifications for ocular/vision-related toxicities ......................... 105 
Table 8 
Dose modifications for cardiac toxicities ............................................. 105 
Table 9 
Dose modifications for gastro-intestinal toxicities ............................... 107 
Table 10 
Dose modifications for non-laboratory toxicities ................................. 108 
Table 11 
NCI CTCAE version 4.03 grading of diarrhoea, nausea and 
vomiting for patients without colostomy .............................................. 109 
Table 12 
Sample size in Part A and Part B of this study ................................... 113 
Table 13 
ECOG performance status scale ........................................................ 122 
Table 14 
Part A ECG schedule (once daily dosing regimen of CB-103) ............ 123 
Table 15 
Part B (Phase IIA, expansion) ECG schedule (once daily dosing 
regimen of CB-103) ............................................................................ 124 
Table 16 
Part A (Phase I) ECG schedule – BID regimen .................................. 126 
Table 17 
Part B (Phase IIA, expansion) ECG schedule – BID regimen ............. 127 
Table 18 
Adverse event severity grading scale ................................................. 143 


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EudraCT No. 2017-001491-35 
 
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Table 19 
Summary of prior distribution ............................................................. 157 
Table 20 
Prior probabilities of DLT at selected doses ....................................... 157 
Table 21 
Sample size consideration for potential indications ............................ 164 
 
LIST OF FIGURES  
Figure 1 
Overview of the NOTCH signalling pathway ......................................... 46 
Figure 2 
Overall survival of patients with breast cancer and adenoid cystic 
carcinomas with and without over-activation of NOTCH signalling 
in their tumour cells .............................................................................. 50 
Figure 3 
NOTCH signalling pathway and binding sites of γ-secretase 
inhibitors (GSIs) and monoclonal antibodies targeting the NOTCH 
ligands or receptors. ............................................................................. 55 
Figure 4 
Overview of study design ..................................................................... 78 
Figure 5 
Study periods ....................................................................................... 79 
Figure 6 
Prior medians and 95% credible intervals........................................... 158 
 
LIST OF APPENDICES  
Appendix 1 
Schedule of Assessments for Part A .................................................. 180 
Appendix 2 
Schedule of Assessments for Part B (Expansion) .............................. 186 
Appendix 3 
Overview of Selected Cancer Indications for the Study ...................... 192 
Appendix 4 
QT Prolonging Drugs with Risk of Torsades de Pointes. .................... 195 
Appendix 5 
Classification of Cytochrome Substrates ............................................ 201 
Appendix 6 
List of CYP3A Inhibitors and Inducers ................................................ 202 
Appendix 7 
Tumour Response Assessment Based on RECIST v1.1 Criteria for 
Solid Tumours .................................................................................... 203 
Appendix 8 
Response Assessment in Acute Lymphoblastic Leukaemia/ 
Lymphoblastic Lymphoma .................................................................. 211 
Appendix 9 
[18F] FDG-PET ................................................................................... 213 
Appendix 10 
Statistical Appendix including Model Performance and Data 
Scenarios ........................................................................................... 214 
Appendix 11 
PK SUB-STUDY 1 .............................................................................. 218 
Appendix 12 
PK SUB-STUDY 2 .............................................................................. 221 


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EudraCT Number 2017-
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACC 
Adenoid cystic carcinoma 
ADC 
Antibody-drug conjugates 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse Event 
AESI 
Adverse events of special interest 
AGA 
American Gastroenterological Association 
AhR 
Aryl hydrocarbon receptor 
ALCOA 
Attributable, Legible, Contemporaneous, Original and 
Accurate 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AR 
Accumulation ratio 
ARA 
Acid-reducing agent 
AST 
Aspartate aminotransferase 
ATC 
Anatomical, Therapeutic and Chemical 
AUC 
Area under the curve 
AUC0-∞ 
AUC from time 0 extrapolated to infinite time 
AUC0-8 
AUC during 8 hours 
AUC0-24 
AUC during 24 hours 
BCP 
B-cell precursor 
BID 
Twice daily 
BLRM 
Bayesian logistic regression model 
BM 
Bone marrow 
BNP 
Brain natriuretic peptide 
Bpm 
Beats per minute 
CCC 
Cholangiocellular carcinoma 
CI 
Confidence interval 
CL 
Clearance 
CL/F 
Oral clearance 
CLL 
Clast 
Chronic lymphocytic leukaemia 
Last measurable plasma concentration 


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Abbreviation 
Definition 
Cmax 
Maximum plasma concentration  
Cmin 
CNS 
Minimum plasma concentration 
Central nervous system  
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CR 
Complete response/Complete remission 
CRC 
Cohort Review Committee; colorectal cancer 
CRF 
Case Report Form 
CRi 
Complete remission with incomplete haematologic 
recovery 
CrCl 
Creatinine clearance 
CRO 
Clinical research organisation 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CV 
confidence value 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DDS 
Dose-determining set 
DLL1 
Delta-like ligand 1 
DLL3 
Delta-like ligand 3 
DLL4 
Delta-like ligand 4 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EMT 
Epithelial-mesenchymal transition 


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Abbreviation 
Definition 
EOS 
End-of-study 
EOT 
End of Treatment 
ER 
Estrogen receptor 
EU 
European Union 
EWOC 
Dose escalation with overdose control 
FCS 
Fetal calf serum 
FDA 
Food and Drug Administration 
F 
Bioavailability 
FDG-PET 
[18F]Fluoro-2-deoxyglucose positron emission 
tomography 
FLC 
Free light chain 
FPFV 
First-patient-first-visit 
γ-GT 
Gamma-glutamyl-transferase 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor  
GI 
Gastrointestinal 
GLP 
Good Laboratory Praxis 
GMP 
Good Manufacturing Practice 
GOF 
Gain of function 
GvHD 
Graft versus host disease 
GSI 
HCC 
Gamma-secretase inhibitors 
Hepatocellular carcinoma 
HCT 
Haematopoietic Cell Transplantation 
HER2 
Human epidermal growth factor receptor 2 
Hgb 
Haemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
HSNTD 
Highest non-severely toxic dose 
HR 
High risk 
HRS 
Hodgkin and Reed-Sternberg cells 
IC50 
Concentration of an inhibitor where the response (or 
binding) is reduced by half 
ICF 
Informed Consent Form 


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Abbreviation 
Definition 
ICH 
International Council of Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
i.m. 
Intramuscular 
IMiD 
Immunomodulatory agent 
IMP 
Investigational medicinal product 
IMWG 
International Myeloma Working Group  
IND 
Investigational new drug (application) 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
IT 
Intra-thecal 
i.v. 
Intravenous 
LLN 
Lower limit of normal 
LOF 
Loss of function 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MAO 
Monoamine oxidase 
MAOI 
Monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 
NICD1 
Notch intracellular domain 1 
NSG 
NOD Scid Gamma 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition 
MZB 
Marginal zone B 
N1, N2, N3, N4 
NOTCH1, NOTCH2, NOTCH3, NOTCH4 receptor 
molecules 
NAT 
N-acetyltransferase 
NCI 
National Cancer Institute 
NGS 
Next generation sequencing 
NICD 
NOTCH intracellular domain 
NIH 
National Institutes of Health 
NMZL 
Nodal Marginal Zone Lymphoma 
NOAEL 
No-observed-adverse-effect level 


Clinical Study Protocol 
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Abbreviation 
Definition 
NOS 
Not Otherwise Specified 
NSCLC 
Non-small cell lung cancer 
NT-pro-BNP 
N-terminal propeptide brain natriuretic peptide 
NYHA 
New York Heart Association 
OS 
Overall survival 
PD 
Pharmacodynamics 
PC 
Plasma cell 
PDx 
PGx 
Patient derived xenograft 
Pharmacogenomic 
PET-CT 
Positron emission tomography–computed tomography 
PFS 
Progression-free survival 
Pgp 
P-Glycoprotein 
PK 
Pharmacokinetic 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PS 
Performance status 
PRBC 
Packed red blood cell 
PT 
Preferred term 
PTT 
Partial thromboplastin time 
PXR 
Pregnane X receptor 
QD 
Once daily 
QRS 
QRS complex 
QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcF 
QT corrected for heart rate using the Fridericia’s 
correction factor 
r/r 
Relapsed or refractory 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RP2D 
Recommended phase 2 dose 
RSI 
Reference safety information 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous 
sCR 
Stringent complete response 


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Abbreviation 
Definition 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SNRI 
Serotonin norepinephrine reuptake inhibitor 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SSRI 
Selective serotonin reuptake inhibitor 
StD 
Standard deviation 
t1/2 
Elimination half-life 
T-ALL 
T-cell acute lymphoblastic leukaemia 
TCA 
Tricyclic antidepressants 
TCP 
T-cell precursor 
TdP 
Torsades de Pointes 
TFH 
T Follicular Helper 
TID 
Three times daily 
tlast 
Time to last measurable plasma concentration 
T-LBL 
T-cell lymphoblastic lymphoma 
tmax 
Time to maximum plasma concentration 
TNBC 
Triple negative breast cancer 
TPN 
Total Parenteral Nutrition 
Trop 
Troponin 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution 
Vd/F 
Apparent volume of distribution 
VGPR 
Very good partial remission 
Vss 
Volume of distribution at steady state 
Vss/F 
Apparent volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 
 
 
 


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1. 
INTRODUCTION 
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 locally advanced or metastatic 
oncology indications. 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) 
including a dose escalation part to determine the maximum tolerated dose (MTD) or 
recommended Phase II dose (RP2D) and a MTD/RP2D confirmatory cohort. Part B (the 
Phase IIA component of the study) is the expansion part of the study with several 
expansion arms in patients with selected tumour indications and to explore preliminary 
clinical efficacy and PD of CB-103 in these indications. While in the dose escalation of 
Part A no patient enrichment for NOTCH will be implemented, in the MTD/RP2D 
confirmatory cohort of Part A and in Part B the patients must have tumours characterised 
by a functionally over-activated NOTCH signalling pathway determined by molecular 
and/or biochemical biomarkers. 
2. 
BACKGROUND INFORMATION 
NOTCH signalling plays a key role in many cellular processes during development. 
NOTCH is a developmental pathway characterised by cell to cell communication 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 deregulation of the self-renewal process resulting 
in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion 
and metastasis, and resistance 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 cancer, 
promoting progression, development of metastasis, escaping apoptosis or to even cause 
resistance against chemotherapy or other targeted therapies.  
2.1 
NOTCH SIGNALLING PATHWAY 
The NOTCH pathway is a cascade that facilitates cell-cell communication during 
development. NOTCH signalling is initiated upon binding of one of the five NOTCH ligands 
(Delta-like ligands DLL1, DLL3, DLL4, Jagged ligands Jag1, Jag2) to one of the four 
NOTCH receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) on adjacent cells (Figure 
1; Table 1). 


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Figure 1 
Overview of the NOTCH signalling pathway 
 
Source: Adapted from Radtke et al., 2013. 
Table 1 
Overview of the NOTCH pathway components and function 
NOTCH pathway 
component 
Function 
Ligands 
 
DLL 1 
Governing cell fate decisions and cell-to-cell communication 
DLL 3 
Suppressing cell growth by apoptosis induction 
DLL 4 
Activating NF-κB signalling to enhance VEGF secretion and 
promote metastasis 
JAG 1 
JAG1 activation of NOTCH enhances angiogenesis 
JAG 2 
Interaction with NOTCH2 to promote cell survival and proliferation 
Receptors 
 
NOTCH1 
Transmembrane receptor involved in cell proliferation, invasion, and 
chemoresistance 
NOTCH2 
Constitutive NOTCH2 signalling induces hepatic tumours 
NOTCH3 
Promoting proliferation and migration, and modifying chemotherapy 
response 
NOTCH4 
Involved in endocrine therapy resistance and EMT in breast cancer 
Example Target 
Genes 
 
Hes1 
Sequence-specific DNA-binding transcriptional factor involved in 
cellular proliferation and differentiation 
Hey1 
Hes-related transcriptional factor involved in neoplastic vasculature 
development 
Source: Adapted from Yuan (Yuan et al., 2015). 


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Upon this ligand-receptor interaction, proteolytic cleavages on the receptor side with the 
last cleavage by the γ-secretase activity leads to the liberation of the NOTCH intracellular 
domain (NICD1, NICD2, NICD3, NICD4). This is a rate-limiting step during NOTCH 
activation, which can be pharmacologically blocked by small-molecule γ-secretase 
inhibitors. Once the NICD is liberated, it translocates to the nucleus and binds to the 
NOTCH-specific transcription complex (Kovall, 2008). The interaction between the 
transcription factors and NICD potentiates the formation of an active transcription complex 
to induce transcriptional expression of downstream target genes (HEY1, HES1, NF-kB, 
MYC, CCND1/3, BCL2, CCR7, human epidermal growth factor receptor 2 [HER2]) 
(Ntziachristos et al., 2014). NOTCH target genes regulate self-renewal, pivotal cell-fate 
choices, including differentiation, cell-cycle progression and survival of diverse cell types 
at various stages of their development. The final phenotypic effect is dependent on the 
specific signalling context, paralogue, ligand and dosage of the intracellular signal (Suresh 
and Irvine, 2015). 
2.2 
NOTCH SIGNALLING IN CANCER 
The canonical NOTCH pathway with four NOTCH receptors and five ligands is an 
evolutionarily conserved cell signalling pathway that plays critical roles in cell-fate 
determination, differentiation, development, tissue patterning, cell proliferation, and death. 
Deregulated NOTCH signalling leads to various organ disorders and diseases, such as 
T-cell leukaemia, Alagille syndrome and a stroke and dementia syndrome known as 
CADASIL as well as it can play a major role in promoting cancer growth, invasion and 
metastasis (Andersson and Lendahl, 2014). 
The oncogenic role of NOTCH signalling in human malignancy was first unravelled in 
T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL/T-LBL) (Reynolds et al., 1987; 
Ellisen et al., 1991) and NOTCH1 gain-of-function mutations were subsequently found in 
approximately 55% of T-ALL (Aster et al., 2017). Since the discovery of NOTCH1 gene 
alterations in T-ALL, aberrant NOTCH signalling was subsequently identified in many solid 
tumours (Ranganathan et al., 2011) and haematological malignancies (Gu et al., 2016). 
Aberrant activation of NOTCH signalling leads to deregulation of the self-renewal process 
resulting in sustained proliferation, escape from apoptosis, loss of differentiation capacity, 
invasion and metastasis, and may also be the cause of developing therapy resistance to 
several treatment modalities (chemotherapy, targeted therapy, radiotherapy), all of which 
are hallmarks of cancer. Over-activation of the NOTCH signalling pathway can lead to 
cancer development like in T-ALL, or, if it occurs during the course of the disease, to a 
more aggressive phenotype and more malignant progression (Takebe et al., 2014). Thus, 
as a consequence these alterations of the NOTCH signalling pathway may result in a 
worse prognosis for these patients. 
NOTCH aberrant regulation of the pathway and its over-activation in cancer cells are 
caused by multiple and distinct mechanisms (Ntziachristos et al., 2014): 


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• 
Chromosomal translocation overlapping with NOTCH regions on the 
chromosomes, leading to fusion of NOTCH related genes and expression of 
truncated versions of the NOTCH1 or 2 proteins, causing ligand-/receptor-
independent constitutive activation of the respective NOTCH pathway. 
• 
Gain of function (GOF) mutations in the NOTCH genes leading to a constitutive, 
ligand-/receptor-independent activation of the respective NOTCH pathway. 
• 
Loss of function (LOF) mutations in negative regulators of the NOTCH pathway, 
like FBXW7 or NUMB. 
• 
Over-expression of the different NOTCH-specific ligands or receptors, 
leading to extended activation of the respective NOTCH pathways 1, 2, 3 or 4. 
This variety of genetic changes of the NOTCH pathway leading to over-activation and 
altered signalling occur in a variety of solid tumour indications and haematological 
malignancies without a specific pattern and in different frequencies. All these different 
genetic lesions may influence tumour initiation, but is also important for aspects of 
promoting tumour growth and progression, including a direct effect on cell cycle regulation, 
inhibition of apoptosis, deregulation of progression and differentiation programs in cancer 
cells, promoting angiogenesis, epithelial to mesenchymal transition (EMT)-driven 
metastatic growth and the formation and maintenance of cancer stem cells (CSC) (Bhola 
et al., 2016; Wieland et al., 2017). Besides the direct effect of NOTCH over-activation on 
promoting tumour growth, invasion and metastasis, NOTCH signalling plays a major role 
in regulating survival and apoptosis pathways. Therefore, NOTCH may play through the 
regulation of these pathways a very significant role in cancer cells to gain a survival 
advantage which leads to the development of treatment resistance to chemotherapy, 
targeted therapies and also radiotherapy. Taken together, all these multiple effects caused 
by NOTCH over-activation and cross-talking to other signalling pathways reveal the 
NOTCH pathway as being an attractive and reasonable therapeutic target for novel 
therapeutic regimens to treat tumour cells directly and to sensitise tumour cells to 
chemotherapeutic agents and radiotherapy (Ranganathan et al., 2011).  
Depending on expression patterns, the NOTCH pathway can function as either oncogenic 
or tumour suppressive depending on the tissue and cellular context. The functional role of 
NOTCH in the different indications has been the subject of intensive studies and in general, 
NOTCH seems tumour-suppressive only in a limited number of malignancies, like in 
several squamous cancers (Nowell and Radtke, 2017), but activating and oncogenic in 
most haematological malignancies (Gu et al., 2016) and adenocarcinomas, reflecting its 
normal functions in those tissues (Previs et al., 2015).  
With whole genome sequencing and other sensitive technologies available to detect all 
the different genetic lesions of the NOTCH pathway at the molecular level, the oncogenic 
function of NOTCH signalling is well understood and can be detected in various solid 


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tumour indications (subtypes of breast cancer, gastrointestinal (GI) cancers, 
cholangiocellular carcinoma [CCC], hepatocellular carcinoma  [HCC], subtypes of 
sarcomas, desmoid tumours, adenoid cystic carcinomas [ACC], malignant glomus tumour) 
(Ranganathan et al., 2011) as well as frequently also in numerous haematological 
malignancies (T-ALL/T-LBL, chronic lymphocytic leukaemia [CLL]  and many subtypes 
of non-Hodgkin lymphomas (Gu et al., 2016)). 
Given the importance of NOTCH signalling in human cancers, several therapeutic 
approaches have been utilised to block NOTCH signalling. Two of these strategies are 
a) the use of monoclonal antibodies (mAbs) against NOTCH ligands and receptors, and 
b) the use of small molecule gamma-secretase inhibitors (GSIs). However, these 
approaches can only be effective if tumour cells express full-length ligand or receptor 
molecules. On the contrary, in human cancers with constitutive activation of the NOTCH 
pathway through NOTCH gene fusion due to chromosomal translocations or specific 
NOTCH mutations, the use of mAbs and GSIs will have very limited clinical benefits 
(Andersson and Lendahl, 2014). In contrast to the aforementioned inhibitors, the pan-
NOTCH inhibitor CB-103 binds to the NOTCH-specific transcription complex in the cell 
nucleus and unfolds its effects at the transcription level of NOTCH target genes at the 
most downstream and central location. CB-103 therefore has the potential to address all 
mechanisms causing NOTCH over-activation. Besides over-expression of ligands and 
receptors, it can also inhibit the ligand- and receptor-independent, constitutive activation 
of NOTCH signalling caused by the various genetic aberrations known to activate the 
pathway. 
Over-activation, in particular the constitutive activation of NOTCH signalling (independent 
of ligand/receptor expression) in these cancer indications 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 (OS) seen in patients with the same tumours 
not having any aberration or dysregulation of the NOTCH pathway. Several studies have 
confirmed the negative prognostic importance of NOTCH over-activation in many cancer 
indications and showed that an aberrant NOTCH pathway in the tumour leads to 
significantly shorter survival of the patients. High co-expression of NOTCH1 and JAG1 in 
tumours of breast cancer patients is associated with poor survival with median OS of 
40 months in patients with high NOTCH activation compared to 83 months in patients 
without such NOTCH overexpression (Reedijk et al., 2005). For patients with adenoid 
cystic carcinomas (ACC), a very aggressive, treatment-refractory tumour of salivary 
glands, this correlation is even stronger with a median OS of only 29.6 months in patients 
with tumours bearing NOTCH1 mutations compared to 121.9 months in patients with 
tumours without any NOTCH activation (Ferrarotto et al., 2017). The respective survival 
curves for both examples can be seen in Figure 2 and additional examples for the negative 
prognostic value of NOTCH are provided in the Investigator’s Brochure. 


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Figure 2 
Overall survival of patients with breast cancer and adenoid cystic 
carcinomas with and without over-activation of NOTCH signalling in their tumour cells 
 
Source: Reedijk et al., 2005, Ferrarotto et al., 2017. 
 
Altogether, these examples of the dependency of the patient’s life expectancy with the 
NOTCH status in their tumours confirms the important role of NOTCH signalling in human 
malignancies, indicating that a strong rationale exists for the development of NOTCH-
tailored therapies (Ntziachristos et al., 2014). 
2.3 
OVERVIEW OF CHOSEN CANCER INDICATIONS 
Patients with advanced and metastatic solid tumours often have limited therapeutic 
options beyond institutional standard of care. For patients whose cancer has become 
refractory to all available treatments, there is a significant unmet therapeutic need. In some 
malignancies, the cancer pathology can be driven by, or be largely dependent, on well-
defined genetic aberrations in selected cellular signalling pathways like mutations, 
chromosomal translocations or overexpression of the respective ligands or receptors. The 
NOTCH signalling pathway is such an example where activating genetic aberrations which 
occur in many different malignancies, lead to an oncogenic transformation of the tumour 
and its microenvironment resulting in NOTCH-driven growth, proliferation, invasion and 
metastasis. The rationale for specific inhibitors of such defined targets is logical, and in 
the case of cancers which have oncogenic aberrations of the NOTCH pathway, 
development of specific NOTCH inhibitors is a reasonable and promising therapeutic 
approach and some of the existing NOTCH inhibitors have already shown clinical activity 
in early stage clinical development in various indications (Previs et al., 2015). 
In order to select the right solid tumour indications for treatment with the pan-NOTCH 
inhibitor CB-103 within this study, a literature research was performed and CB-103 was 
studied in various non-clinical in vitro and in vivo pharmacology studies in models derived 
from different cancer indications. Criteria for the selection of indications are that activation 
of the NOTCH pathway by genetic aberrations based on known mutations, translocations 
or overexpression of ligands/receptors are known to be present and well characterised to 
be biologically active as oncogenic growth drivers. Any indication where the functional role 


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of NOTCH is not clear or described in literature as tumour-suppressive will be excluded 
and will not be considered for this clinical study (Nowell and Radtke, 2017). 
2.3.1 
Advanced and Metastatic Solid Tumours 
Since discovery of NOTCH1 gene alterations in T-ALL, aberrant NOTCH signalling was 
subsequently identified in many solid tumours (Ranganathan et al., 2011). NOTCH-related 
somatic mutations and chromosomal translocations have been characterised and are 
infrequent in the members of the NOTCH family in solid tumours. These specific genetic 
aberrations of the NOTCH pathway and the functionally oncogenic effect of these lesions 
have been characterised and are found in several solid tumour indications that include all 
subtypes of breast cancer (estrogen receptor [ER]+/-), progesterone receptor [PR]+/-, 
HER2+/-, triple negative breast cancer [TNBC], GI cancers (colorectal cancer, CCC, HCC), 
subtypes of sarcomas, desmoid tumours, adenoid cystic carcinomas, malignant glomus 
tumour and non-Hodgkin lymphomas (Egloff and Grandis, 2012). Additionally, 
deregulated expression of wild-type NOTCH receptors and NOTCH ligands has been 
found in a growing number of human solid tumours including pancreatic, prostate, breast, 
lung, GBM, sarcomas, desmoid tumours, adenoid cystic carcinomas, cervical, melanoma, 
head and neck, and renal cancers (Takebe et al., 2014). Aberrant activation of NOTCH1 
signalling was associated with loss of Numb activity, a negative regulator of NOTCH 
pathway, in about 40% of breast cancers and 30% of lung cancers (Stylianou et al., 2006). 
High levels of JAG1 or NOTCH1 was seen in about 25% of human breast tumours by in 
situ hybridisation; and high versus low levels of co-expression of NOTCH1 and JAG1 were 
associated with reduced overall survival (Reedijk et al., 2005). 
The solid tumour indications under investigation in this study must have reported genetic 
aberrations of the NOTCH pathway, characterised as being biologically active and 
functionally oncogenic, in driving tumour growth, proliferation, survival, escape from 
apoptosis, invasion and metastasis. Non-clinical in vitro and in vivo studies have been 
performed for some of the selected indications to identify and confirm the occurrence of 
these aberrations in the tumour cells and to investigate the cytotoxic effects of CB-103 
treatment. Indications such as squamous cell carcinomas, pancreatic cancer and HNSCC, 
with known or suspected NOTCH signalling involvement in tumour suppression, are not 
under investigation in this study.  
Furthermore, selection of indications is also made based on strategical considerations by 
the Sponsor with regards to the future development plans for CB-103 in these indications. 
The following tumour indications are selected to be included in this study:  
• 
Breast cancer (ER+/-, HER2+/-, TNBC), GI cancers (resistant to oxaliplatin or 
irinotecan-based 
therapy 
colorectal 
cancer, 
hepatocellular 
carcinoma), 
osteosarcoma, adenoid cystic carcinoma (ACC), malignant glomus tumour and T-
ALL/T-LBL.  


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More details on the known genetic aberrations of NOTCH signalling in these indications 
and their frequency are provided in the Investigator’s Brochure and in Appendix 3. 
Additionally, NOTCH pathway activation has been reported in other malignancies with 
lower frequency. Patients whose tumours exhibit Notch pathway activation are eligible for 
this study even if the tumour is not among the indications mentioned above. 
2.3.2 
Acute Lymphoblastic Leukaemia / Lymphoma  
The incidence of ALL follows a bimodal distribution, with the first peak occurring in 
childhood and a second peak occurring around the age of 50 (Dores et al., 2012). In 
Western countries, the annual incidence rate of adult ALL (i.e. patients older than 15) is 
approximately one per 100,000 (Sant et al., 2010; Howlander et al., 2014). In adult ALL, 
B-cell ALL accounts for ~75% of cases, while T-cell ALL comprises the remaining cases. 
In the EU, with the current population of 510,000,000 inhabitants, about 1250 new cases 
of adult T-ALL are expected every year.  
The OS rates in adult ALL is still <45% (Bassan et al., 2011) despite the addition of CNS 
prophylaxis, late intensification with prolonged maintenance chemotherapy, and an 
extensive use of allogeneic Haematopoietic Cell Transplantation (HCT) in high-risk (HR) 
subsets. Paediatric-inspired regimens, initially reserved for adolescents and young adults 
(Stock et al., 2008; Ribera et al., 2008; Boissel et al., 2003) and later applied to patients 
up to 50-60 years of age (Huguet et al., 2009; DeAngelo et al., 2015; Storring et al., 2009), 
have increased the 5-year OS rate to ≥ 50%, and up to 70%-80% in favourable subsets  
(Curran et al., 2015). Finally, allogeneic HCT is often considered in first complete 
remission (CR) in adults with HR disease to reduce the risk of relapse (Goldstone et al., 
2008), but potential benefits may be offset by transplant-related morbidity and mortality, 
especially in the elderly (Gupta et al., 2013). Relapse affects one-third or more of the 
patients and remains an unsolved issue due to extremely poor results with standard 
salvage chemotherapy. An international study of 1,706 patients with refractory or recurrent 
(r/r) B-cell precursor (BCP) ALL reported 3-year survival rates of only 10% (Gökbuget et 
al., 2016). Results are worse in Ph+ ALL (Cortes et al. 2012) and T-cell precursor (TCP) 
ALL, with some mitigation provided by nelarabine (DeAngelo et al., 2007). 
Nelarabine was approved in the US and Europe for the treatment of patients with T-ALL 
and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has 
relapsed following treatment with at least two chemotherapy regimens. The approval in 
adult patients was based on an open-label study carried out by the Cancer and Leukaemia 
Group B and the Southwest Oncology Group, which evaluated the safety and efficacy of 
nelarabine in 39 adults with T-ALL T-LBL (DeAngelo et al., 2007). Twenty–eight of the 39 
adults had relapsed or were refractory to at least two prior inductions. Of the 28 patients 
who had previously received at least 2 prior induction regimens, 8 (29%) experienced a 
complete remission (CR) with or without hematopoietic recovery (CRi). In comparison, 4 
of 11 (36%) patients who had received only one prior induction regimen demonstrated a 
CR or a CRi to nelarabine. Time to complete response in both classifications of response 


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ranged from 2.9 to 11.7 weeks. Of the 28 patients with 2 or more prior inductions, the 1-
year survival rate was 25%. The most common non-hematologic toxicity of neralabine is 
reversible peripheral sensory and motor neuropathy, which limits the combination of the 
drug with standard combination chemotherapy. As many of the commonly-used agents 
for ALL therapy, such as vincristine and methotrexate, also have neuropathic toxicities, 
nelarabine use remains limited. 
The oncogenic role of NOTCH signalling in human malignancy was first unravelled in T-
ALL/T-LBL: the most frequent actionable mutations are NOTCH1 (Aster et al., 2017) 
occurring in approximately 55%  of T-cell ALL cases, and FBXW7-inactivating gene 
mutations occurring in approximately 30% of cases (Yet et al., 2016), with the result that 
approximately 80% of cases have Notch pathway activation by mutations in at least one 
of these genes. 
In T-ALL, NOTCH1 inhibitors and the strictly associated γ-secretase inhibitors were tested 
in late-stage disease, with some responses of short duration and considerable gut toxicity 
(Gu et al., 2016). The best study reported one CR and an overall 32% response rate in 25 
patients with relapsed disease (Weidler-McKay et al., 2014). Theoretically, targeting 
NOTCH1-related overexpression of the chemokine receptor CCR7 and its ligand CCL19 
could also reduce the risk of CNS disease (Buonamici et al., 2009).  
2.4 
NOTCH TARGETING THERAPIES 
The therapeutic rationale for the use of NOTCH-inhibiting strategies is based on the fact 
that blocking this pathway can have both direct effects on cancer cells, and can also 
indirectly hinder tumour growth by reducing blood supply through angiogenesis 
dysregulation and by disrupting the tumour stem cell niche. Furthermore, the fact that 
tumour cells often acquire multiple mutations in several different pathways interplaying 
with NOTCH, such as Hedgehog, WNT, PI3K, mTOR, NF-kb and others, supports the use 
of combination targeted therapies. Importantly, combination with traditional chemo-
radiotherapy also seems promising as their therapeutic effect can also be enhanced by 
the use of NOTCH inhibitors (Takebe et al., 2015). 
At present, several classes of NOTCH pathway inhibitors are in clinical development, with 
significant differences in the targets, mechanism of action, and drug class. The two main 
classes of NOTCH inhibitors are the γ secretase inhibitors (GSIs) and monoclonal 
antibodies targeting either the NOTCH ligands or receptors (Figure 3): 
1. A major class of agents targeting the NOTCH pathway is the γ secretase 
inhibitors (GSIs), which prevent the final proteolytic cleavage of NOTCH 
receptors that releases the active intracellular fragment. GSIs were initially 
developed as treatment for Alzheimer’s disease and were subsequently the first 
class of NOTCH inhibitors to reach clinical development in oncology (De Strooper, 
2014). However, there are systemic toxicities and off-target effects, as γ secretase 
has > 80 substrates related to different pathways in addition to the NOTCH 


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receptors. GSIs potentially inhibit the cleavage of all substrates, which might 
contribute to their toxicity and/or effectiveness in ways that are not currently 
understood. Based on the toxicities and moderate efficacy seen in early clinical 
development several GSI programs were terminated and a few second generation 
GSIs are continuing in several Phase I/II clinical studies either as monotherapy or 
in combination with different chemotherapies and targeted therapies (Takebe et 
al., 2015). 
2. Another class of agents under development is the monoclonal antibodies (mAb) 
either against NOTCH receptors (NOTCH1, NOTCH2, NOTCH3) or NOTCH 
ligands (DLL3, DLL4). Experimental evidence demonstrates that NOTCH inhibition 
by either mAb against NOTCH1 or NOTCH2 alleviates the toxicities seen with 
GSIs while simultaneous inhibition of NOTCH1 and 2 leads to severe GI toxicities 
(Wu et al., 2010). It is hoped that this category of drugs could reduce or spare 
some of the toxicities associated with GSIs. Besides monoclonal antibodies 
binding to the different NOTCH receptors, there are also several mAb in early 
clinical studies binding to different NOTCH ligands with most of them targeting 
DLL4 and an antibody-drug-conjugate (ADC) binding to DLL3 with subsequent 
internalisation of the ADC complex and release of the cytotoxic payload within the 
cells. Most of these programs are in early clinical development (Takebe et al., 
2014). 


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Figure 3 
NOTCH signalling pathway and binding sites of γ-secretase inhibitors (GSIs) 
and monoclonal antibodies targeting the NOTCH ligands or receptors. 
 
Source: Sponsor 
 
Besides the drug classes of monoclonal antibodies and GSIs being currently in early stage 
clinical development and the clinical experience that the effects of these may be limited 
by the toxicities observed, other potential therapeutic approaches are currently under 
pre-clinical investigation including mAbs targeting various NOTCH receptors, mAbs to the 
γ-secretase complex component nicastrin, and soluble decoy NOTCH receptors that 
interfere with ligand–receptor interactions (Takebe et al., 2015). 
Despite the promising therapeutic potential however, limiting toxicities and on-target side 
effects associated with the various NOTCH therapies have been observed in pre-clinical 
and clinical studies. Early discontinuation of patients and drug exposure below the 
therapeutic range might be the reason for the moderate clinical activity observed so far in 
clinical studies. For example, the success of GSI-based therapies in Phase I trials have 
been hampered by their GI toxicity, explained by normal NOTCH signalling directing GI 
stem cells towards an epithelial fate, with subsequent blockade causing increased 


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numbers of mucus-secreting goblet cells in the small intestine (Gu et al., 2016). Based on 
the negative prognostic relevance of NOTCH signalling and knowledge of the oncogenic 
function of NOTCH in many solid tumours and haematological malignancies, together with 
the high unmet medical need in those patients with NOTCH-driven tumours, there is still 
a strong rationale to therapeutically target this pathway with specific NOTCH inhibitors. It 
will be important to discover novel NOTCH signalling inhibitors with a new mode of action 
which may lead to an improved safety profile and increased efficacy. Additionally, another 
key success factor for NOTCH inhibitors will be to consider a biomarker strategy and 
development of a companion diagnostic to characterise NOTCH pathway aberrations in 
order to select the most suitable patient population for a particular NOTCH-targeted 
therapy. 
Further information on the different drug classes of NOTCH inhibitors and the current 
stage of clinical development for selected candidates can be found in the Investigator’s 
Brochure. 
2.5 
CB-103 – PAN-NOTCH TARGETING DRUG CANDIDATE 
CB-103 is an orally bioavailable synthetic small molecule (Molecular weight: 278.78 g/mol) 
and a first-in-class pan-NOTCH inhibitor. It targets the NOTCH signalling pathway in its 
most downstream part by binding to the NOTCH-specific transcription complex located in 
the cell nucleus. CB-103 is an oral drug administered as a capsule. In animals, the 
compound is rapidly absorbed after administration, distributes rapidly into tissue and 
diffuses into the nucleus of malignant cells, binds to the transcription complex and inhibits 
translation and protein expression of NOTCH-related target genes which are responsible 
for the various functions NOTCH can trigger and modulate in many fundamental 
processes and in a wide range of tissues. 
2.5.1 
Mechanism of Action 
After entering the tumour cells, CB-103 translocates to the cell nucleus and binds to the 
NOTCH-specific transcription complex hindering subsequent binding of the NICD and 
therefore blocking the transcription and translation of the NOTCH target genes. The 
molecular target and binding site of CB-103 at the NOTCH-specific transcription complex 
has been identified. Two pharmacodynamics studies were conducted to confirm the 
mechanism of action and characterise the cellular target of CB-103 at the transcription 
complex. Further details on these studies can be found in the Investigator’s Brochure. 
2.5.2 
Non-Clinical Pharmacology 
A summary of the in vitro and in vivo pharmacology studies is given in the Investigator’s 
Brochure. 
2.5.2.1 
Safety Pharmacology 
Single oral doses of CB-103 at 10, 30 and 80 mg/kg had no effect on respiratory function 
in the rat. In addition, CB-103 at 10 mg/kg was devoid of effects on the CNS in the rat. 


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Single oral doses of CB-103 up to and including 200 mg/kg had no effect on blood 
pressure and heart rate in the conscious telemetered rat. Likewise, the compound had no 
effect on blood pressure, heart rate or the PR and RR intervals of the electrocardiogram 
(ECG) in the conscious dog when administered as a single dose up to 26.3 mg/kg or two 
doses of 10 mg/kg given 12 hours apart. 
CB-103 at 0.8 mg/kg had no effect on the QRS complex (QRS) QT interval corrected for 
heart rate or (QTc) intervals of the ECG. 
The higher doses of CB-103 caused an increase in the QTc in dogs. These increases in 
QTc were transient with a single time point at 0.5 hour post-dose being statistically 
significant following treatment with 7.8 mg/kg and values up to 6.0 hours post-dose being 
statistically significant after the top dose (26.3 mg/kg). Similar effects on the QTc interval 
were observed when CB-103 was given as two 10 mg/kg doses 12 hours apart. The 
plasma concentrations associated with these effects are estimated to be >> 3000 ng/mL 
total CB-103 (free concentration >> 90 ng/mL) and the most likely mechanism for the effect 
of CB-103 on the QTc interval in the dog is inhibition of the hERG-mediated potassium 
current (IC50 = 38.5 µM=9333 ng/mL) and the inhibition of L-type calcium channel 
(hCav1.2) at lower concentrations (IC50 = 26.88 µM=6516 ng/mL). Compounds with this 
profile (greater calcium antagonist potency than hERG) have been shown to have a lower 
pro-arrhythmic potential than ‘pure’ hERG blockers and therefore CB-103 may have a low 
risk for Torsades de Pointes arrhythmia in man (Kramer et al., 2013b). 
CB-103 at a dose of 0.8 mg/kg had no effect on the QRS interval in the dog. However, the 
higher doses of 7.8 and 26.3 mg/kg caused a dose-related increase in the QRS interval, 
with the duration of action being longer at the top dose (~6 hours) than that observed at 
the mid-dose (~1 hour). These effects were also associated with some morphological 
changes in the ECG waveform in 2 of 4 dogs after 7.8 mg/kg and in all 4 dogs after 
26.3 mg/kg. Prolongation of the QRS interval is indicative of the slowing of conduction 
through the heart and the most likely mechanism for this effect is inhibition of cardiac 
sodium channels (Nav1.5 (IC50 = 58.9 µM to 60.66 µM)). Cardiac sodium channel 
blockers can also reduce the force of contraction of the heart and this may explain the 
small increase in the QA interval observed in dogs treated with CB-103 at doses of 7.8 
and 26.3 mg/kg. 
Thus, these data suggest that CB-103 has some potential to affect cardiac repolarisation 
and cardiac conduction and careful monitoring of the ECG will be warranted in human 
clinical trials. 
Gastrointestinal (GI) safety studies revealed for CB-103-treated mice completely normal 
intestinal tissues and no indication of goblet cell accumulation. At an increased dosing 
frequency (3 x daily), CB-103 exhibited a mild intestinal toxicity apparent by an increase 
in goblet cell population in the intestine. In the spleen, CB-103 mediated inhibition of 
NOTCH2 signalling led to more than 90% reduction in the MZB confirming its in vivo 
activity. Overall in all animal studies performed in different species (mice, rats and dogs) 
and with different doses and schedules of CB-103, there were no signs of diarrhoea 
reported suggesting that the typical gastro-intestinal toxicities seen caused by the goblet 


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cell metaplasia reported for the other classes of NOTCH inhibitors, may not be the key 
toxicity driver and limiting-factor with regards to exposure for CB-103. 
2.5.3 
Pharmacokinetics 
2.5.3.1 
Animal Pharmacokinetics and Drug Metabolism 
The absorption, distribution, metabolism, and excretion (ADME) profile of CB-103 has 
been investigated in in vitro and in vivo studies and the repeat dose PK in rats and dogs 
was assessed as part of the toxicokinetic program. The study results are summarised in 
this section and more detailed information can be found in the Investigator’s Brochure. 
CB-103 shows excellent drug-like properties based on the pre-clinical in vitro and in vivo 
ADME profile. The compound is highly permeable and well absorbed after oral 
administration with a time at which the maximum serum concentration (Cmax) is observed 
(tmax) of about 1 hour. CB-103 is not a substrate for P-Glycoprotein (Pgp). Bioavailability 
after various formulations given to mice and dogs is high or complete. Rats show a lower 
bioavailability most likely due to a combination of high first past metabolism and potentially 
incomplete absorption. 
Despite its high binding to plasma proteins from various animal species and humans 
(≥ 97%) CB-103 distributes widely into the body and was detectable in brain, kidney, liver, 
spleen and skin tissues from rats. The elimination of CB-103 in animals is relatively fast 
(elimination half-life [t1/2]: 2 hours in mice, 3 hours in rats and 7-10 hours in dogs), and no 
signs of significant accumulation have been observed with daily dosing. The expected t1/2 
in humans is around 16 hours (see Section 2.5.3.2) Overall, the PK parameters after first 
and repeated administration were comparable, except for a decrease in exposure over 
time during the 28-day Good Laboratory Praxis (GLP) toxicity study in dogs at all doses 
and in both genders. No explanation for this observation has been found, but the exposure 
coverage at the end of this study was still sufficient to allow a valid assessment of CB-103 
toxicity in dogs for the calculation of safety margins. 
In general, the PK of CB-103 is dose proportional, with a tendency to higher than dose 
proportional exposure in dogs in the range of 1 to 10 mg/kg/day. At 50 mg/kg given to 
dogs absorption of CB-103 is delayed and the Cmax is lower than expected. In rats an 
absorption plateau is reached with 200 mg/kg. 
All human metabolites formed in hepatocytes are covered by the toxicology species (rats 
and dogs), but some species differences have been observed with respect to CB-103 
metabolism. The predominant metabolic conversion of CB-103 in rodents, monkey and 
humans seems to be N-acetylation. Oxidative metabolism occurs as well, but seems to 
play a minor role in humans. Dogs are deficient of the enzymes catalysing N-acetylation 
(N-acetyltransferase [NAT] isoforms 1 and 2) and have a lower intrinsic clearance (CL) of 
CB-103. The predominant metabolic route of clearance in the dog is oxidative metabolism 
combined with glucuronidation. 


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The involvement of NAT1/NAT2 in the metabolism of CB-103 in humans might be of 
relevance since NAT polymorphism results in high- and low metabolizing individuals. 
Metabolic stability of CB-103 in human hepatocytes from individuals genotyped as slow, 
intermediate and fast NAT metabolizers showed a relationship of metabolic in vitro 
turnover and genotype. Genotyping patients for polymorphisms of metabolising enzymes 
to understand its impact on the clinical PK of CB-103 is foreseen in the clinical protocol 
(refer to the Schedule of Assessments). Preliminary results of these pharmacogenetic 
investigations exploring the potential influence of NAT genotypes on the PK of CB-103 
have not revealed any correlation or effect on the pharmacokinetics of CB-103. 
2.5.3.2 
Prediction of Human PK from Non-Clinical Studies (Allometric 
Scaling) 
Allometric scaling for CB-103 using mouse, rat and dog intravenous (i.v.) PK data was 
performed to predict the human PK parameters CL, volume of distribution at steady state 
(Vss) and t1/2.  
Table 2 summarises the prediction along with the input values for the scaling. No 
correction for plasma protein binding was performed as the differences across species is 
minimal (binding approx. 98% in all species). 
Table 2 
Pharmacokinetic parameters observed in mouse, rat and dog and 
predicted for humans using allometric scaling 
Species 
Data Source 
 
Body weight 
Mouse 
CB-103-
ADME010 
0.025 kg 
Rat 
CB-103-
ADME011 
0.3 kg 
Rat 
CB-103-
T002  
0.38 kg 
Dog 
CB-103-
T001 
12 kg 
Human 
PREDICTED 
 
70 kg 
CL (mL/h/kg) 
3627.5 
2481.3 
3940 
456 
 
CL (mL/h) 
90.7 
744.39 
1497.2 
5472 
23520 
Vss (mL/kg) 
1664.8 
1125.3 
897 
5670 
 
Vss (L) 
0.042 
0.338 
0.341 
68.0 
380 
T1/2 (h) 
0.49 
0.73 
0.157 
10.2 
16.2 
Bioavailability (F) 
100% 
16.3% 
15.4% 
81% 
 
Plasma Protein 
Binding (%) 
98.3 
98.2 
98.7 
97.0 
 
Data in bold are measured, data in italics are calculated. Parameters for humans are predicted. 
 
For the human predicted values of CL 23520 mL/h (or 23.52 L/h) and of Vss 380 L, the 
estimated half-life (Vss/CL) is around 16 hours. It is therefore expected that CB-103 needs 
about 3 to 4 days to reach steady state concentrations. With daily administration, the 
predicted accumulation ratio (AR) would be 1.5. The first dose level administered in this 
clinical protocol is 15 mg (fixed dose) and the expected AUC at this dose is 639 µg*h/mL 


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assuming complete bioavailability of the compound after oral administration. If the 
bioavailability of CB-103 in humans is less than 100% the exposure with be respectively 
lower. 
2.5.4 
Animal Toxicology and Toxicokinetics 
The pre-clinical safety and toxicology package presented for CB-103 determined the 
tolerability of the compound in rodent and non-rodent species over a wide range of doses 
and exposure levels. 
The assessment of the safety of CB-103 in rats and dogs demonstrates a safety profile 
commensurate with administration to cancer patients. A finding common to both rat and 
dog toxicology studies with CB-103 was reduced thymus weight with accompanying 
histological changes. Effects in the thymus, as described in rats and dogs dosed with 
CB-103, are commonly associated with stress induced by many different stressors, 
including high systemic exposure to xenobiotics (Everds et al., 2013), therefore these are 
not a safety risk for humans.  
The liver was a target organ in both rats and dogs. In rats, hypertrophy and resultant 
increased liver weight are indicative of an adaptive response due to the presence of large 
amounts of a xenobiotic present in the liver. Likewise, the hepatomegaly and histological 
changes that occurred in the MTD study are considered due to the presence / 
accumulation of large amounts of compound. Of note, no changes occurred in livers of 
dogs from the 28-day GLP study, therefore the changes in the livers of rats and dogs given 
high doses of CB-103 are not a toxicological risk to cancer patients. 
In both rats and dogs, dilation of the pupils occurred. In rats this effect was evident at 
doses of 10 and 30 mg/kg/day (GLP 28-day study). In dogs this was evident at all doses 
in the GLP 28-day study (1, 3, 10 mg/kg/day) and at 25 mg/kg/day in the non-GLP 
MTD/fixed-dose study.  In rats, retinal atrophy was present in females at the end of the 
28-day GLP study and was still present at the end of the recovery period. Retinal atrophy 
was also present in males at the end of the recovery period whereas it was not present at 
the end of the dosing period. The exact mechanism of retinal atrophy caused by CB-103 
remains unclear, however it is consistent with observations in albino rats exposed to 
excess light (De Vera Mudry et al, 2013), therefore the retinal degeneration is considered 
secondary to dilation of the pupils. Importantly, retinal atrophy was not present in dogs 
and is therefore not expected in humans. No specific eye exams are foreseen in the clinical 
protocol, but pupil size in patients will be monitored as part of the regular physical 
examination occurring at every study visit. 
Severe toxicity and unscheduled death were only observed at very high doses given 
repeatedly to rats and dogs leading to exposure levels above 4000 ng/mL (Cmax) and 
30,000 ng*h/mL (AUC0-24). The 28-day GLP toxicity studies in rats and dogs determined 
10 mg/kg/day and 2.6 mg/kg/day as the no observed adverse effect level (NOAEL), 
respectively with minimal signs of toxicity and exposure levels of approx. 300-500 ng/mL 
(Cmax) and approx.1300-3400 ng*h/mL (AUC0-24). The findings at the next higher dose 


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levels in both species were still mild and reversible. The observations in rats at 30 
mg/kg/day included transient clinical signs (ploughing, salivation, decreased activity and 
pale/dark eyes), decreased body weight gain, changes in haematology, clinical chemistry 
parameters and increased liver and spleen weights correlating with erythropoiesis in the 
spleen and hypertrophy on the liver. The observations at 8.6 mg/kg/day in dogs included 
dilated pupils, pale skin and gums, rimmed eyelids and lacrimation, decreased activity, 
apparent pain, changes in thymus and spleen and an increased reticulocyte count. 
Therefore, 30 mg/kg/day in rats and 8.6 mg/kg/day in dogs are considered the highest 
non-severely toxic doses (HSNTD) with exposure levels of approx. 1200-3100 ng/mL 
(Cmax) and 6000-9000 h.ng/mL (AUC0-24). The starting dose in humans (15 mg) targets an 
AUC0-24 of 600 h.ng/mL after repeated administration (Section 2.5.3.2), which equals 
1/10th of the HSNTD in the most sensitive species (rat AUC0-24 on Day 28 at 30 mg/kg/day 
5980 h*ng/mL in male rats). 
CB-103 is not mutagenic in the S. typhimurium tester strains (TA1537 or TA98) or E. coli 
reverse mutation assay strain WP2uvrA. The positive results from the S9-mix showing 
mutagenic response with the tester strains TA1535 and TA100 of S. typhimurium in the 
presence of S9-mix suggest that metabolites of CB-103 generated in the presence of 
S9-mix might be mutagenic. However, no additional studies were performed as these were 
not required according to the “ICH S9 Nonclinical evaluation for anticancer 
pharmaceuticals Guideline” to support clinical trials for therapeutics intended to treat 
patients with advanced cancer. 
2.5.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biological 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. Multiple potential biomarkers relevant to the NOTCH signalling pathway and 
mechanism of action of CB-103 have been incorporated into this study to explore the 
relationship between the expression or presence of appropriate markers and clinical 
outcome. In addition, the PD effects of CB-103, including their usefulness in determining 
the recommended phase 2 dose based on considerations for optimal biological dosing of 
CB-103 will be explored. The success of the overall biomarker strategy will be dependent 
on obtaining sufficient tumour material at pre- and post-treatment with CB-103 at a 
selected time point after the initiation of CB-103 dosing. 
2.5.5.1 
Patient Profiling Biomarkers 
Various biomarker approaches to detect genetic aberrations of NOTCH signalling and to 
characterise the functional level of NOTCH activation have shown to be of value with 
regards to the prognostic value that these NOTCH aberrations have in terms of poorer 
survival seen in patients of different tumour indications, as well as to be used to select the 
right patient population for treatment with a NOTCH inhibitor (Takebe et al., 2015). As 
there are different genetic alterations of the NOTCH pathway, known to cause NOTCH 
over- and constitutive activation and that their functional role may be different in different 


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cancer indications, there will be a need to develop and apply several methods to detect 
and characterise these in tumour samples.  
NOTCH1-mutant ACC tumors have demonstrated significantly higher levels of Notch1 
pathway activation than wild-type tumors on the basis of Notch1 intracellular domain 
staining. NOTCH1 mutations define a distinct disease phenotype characterized by solid 
histology, liver and bone metastasis, poor prognosis, and potential responsiveness to 
Notch1 inhibitors (Ferrarotto et al 2016).  
The use of NOTCH-specific biomarkers and different methods used for their detection for 
patient selection will be explored in Part A (escalation) in a retrospective fashion, whereas 
it will be prospectively applied for patient selection in Part B (expansion) of the study. 
Characterisation of functional NOTCH activation in tumour samples will be based on 
detection of the different genetic aberrations of the NOTCH signalling pathway found in 
various cancer indications and/or the characterisation of the activation level of NOTCH 
signalling at the protein and/or RNA level.  
Genetic mutations of the NOTCH pathway known to cause over-activation of NOTCH 
signalling (such as single nucleotides variations, InDels, structural variations 
(rearrangements), copy number variations) will be assessed by next-generation 
sequencing (NGS). NICD1 IHC and/or gene expression analysis can also be used to 
assess NOTCH pathway activation.  
Details on the collection, handling and processing of the required specimens for the 
diagnostic (patient selection) and exploratory biomarker studies will be provided in a 
separate Laboratory Manual. 
2.5.5.2 
Pharmacodynamic Markers of NOTCH Inhibition 
The available published data show that NOTCH inhibitors produce demonstrable PD 
effects, such as the reduction of NOTCH pathway components (e.g. NOTCH NICD) and 
the down-regulation of various NOTCH target genes in both tumours and surrogate tissues.  
For GSI treatment reports have shown that measurement of NOTCH1 NICD by 
immunohistochemical (IHC) staining (Kluk et al., 2013) and HES-1 and HES-4 as NOTCH 
target genes represent the most promising predictive biomarkers of response to NOTCH-
targeted therapies in TNBC and ACC (Stoeck et al., 2014). 
In this clinical study, NOTCH inhibition will be assessed in whole blood and plasma 
samples, in hair follicles and available tumour specimens (pre- and post-treatment) by 
evaluating several PD markers of target modulation and mode of action such as the 
reduction of certain NOTCH-related components of the pathway, as well as the modulation 
of key NOTCH-specific and -related genes.  
Technologies as NGS and nCounter Nanostring gene expression analysis will be used to 
detect the different genetic lesions of the NOTCH pathway, and the expression of the 
functional target genes at the molecular level. IHC or Western Blot may be used to assess 
expression levels of NOTCH pathway related proteins. The oncogenic function of NOTCH 


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signalling is well understood and can be detected in various solid tumour indications and 
frequently in numerous haematological malignancies. 
Details on collection, handling and processing of the required specimens for the PD 
biomarker analysis will be provided in a separate Laboratory Manual. 
2.5.5.3 
Pharmacodynamic Markers of Cellular Effects 
The response biomarkers for NOTCH inhibitors primarily include tumour or cellular effect 
markers that indicate changes in tumour cell growth or viability that may be necessary for 
inducing a clinical response. Cellular signalling through the oncogenic NOTCH target 
proteins is critical for cell proliferation and survival, which is obtained through the positive 
regulation of cell cycle, transcription, translation, and the repression of apoptotic 
machinery. Inhibition of NOTCH signalling will result in a reduced expression of the target 
proteins and as a result, a decrease in cellular proliferation and/or an increase of apoptosis 
is expected, and both of these effects can be quantitated as early response markers. 
Specifically, it is planned to measure apoptosis markers and Ki67, a cellular proliferation 
marker, by IHC in pre- and post-treatment tumour biopsy samples and hair follicles, or T-
lymphocytes from blood and/or bone marrow samples in T-ALL/T-LBL.  
Details on the collection, handling and processing of the required specimens for the 
biomarkers’ analysis will be provided in a separate Laboratory Manual. 
2.5.6 
Clinical Experience 
This is the first clinical study on the safety and efficacy of CB-103 oral capsules for the 
treatment of patients with locally advanced or metastatic solid tumour and haematological 
malignancies to date. 
As of 20 August 2020, 41 patients (median age 55 years, range 25 to 76 years) with solid 
tumours have been treated with CB-103 in the dose escalation part of the clinical study at 
oral doses of 15 mg-600 mg QD. Preliminary safety data indicates that CB-103 is well 
tolerated with 73.3% of adverse events (AEs) being mild (Grade 1) or 21% moderate 
(Grade 2) in severity, and 5.7% Grade 3. All AEs were evenly distributed over the dose 
cohorts with no evidence of dose relation. Cumulatively, a total of 352 AEs has occurred 
in 41 patients since study initiation, of which 132 AEs (37.2%) in 31 patients were 
considered related to the study drug. The treatment-related treatment-emergent AEs 
(TEAEs) most commonly reported (≥10% of patients) were nausea (24%), diarrhea (20%), 
dyspepsia (15%), fatigue (12%), and vision blurred (12%). 
The majority of treatment-related TEAEs resolved or were resolving at the time of data 
cut-off without requiring medications or discontinuation of CB-103 dosing. The study 
includes intense ECG monitoring. There was one related AE of tachycardia Grade 1 (in 
cohort 2; 30mg QD). Overall, there was no signal of cardiotoxicity and no QTc 
prolongations have been reported to date.  


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No events of skin phototoxicity or eye mydriasis have been reported to date in this study. 
Of the 352 AEs reported, 12 (3.4%) were considered serious adverse events (SAEs) and 
included abdominal pain, anorexia, atrial flutter, cardiac failure congestive, drug-induced 
liver injury, duodenal haemorrhage, dyspnoea, general physical condition decreased, 
respiratory tract infection, spinal cord compression, transaminase increase, and tumour 
pain. Of these, one SAE was considered related to study drug (drug-induced liver injury), 
which was reported in a patient with metastatic adenoid cystic carcinoma with extensive 
liver involvement, treated at an intermediate dose level. 
One patient in cohort 8 (600mg) experienced one dose limiting toxicity (DLT). This was an 
elevation of the gamma-glutamyl transferase (GGT), grade 3, that was asymptomatic and 
deemed not clinically significant by the investigator. There has been one unrelated SAE 
with fatal outcome due to respiratory tract infection in cohort 1 (15 mg). No deaths due to 
drug-related AEs have been reported to date. 
CB-103 is rapidly absorbed after oral administration and reaches Cmax within 1 to 2 hours 
of dosing. Plasma exposure increases with increasing doses. There were no signs of 
saturated absorption in the dose range tested. The elimination half-life is approximately 
20 hours and CB-103 accumulates about 2-fold with repeated daily administration. Steady 
state concentrations are reached within one week of dosing. 
Hair follicles used as surrogate tissue were obtained at pre-defined time points to measure 
changes in NOTCH target genes expression by CB-103 treatment. In patients in the 
ongoing phase 1 study, average target gene downregulation on Cycle 2 day 1, 1h post-
dose compared to baseline prior to treatment with CB-103 showed a strong dose-
dependent down-regulation of several NOTCH target genes, reaching values higher than 
70% inhibition at the highest CB-103 dose tested in this series (250mg). Additionally, a 
sustained time-dependent down-regulation of NOTCH target genes was observed, 
reaching up to a 90% inhibition after 4 weeks of daily administration of CB-103 at 250mg 
dose. 
Clinically, best response was durable stable disease (SD) with no or only mild AE at doses 
showing target engagement. Ten patients with ACC had radiologically confirmed SD, of 
whom 4 patients had a Notch activating mutation or fusion. The Notch status of the other 
patients is under investigation. Disease control rate (DCR) of 19 ACC patients at 3 months 
was 68% (DCR defined as number of patients with CR, PR, or SD divided by the number 
of patients treated).  
Based on the safety profile, the Cohort Review Committee declared the dose of 600mg 
given once daily QD as a safe dose. The MTD was not reached. The Bayesian statistical 
model allows further dose escalation to 800mg. Because the visual symptoms caused 
considerable discomfort to some patients, the 600mg dose was declared as provisional 
RP2D for further exploration in the dose confirmatory cohort. In parallel, a twice daily 
schedule of CB-103 is being explored. 


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Emerging clinical data and any safety findings from this study will be summarized in the 
Investigator Brochure for CB-103.  
2.5.6.1 
Risk Mitigation Strategies 
For this first-in-human study, strategies to mitigate risks have been considered as per the 
Guideline on strategies to identify and mitigate risks for FIH and early clinical trials with 
investigational medicinal products (EMEA/CHMP/SWP/28367/07). Based on the findings 
from the GLP Safety Pharmacology and Toxicology studies, a thorough cardiac monitoring 
with frequent ECG, periodical Holter monitoring and echocardiogram (ECHO)/multigated 
acquisition (MUGA) scans will be performed to detect any early cardiac effects of CB-103 
in patients and a continuous central reading for the ECGs will be implemented in Part A 
(dose escalation) and also in Part B of this study (depending on the results from Part A). 
Additionally, adverse events will be strictly monitored within each part of the study. 
Sufficient data from Part A will be collected in order to ensure safety of selected 
dose/exposure for Part B. For any unanticipated pharmacological responses detected, a 
revised dose escalation will be required. 
2.5.6.2 
Drug-Drug Interaction Potential 
Based on available in vitro data with CB-103 the following points regarding potential drug-
drug interactions (DDI) have been considered. 
Absorption DDI 
A majority of the novel orally administered, molecularly targeted anticancer therapies are 
weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with 
acid-reducing agents (ARAs) could potentially influence their absorption (Budha et al., 
2012). ARAs are the most commonly prescribed medications in North America and 
Western Europe and the prevalence of their use among cancer patients is high. Smelick 
et al (Smelick et al., 2013) reported that among all cancer patients, the total prevalence 
proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) 
was 20% and 33% from the MarketScan and VA databases, respectively. Proton pump 
inhibitors (PPIs) were the most commonly prescribed agent, comprising 79% and 65% of 
all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a 
PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, 
respectively. 
CB-103 is a weak base and its solubility is pH dependent. The solubility is 0.77 mg/mL at 
pH 1.6 and drops steeply to 0.26 mg/mL at pH 2.9 and 0.11 mg/mL at pH 3.3. At pH values 
of 3.9 and higher the compound is very poorly soluble (approx. 0.06 mg/mL). It is therefore 
possible that the concomitant administration of ARAs may reduce the absorption of the 
drug and lead to lower drug exposure.  


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In a PK sub-study to this protocol, where ranitidine was given to a group of patients prior 
to dosing with CB-103, there was no difference in plasma concentrations of CB-103 
compared to patients who did not take ranitidine.  
Metabolism DDI 
Effect of CB-103 on other drugs: In vitro testing of Cytochrome P450 (CYP) inhibition 
with pooled probe substrates in human liver microsomes by CB-103 (10 µM) showed a 
low potential to directly inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4. Furthermore, in vitro 
experiments showed no indication for CYP induction by interactions with the pregnane X 
receptor (PXR) or aryl hydrocarbon receptor (AhR). It appears therefore, that the potential 
for CB-103 to cause significant drug-drug interaction via inhibiting or inducing CYP 
isoenzymes is low. However, since the in vitro data are preliminary at this stage and since 
the results of experiments to investigate time dependent inhibition of CYP isoenzymes by 
CB-103 are still pending, caution should be exercised when CB-103 is combined with 
substrates of CYP enzymes that have a narrow therapeutic index. 
Effect of other drugs on CB-103: The metabolism of CB-103 in humans is still under 
investigation. In vitro data using human recombinant CYP enzymes have shown that CB-
103 is a substrate for CYP1A1 and 2C19 and can also be metabolized by 2B6, 2C9, 2E1 
and 4A4. However, CB-103 is metabolically very stable in human liver microsomes, 
indicating that even though CB-103 is a substrate for several CYP isoenzymes, the overall 
contribution of CYP-mediated metabolism to CB-103 elimination in humans could 
potentially play a minor role. Metabolism of CB-103 in human hepatocytes is much faster 
than in microsomes and seems to be driven by N-acetylation via N-acetyl transferase 
(NAT). As the prediction of clinically relevant drug-drug interactions affecting CB-103 
plasma concentration is difficult at this stage, it is advised that strong inhibitors and 
inducers of CYP isoenzymes and NAT1/2 should be avoided during treatment with CB-103. 
Monoamine Oxidase 
CB-103 can inhibit MAO-A and B at high concentrations (IC50 9.8 and 4.3 µM), but 
clinically relevant drug-drug interactions are unlikely at therapeutic concentrations of CB-
103 (1 µM) due to the high plasma protein binding of the compound. Nevertheless, as 
interactions of monoamine oxidase inhibitors with compounds that affect serotonin levels 
(e.g. SSRIs, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, 
tryptophan, dextromethorphan, meperidine) can increase the risk of serotonin syndrome 
(caused by excessive activation of serotonin receptors in the central nervous system) 
caution should be exercised when these drugs are combined with CB-103. Clinical 
manifestations represent a concentration-dependent spectrum of toxicity ranging from 
barely noticeable to seizures, coma and death. Early recognition and treatment are 
therefore essential. 
 
 


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3. 
STUDY RATIONALE AND PURPOSE 
3.1 
STUDY RATIONALE 
The primary purpose of this Phase I/IIA study is to establish the safety profile and to 
determine and subsequently confirm the MTD or RP2D of CB-103 when administered 
orally on a continuous daily dosing schedule in adult patients with locally advanced or 
metastatic solid tumour and haematological malignancies. If MTD cannot be reached, the 
RP2D will be determined based on the dose level which can be taken by the patient with 
an acceptable risk-benefit.  
The recruitment of patients into several expansion arms in Part B of the study will allow to 
further characterise the safety, preliminary efficacy and multiple dose PK of CB-103 at the 
MTD/R2PD and schedule determined in Part A of the study. In this expansion part of the 
study, the tumours are required to have confirmed genetic alterations or over-activation of 
the NOTCH signalling pathway. Several cancer indications are investigated in this study 
in order to confirm the safety and tolerability of the MTD/RP2D and to assess preliminary 
efficacy, as outlined below.  
NOTCH pathway activated tumours under investigation: 
• 
Breast cancer (TNBC, estrogen receptor [ER]+/-, HER2+/-), gastro-intestinal 
cancers (resistant to oxaliplatin or irinotecan-based therapy colorectal cancer, 
hepatocellular carcinoma), osteosarcoma, ACC, malignant glomus tumour, and T-
ALL/T-LBL. 
For some of the indications mentioned above there are only specific subtypes selected for 
the study. The respective subtypes of these indications are presented in Appendix 3. 
Additionally, NOTCH pathway activation has been reported in other tumours with lower 
frequency. Patients whose tumours exhibit Notch pathway activation are eligible for this 
study even if the tumour is not among the indications mentioned above. 
3.2 
POTENTIAL RISKS AND BENEFITS 
The Risk/Benefit assessment is based on (i) numerous pre-clinical models demonstrating 
the anti-tumour activity of CB-103, (ii) several non-clinical repeat dose toxicity studies 
conducted in rats and dogs, with GLP-compliant studies with dosing up to 28 days 
conducted in each species and (iii) and on the available documentation of the safety of 
other NOTCH inhibitors currently in early clinical development with different modes of 
actions taken into account. 
Unmet clinical need: For many patients with advanced solid tumour or hematologic 
malignancies where the available and approved curative treatments have failed and the 
disease progresses and becomes treatment resistant and refractory, there is no further 
therapeutic option available and this represents a patient population with high unmet 
clinical need. In this context, many studies report a negative correlation of NOTCH 


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signalling activation and survival in patients with tumour cells characterised by genetic 
aberrations or over-activation of NOTCH signalling. These patients have a worse 
prognosis and significantly shorter survival than patients with a NOTCH wild-type tumour. 
Potential benefits: Based on nonclinical studies and the known clinical efficacy 
deficiencies of other NOTCH inhibitors in clinical testing as well as the strong negative 
prognostic impact of NOTCH over- and constitutive activation, it is thought that CB-103 
could provide benefit and an improvement to the treatment of NOTCH-positive solid 
tumour and haematological malignancies. In addition to the impact of aberrant NOTCH 
signalling on malignant proliferation and growth, the well-defined target of CB-103 and its 
new mode of action to block NOTCH signalling most downstream of the pathway at the 
level of the transcription complex and its proven ability to kill tumour cells in different in 
vitro and in vivo cancer models, as well as ex vivo to directly kill primary patient-derived 
leukaemia cells, supports the rationale and hypothesis that CB-103 will show efficacy in 
various solid tumour and haematological malignancies. 
Potential risks: As outlined in Section 2.4, other NOTCH inhibitors with different modes 
of action compared to the central binding of CB-103 to the NOTCH-specific transcription 
complex, namely the GSIs and mAB targeting NOTCH receptors or ligands, have shown 
clinical efficacy in early stages of clinical development. However, due to the occurrence of 
toxicities reported in several clinical studies many patients had to discontinue treatment 
before the full benefit of anti-NOTCH treatment was achieved. The dose-limiting toxicities 
seen with GSIs are gastrointestinal with partially severe episodes of diarrhoea (goblet cell 
accumulation) leading to early and permanent treatment discontinuation. Besides the 
gastrointestinal toxicities, observed also with several of the mABs, there were also some 
cardiotoxicities reported from clinical studies with this class of drugs. In particular, with the 
anti-DLL-4 antibody Demcizumab, some patients were identified with cardiac 
insufficiencies leading also to early and permanent treatment discontinuation and 
correction of the dose and schedule of these drugs had to be made for these programs. 
These toxicities have not been observed in the non-clinical studies of CB-103 at the doses 
and schedules used and therefore the Sponsor believes that the safety profile to be 
established for CB-103 in humans might be better than those observed with the other 
NOTCH inhibitors which are currently in phase I and II clinical testing. 
The safety and toxicology of CB-103 has been adequately evaluated in rat and dog during 
the non-clinical development following the current regulatory requirements for the support 
of the proposed Phase I/IIA clinical trial. Several non-GLP and two GLP-compliant 28-day 
MTD in vivo single and repeated dose toxicology studies, have been performed in one 
rodent (rat) and one non-rodent (dog) species following oral administration for the 
treatment duration up to 28 days. In these studies, no major signs of toxicity were observed 
and the dose-limiting factors in rats were adverse event findings in lungs, eyes (dilated 
pupils), liver and spleen (increased extramedullary erythropoiesis). In dogs, the dose-
limiting factor was the slight transient changes in heart rate and QTc. The ECG changes 
seen in dogs together with the non-clinical finding that CB-103 can block the hERG and 


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ion channel at high doses with a high peak concentration, suggest that CB-103 may have 
some potential to affect cardiac repolarisation and cardiac conduction. The clinical 
consequence of this finding is currently unknown as the translatability of ECG changes 
from dogs to humans is not known. As part of risk management, a robust, multiple ECG 
monitoring aligned with PK sampling - including periodical Holter monitoring, with 
concentration-response analysis and a central review performed by a cardiac expert - will 
be implemented in the study. Furthermore ECHO/MUGA scans will be performed at 
selected time points in the study to also investigate any effect of CB-103 on heart 
contractility. Patients should be monitored for clinical signs of heart abnormalities, and 
consideration be given to withdrawal from the study of any patients who develop signs of 
cardiac abnormalities taking into consideration overall benefit and risks for the patients. 
Based on pre-clinical data with CB-103 and on information known from other drugs 
inhibiting the NOTCH pathway the following events might appear after CB-103 oral 
administration (see also Investigator’s Brochure): 
• 
ECG alterations 
• 
Hypertensive events 
• 
Cardiac dysfunction (New York Heart Association [NYHA] Class II-IV) including 
congestive heart failure with signs and symptoms of cardiac dysfunction such as 
dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or 
reduced ventricular ejection fraction, that can be associated with fatal outcome. 
• 
Increased extramedullary haematopoiesis (e.g. erythropoiesis) 
• 
Splenomegaly 
• 
Gastro-intestinal toxicities (diarrhoea, nausea, vomiting, abdominal pain) 
• 
Mydriasis (dilated pupils) 
• 
Phototoxicity  
• 
Skin rash and redness 
• 
Decreased physical activity and fatigue 
• 
Decreased body weight 
• 
Convulsions 
• 
Oedema 
The severity and seriousness of adverse events cannot be defined yet as this will be the 
first clinical study with CB-103. With respect to additional unknown risks, as per normal 
practice for Phase I, FIH clinical trials, the patients will be closely monitored in order to 
detect any additional, study drug-related adverse events.  
The phototoxicity was deemed a hypothetical risk solely based on the UV spectrum peak 
absorption of the drug substance (CB-103 HCl) in the wavelength of 290 - 700 nm; 
phototoxicity was not observed in any pre-clinical studies with CB-103. 
The potential risk of phototoxicity and occurrence of mydriasis are two distinct potential 
risks to be considered separately as the occurrence of both in the eye is rather rare, but 
the below precautionary measures will also cover this risk of coincidence. 


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In order to avoid potential drug-induced phototoxicity and to protect the patient from any 
harm caused by the occurrence of dilated pupils the measures below should be followed 
and the patients should be informed accordingly:  
• 
Limit prolonged sun exposure 
• 
Wear protective clothes 
• 
Wear sunglasses when exposed to bright sun 
• 
Use sun cream with high sun protection factor on skin when exposed to bright sun 
• 
Immediately notify the study doctor about any eye symptoms or blurred vision 
• 
Refrain from activities that may cause the risk of an accident, in the event of any 
eye symptom or vision impairment (e.g. driving car, bike, operating machines). 
In order to detect any potential cardiac effects of CB-103 already early on, an intense, 
continuous ECG monitoring with central management and read by a specialised CRO to 
assess cardiac safety as well as Holter ECG monitoring to detect any arrhythmias and 
echocardiogram/multi-gated acquisition (ECHO/MUGA) scans to assess LVEF will be 
assessed at baseline and at selected time points throughout the study to ensure the 
patients’ health and safety at all times during the treatment period. 
CB-103 will be administered orally as single agent. 
In summary, the risks for patients in the FIH clinical trial are expected to be acceptable as 
they are largely predictable, monitorable and treatable in an appropriately equipped 
hospital environment. 
Conclusion: Taking these potential benefits and risks into consideration, the Sponsor is 
of the opinion that the potential benefit of CB-103 for patients with locally advanced or 
metastatic solid tumours and haematological malignancies outweighs the potential risk.  
3.3 
CONDUCT OF STUDY 
This clinical study will be conducted in compliance with this protocol, the guidelines of the 
World Medical Association Declaration of Helsinki, the ICH, Harmonised Tripartite 
Guidelines for GCP (R2), the European Directive 2001/20/EC, designated standard 
operating procedures (SOPs), and with local laws and regulations relevant to the use of 
new therapeutic agents in the country of conduct. 
 
 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
STUDY OBJECTIVES 
4.1.1 
Primary Objectives 
Phase I, Part A - Dose Escalation: 
• 
To determine the MTD or RP2D of CB-103 as a single agent in adult patients.  
Phase I, Part A – Confirmatory Cohort: 
• 
To confirm safety of the RP2D of CB-103 as a single agent in adult patients.  
Phase IIA, Part B - Expansion: 
• 
To assess preliminary anti-tumour activity of single agent CB-103 in the different 
expansion arms across the different indications. 
4.1.2 
Secondary Objectives 
The secondary objectives for parts A and B of this study are: 
• 
To characterise the PK characteristics of CB-103 in patients after single and repeated 
administration at various dose levels. 
• 
Part A only:  
‒ 
To characterise safety and tolerability of the MTD/RP2D of CB-103 in 
patients with selected solid tumours and hematological malignancies. 
‒ To assess preliminary anti-tumour activity of single agent CB-103. 
• 
Part B only: 
‒ 
To further characterise safety and tolerability of the MTD/RP2D of CB-103 
in patients with selected solid tumours and haematological malignancies, 
stratified by disease into separate expansion arms. 
4.1.3 
Exploratory Objectives 
The exploratory objectives for parts A and B of this study are: 
• 
To characterise the pharmacokinetic (PK) characteristics of CB-103 in subgroups of 
patients (e.g., by indication or ethnicity) after single and repeated administration at 
various dose levels. 
• 
To explore potential correlations between PK and parameters of efficacy (e.g. tumour 
response, tumour shrinkage, tumour metabolic activity), PD markers (genes and 
proteins) and safety (e.g. occurrence of adverse events, relationship of CB-103 
concentration versus 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]). 


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• 
Positron Emission Tomography (PET) in selected tumours: baseline and on-treatment, 
18Fluoro-deoxyglucose positron emission tomography (FDG-PET) in combination with 
CT (PET-CT) will be collected to determine changes in glucose metabolism of the 
tumour lesions in tumour types exhibiting FDG-uptake. 
• 
To investigate plasma levels of metabolite(s) when feasible. 
• 
To explore the CB-103 metabolic profile in biological matrices such as urine and/or 
stool samples. 
• 
To assess changes in NOTCH target and downstream PD markers (genes, proteins) 
in solid tumours:  
‒ 
pre- and post- CB-103 dosing in tumour tissue biopsies as a measure 
of NOTCH pathway inhibition; 
‒ 
pre- and post- CB-103 dosing in whole blood, plasma samples and hair 
follicles (if the appropriate laboratory is available) as a surrogate model 
to measure NOTCH pathway inhibition. 
• 
To assess changes in NOTCH target genes and downstream PD markers (genes, 
proteins) in haematological malignancies: 
‒ 
pre- and post- CB-103 dosing in T-lymphocytes from blood and/or bone 
marrow samples; 
‒ 
pre- and post- CB-103 dosing in whole blood and plasma samples (if 
the appropriate laboratory is available). 
• 
To assess the changes in the percentage of mutated alleles in liquid biopsies pre- 
and post CB-103 dosing and their relation to the effect of CB-103 treatment. 
• 
To evaluate the cerebrospinal fluid (CSF) exposure of CB-103 in patients with 
haematological malignancies, in whom intra-thecal (IT) prophylaxis is planned by the 
treating physician. 
• 
To explore the potential influence of certain genotypes (e.g. CYP enzymes or NAT) 
on the PK of CB-103. 
• 
Exploratory analysis may be performed on tumour tissue samples or on blood 
and/or bone marrow samples as a part of this study to identify gene 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. 
• 
Exploratory CB-103 quantification analysis may be performed on tumour tissue 
samples. 
• 
To evaluate the potential role of biomarkers and genetic markers for safety, PD, and 
anti-tumour activity of CB-103 and to define the optimal biological dose of CB-103. 
• 
To explore and assess changes in the immune system in pre- and post-CB-103 
dosing whole blood and plasma. 
• 
Additional exploratory analyses may be performed on available samples from the 
study, for example to establish a correlation of biomarkers across methods or types 
of tissue. 


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Note: during the course of the study, sample collection for and analysis of any of the 
above-mentioned exploratory objectives may be stopped for all patients or in selected 
patients’ groups depending on the emerging preliminary data; the decision will be 
documented in a Note to File. 
4.2 
STUDY ENDPOINTS 
4.2.1 
Primary Endpoints 
The primary endpoint for Phase I, Part A (dose-escalation) of this study is as follows: 
• 
The number of patients experiencing dose-limiting toxicity (DLT) during the first 
28-day cycle of CB-103 treatment 
The primary endpoint for Phase I, Part A (confirmatory) of this study is as follows: 
• 
The incidence rate, severity and relationship to CB-103 of adverse drug reactions and 
serious drug reactions according to common terminology criteria for adverse events 
(CTCAE) V4.03, safety laboratory, vital signs, ECG and ECHO/MUGA assessments. 
The primary endpoint for Phase IIA, Part B of this study is as follows: 
• 
To assess tumour response rates in each expansion arm as best overall response 
rate (in solid tumours complete response [CR] + partial response [PR]) assessed by 
Response Evaluation Criteria in Solid Tumours (RECIST 1.1); in T-ALL/T-LBL 
patients, confirmed CR and Complete Remission with Incomplete Hematologic 
Recovery (CRi) assessed by the criteria according to NCCN Guidelines on Adult 
Acute Lymphoblastic Leukaemia (Version 1.2020). 
4.2.2 
Secondary Endpoints  
The secondary endpoints for both Part A and B of this study are as follows, unless 
otherwise specified: 
• 
The incidence rate, severity and relationship to CB-103 of adverse drug reactions and 
serious drug reactions according to common terminology criteria for adverse events 
(CTCAE) V4.03, safety laboratory, vital signs, ECG and ECHO/MUGA assessments 
in each dose group and expansion arm. 
• 
CB-103 plasma concentrations, PK parameters: Cmax, tmax, Cmin, Clast, tlast, area under 
the curve (AUC) during 8 and 24 hours (AUC0-8, AUC0-24), AUC from time 0 
extrapolated to infinite time (AUC0-∞), apparent volume of distribution (Vd/F), apparent 
volume of distribution at steady (Vss/F), apparent clearance after oral administration 
(CL/F), t1/2 and AR. 
• 
Part A only: to assess tumour response rates 
‒ 
For solid tumour indications:  to assess best overall response rate (CR + 
PR), assessed by RECIST 1.1 (Eisenhauer et al., 2009). 
‒ 
For haematologic malignancies: to assess the best overall response rate 
(CR or CRi) per NCCN guidelines. 
• 
To assess clinical benefit rate 


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‒ 
For solid tumour indications:  clinical benefit rate (CR + PR + SD), 
assessed by RECIST 1.1. (Eisenhauer et al., 2009). 
• 
Duration of response (DOR), time to response, progression-free survival (PFS), OS. 
4.2.3 
Exploratory Endpoints 
The exploratory endpoints for both Part A and B of this study are as follows: 
• 
To assess plasma levels and PK parameters (Cmax, tmax, Cmin, Clast, tlast, AUC0-8, 
AUC0-24, AUC0–∞, t1/2 and AR) of metabolite(s) when feasible. 
• 
To evaluate the relationship between CB-103 plasma concentrations and/or PK 
parameters (e.g., Cmax and AUC0-24) and safety, efficacy and PD parameters. 
• 
To assess NOTCH, NOTCH-related genes, and NOTCH target genes expression 
changes in pre- and post-treatment tumour tissue samples, whole blood / plasma 
samples and hair follicles in solid tumours and  in T-lymphocytes from blood and/or 
bone marrow samples, whole blood and plasma in T-ALL/T-LBL, and assess their 
relation to clinical activity of CB-103. 
• 
To assess the cerebrospinal fluid (CSF) exposure of CB-103 in haematological 
malignancies, in patients in whom IT prophylaxis is planned by the treating physician. 
• 
To assess certain genotypes (e.g. cytochrome P450 enzymes or NAT) and assess 
relation to PK outcome data. 
• 
To assess NOTCH1-4 NICD expression assessed by IHC staining or by Western Blot 
in pre- and post-treatment in solid tumour tissue samples and to assess their relation 
to clinical activity of CB-103. 
• 
To assess NOTCH mutations by genomic mutation analysis in tumour tissue samples 
in solid tumours and in T-lymphocytes from blood and/or bone marrow samples, 
whole blood and plasma in T-ALL/T-LBL, and to assess their relation to clinical activity 
of CB-103 treatment. 
• 
To assess the changes in the percentage of mutated alleles in liquid biopsies pre- 
and post CB-103 dosing and their relation to the effect of CB-103 treatment. 
• 
To evaluate the intra-tumoral quantification of CB-103 in solid tumour tissue samples.  
• 
To profile tumour tissue samples in solid tumours and T-lymphocytes from blood 
and/or bone marrow samples in T-ALL/T-LBL by single cell RNA-seq and/or other 
gene expression and genetic profiling techniques.  
• 
To explore and assess changes in the immune system in pre- and post-CB-103 
dosing whole blood and plasma (e.g., measure expression of cytokines/chemokines 
by RNA expression analysis, quantify pro-inflammatory and anti-inflammatory 
cytokines and chemokines, phenotype different types of immune cells (T cells, B cells, 
dendritic cells and macrophages, etc.) using flow cytometry). 
• 
To assess change from baseline cardiac intervals versus increasing plasma CB-103 
concentrations. 


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• 
To assess the metabolic profile of CB-103 in biological matrices such as urine and/or 
stool samples based on metabolic expressions of CB-103 in urine and/or stool 
samples 
 
 


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5. 
STUDY DESIGN 
5.1 
DESCRIPTION OF STUDY 
5.1.1 
Overview of Study Design 
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 followed by an MTD/RP2D confirmatory cohort is to determine the 
MTD/RP2D. An adaptive 2-parameter BLRM for EWOC will be used in Part A to guide 
determination of the MTD or the RP2D.  
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.  
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. 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, with at least 1 day apart from the second patient, whereby a 
dose cohort must be completed with regards to the DLT assessment period and be 
reviewed by the Cohort Review Committee (CRC) established for this study before further 
patients are dosed in 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 the CRC 
consisting of the Investigators, Sponsor and CRO representatives, and independent 
functional experts as required (see Section 5.1.4.1). The CRC will make the decision to 
determine the next dose level and schedule for the next dose cohort.  
Any dose level cohort that has been declared safe after the DLT period, may be expanded 
by individual patients in order to collect additional pharmacodynamic (PD) and 
pharmacokinetic (PK) information to support and/or confirm the mechanism of action and 


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explore doses at the currently tolerated dose level or below. These patients will be 
counted for the respective cohort at the future CRC meetings and will contribute towards 
the overall safety, PK, PD and clinical efficacy evaluation. 
When the MTD/RP2D is defined, based on the decision of the CRC, approximately 45 
additional NOTCH-positive patients with recurrent/metastatic ACC, breast cancer, r/r T-
ALL/T-LBL, or any other solid tumour with proven Notch pathway activation will receive 
the MTD/RP2D dose to ascertain that optimal safety related to efficacy and 
pharmacodynamics in the tumour and in peripheral blood are achieved. 
Part B - 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 arms. These arms will consist of 
patients with pre-selected cancer indications with tumour cells characterised by NOTCH 
over-activation to confirm safety of the MTD/RP2D of CB-103 and to explore 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 study design is depicted in Figure 4. 


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Figure 4 
Overview of study design 
 
Abbreviations: ACC, adenoid cystic carcinoma; DG, dose group; MTD, maximum tolerated dose;  
pts, patients; ER, estrogen receptor; CRC, colorectal cancer; HCC, hepatocellular carcinoma; 
HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; r/r, 
relapsed/refractory; RP2D, recommended phase 2 dose; TNBC, triple negative breast cancer. 
  
5.1.1.1 
Study Periods 
The study is split into three periods in Part A and into 4 periods in Part B (Figure 5): 
• 
Pre-screening period (Part A MTD/RP2D confirmatory cohort & Part B) 
• 
Screening period (including baseline assessments) 
• 
Treatment period (including an End-of-Treatment [EOT] visit) 
• 
Safety follow-up period 


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Figure 5 
Study periods 
 
 
 
Pre-screening period (Part A MTD/RP2D confirmatory cohort & Part B), for patients 
whose Notch pathway activation status is not known 
The pre-screening period starts once the patient has signed the “pre-screening” informed 
consent form (ICF) and ends once the patient has signed the “study” ICF. 
In Part A (MTD/RP2D confirmatory cohort) & Part B, if the Notch status of the cancer has 
not been ascertained previously, investigational sites will need to pre-screen patients for 
either NOTCH pathway activating mutations, amplifications/translocations or gene/protein 
expression alterations. The investigational site must obtain the signature of the patient on 
the pre-screening consent form. If there is no archived tumour sample available or if 
available, but older than 6 months, then a fresh tumour biopsy has to be obtained. The 
patient’s tumour samples can be sent for characterisation of NOTCH pathway-activation 
to the central laboratory if the analysis cannot be done locally. The result of the analysis 
will be communicated within approximately 7 working days to the respective 
investigational site. 
Screening period 
The 28-day screening period includes the baseline and starts once a patient has provided 
written informed consent to participate in the study; it ends on the day prior to the planned 
1st administration of CB-103 (day -28 to day -1). 
Because of the low overall incidence of cancers with an activated NOTCH signalling 
pathway (Ntziachristos et al., 2014), enrolment of patients in Part A (dose-escalation) will 
not include mandatory screening for NOTCH pathway over-activation in tumour tissue. 


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However, in line with the site’s standard-of-care, the investigational sites are encouraged 
to evaluate their patients prior to study entry with regard to the NOTCH activation level in 
tumours (either mutations, amplifications/translocations or gene/protein expression 
alterations) and to consider enrolling patients preferably with a signal of NOTCH over-
activation.  The selection of patients for Part A (dose-escalation) may be done in favour of 
those who show evidence of over-activation and genetic aberrations of the NOTCH 
signalling pathway.  
Patients enrolling in the Part A MTD/RP2D confirmatory cohort and in Part B (dose 
expansion) have to have tumours with demonstrated NOTCH pathway activation. NOTCH 
status will be determined as outlined in the Inclusion Criteria by using established 
methods.  
Baseline period 
Baseline assessments are performed from three days prior to, until the day prior to the 
planned 1st administration of CB-103 (day -3 to day -1). 
Treatment period 
Solid tumours (six-twelve cycles): the treatment period commences on the first day of the 
first cycle of CB-103 treatment (1st administration of CB-103) and ends on the last day of 
dosing (within the 6 cycles period for Part A or 12 cycles period for Part B). 
T-ALL/T-LBL: initial treatment with CB-103 single agent is given for 28 days (one cycle). 
Patients are assessed for disease response on day 29 (±3 days); however, if the day 29 
marrow is hypocellular (cellularity ≤ 15%), then treatment with CB-103 may continue and 
a repeat bone marrow biopsy is obtained one week later (day 36) to assess response.  
Patients achieving a CR are eligible to receive 2 additional courses of CB-103 as 
consolidation therapy at the same dose and schedule as outlined above. Treatment may 
be discontinued if the patient is scheduled for HCT, otherwise additional courses of CB-
103 until relapse may be given after discussion with the Sponsor. 
If residual leukaemia/lymphoma is documented at the point of marrow recovery (cellularity 
≥ 15%) after the first induction cycle, then a second course of CB-103 is administered. 
End of Treatment (EOT) 
The EOT visit occurs within 14 days after the last administration of CB-103. All 
participating patients must complete this visit even if they have had to prematurely 
discontinue treatment with CB-103. 
Safety follow-up period 
All patients will have a safety follow-up for adverse events and serious adverse events 
28 days after the last dose of CB-103 after which the end-of-study is reached. The safety 
follow-up visit must be performed by all patients who have received at least one 
administration of CB-103. All adverse events and/or serious adverse events occurring 


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during this period will be recorded in the Adverse Event electronic Case Report Form 
(eCRF).  
5.1.2 
Study Duration 
The overall study will be completed 28 days after the last patient in Part B of the study 
received the last treatment.  
5.1.3 
End of Study 
The end-of-study overall is reached when the last patient in Part B has been on study 
treatment for up to 12 cycles (or after completion of the treatment period in T-ALL/T-LBL 
patients as defined above) plus the safety follow-up period of 28 days. In case the study 
is stopped before any patient was treated for 12 months, the end-of-study is reached 28 
days after the last patient in Part B of the study has received his/her last dose of CB-103. 
If the last patient in Part B of the study remains on treatment for more than 12 cycles for 
the purposes of generating the Clinical Study Report (CSR), the end of the study will be 
defined as the point where the last patient enrolled in Part B has had the opportunity to be 
dosed for up to 12 cycles after 1st CB-103 administration and has completed the safety 
follow-up/ end-of-study (EOS) visit. Patients on treatment at that time may be eligible to 
continue treatment with CB-103. The Sponsor reserves the unilateral right, at its sole 
discretion, to determine whether to supply CB-103, and by what mechanism, after the end 
of study is reached or termination of the trial and before it is commercially available.  
With respect to the Part A of the study, a separate CSR will be prepared and the cut-off 
for the data to be included in this report will be set after the safety follow-up visit is 
performed by all patients in Part A of the study, that will occur 28 days after the last dose 
of CB-103 and the last patient in Part A has been on treatment for a maximum of 6 cycles. 
An addendum (or addenda) to the CSRs of Part A and Part B may be generated to report 
the remaining data from patients continuing to be followed up for progression and survival 
outcome beyond the cycle 6 or cycle 12, respectively. 
The study procedures to carry out beyond 6 cycles (Part A) or 12 cycles (Part B) are 
indicated in the schedule of assessments. Data from these patients will be summarised 
and reported in a separate, abbreviated CSR. 
5.1.4 
Committees 
5.1.4.1 
Cohort Review Committee 
Prior to enrolment of patients into Part A (escalation) of the study, a cohort review 
committee (CRC) will be established, consisting of the Principal Investigators of at least 
those sites where the patients are enrolled, Sponsor CMO/designee and representatives, 
CRO representatives (e.g. medical monitor, statistician) and independent experts as 
required (e.g. cardiology expert). The CRC will oversee safety, cohort evaluation, dose 
escalation and the evaluation of MTD/RP2D for the study. A formal charter which will 


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establish the rules, meeting frequency and scope of responsibilities of the CRC will be 
prepared prior to the start of the study. 
For the review of a dose level by the CRC, there will be at least 3, up to 6 patients 
evaluable for DLT. The CRC will review data from one complete treatment cycle (28 days) 
for at least 3 patients in the respective dose cohort to authorise dose escalation.  
5.2 
INVESTIGATIONAL SITES 
This is a multi-centre study to be conducted globally in several countries. Additional site(s) 
may be included for back-up purposes and may be activated if needed. 
Administrative and Contact Information, and List of Investigators are provided separately.  
 
 


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6. 
STUDY POPULATION 
This study will include adult male and female patients ≥ 18 years. Patients must meet all 
of the inclusion criteria and none of the exclusion criteria in order to qualify for the study.  
Adult patients with locally advanced solid tumour or haematological malignancies 
(surgically unresectable locally advanced or metastatic solid tumours or haematological 
malignancies) whose disease has progressed on at least one line of systemic therapy and 
for whom no standard curative therapy exists will be enrolled into Part A (Phase I dose-
escalation). All participants must have histological or cytological evidence for the diagnosis 
of the respective cancer indication. CB-103 has been shown to cross the blood-brain-
barrier in animals. All patients must be in an advanced or metastatic stage of disease after 
available curative therapies have failed to confer acceptable clinical benefit/risk to their 
advanced or metastatic cancer. Patients may be enrolled into the study and treated with 
CB-103 at an earlier line of treatment if they have a tumour with confirmed NOTCH 
pathway activation assessed by at least one diagnostic method, justifying the treatment 
with a NOTCH pathway inhibitor in an earlier line of treatment. This will be at the discretion 
of the Investigator. 
When the MTD/RP2D is defined, based on decision of the CRC, the MTD/RP2D 
confirmatory cohort will open to include approximately 45 additional NOTCH-positive 
patients with recurrent/metastatic adenoid cystic carcinomas (ACC), breast cancer, r/r T-
ALL/T-LBL, or any other solid tumour with proven Notch pathway activation, who will 
receive the MTD/RP2D dose to ascertain that optimal safety related to efficacy and 
pharmacodynamics in the tumour and in peripheral blood are achieved. 
For the expansion arms in Part B of the study, the following are the preliminary indications 
for patients with NOTCH activated pathways planned: 
1. Adenoid cystic carcinoma (ACC) 
2. Triple negative breast cancer (TNBC) 
3. Breast cancer (ER+/-, HER2+/-) 
4. Osteosarcomas, Malignant glomus tumour 
5. GI cancers (resistant to oxaliplatin or irinotecan-based therapy colorectal cancer, 
hepatocellular carcinoma) 
6. r/r T-ALL/T-LBL  
7. Any other cancer (haematologic or solid) with confirmed Notch pathway 
activation (basket arm) 
The preliminary indications considered for the expansion arms may be adapted and 
modified based on the results of Part A of this study as well as from the outcome of future 
in vivo pharmacology studies with CB-103. All the adaptations will result in a protocol 
amendment. 


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6.1 
RECRUITMENT PROCEDURES  
Patients will be recruited primarily from investigational site/country clinical databases; 
however, in some cases, potential patients may be identified prior to consenting to take 
part in this study using pre-screening enrolment logs, Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) approved newspaper/radio advertisements and 
mailing lists. 
6.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Disease 
a. Histologically or cytologically confirmed solid tumours that are surgically 
unresectable, locally advanced, or metastatic, which have progressed on at least 
one line of systemic therapy (with the exception of ACC patients who are allowed 
to be systemic treatment-naïve) and for which no established therapeutic 
alternatives exist. 
or 
b. Relapsed or refractory (r/r) T-ALL or T-LBL. Refractory patients are defined as T-
ALL/T-LBL patients with ≥ 5% bone marrow blasts and/or concomitant 
extramedullary involvement, who have not achieved a CR after standard 
induction/consolidation therapy attempt. Relapsed patients are defined as T-
ALL/T-LBL patients who have recurrent disease, i.e. ≥ 5% bone marrow blasts 
and/or concomitant extramedullary relapse, after having achieved a prior CR. 
c. For Part A (dose-escalation) solid tumour indications based on known frequent 
involvement of the NOTCH pathway activation in these indications, and tumours 
with an a priori known NOTCH1-4 pathway activation are also eligible, as defined 
below:  
• 
Breast cancer (TNBC, ER+/-, HER2+/-), GI cancers (resistant to oxaliplatin 
or irinotecan-based therapy colorectal cancer, hepatocellular carcinoma), 
osteosarcoma, ACC and malignant glomus tumour. 
• 
Any other solid cancer (including lymphoma) with a confirmed NOTCH1-4 
activating mutation or genetic lesion. 
d. For Part A (MTD/RP2D confirmatory cohort) and Part B expansion cohorts, 
solid and haematological tumour indications with confirmed Notch pathway 
activation as follows: 
• 
ACC 
• 
Metastatic breast cancer (regardless of receptor status of ER/PR, HER2) 
• 
r/r T-ALL/T-LBL  
• 
Any other cancer (haematologic or solid) with a confirmed NOTCH pathway 
activation, after approval by the Sponsor 


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Notes:  
- 
Patients are eligible if Notch pathway activation was determined in the past. 
If the Notch status is unknown, it will be determined on fresh bodily material.  
- 
The pathogenic character of the detected mutation/genetic alteration needs 
to be confirmed before the patient can be enrolled. Patients whose tumour 
mutations/alterations are not unambiguously pathogenic will be included at 
the Sponsor’s discretion. Details on molecular alterations as signs of Notch 
pathway activation and the specific test method can be found in the 
laboratory manual. 
e. Patients with solid tumours must have at least one measurable lesion (at least 
1.0 cm in diameter) according to RECIST v1.1 guideline for solid tumours 
(irradiated lesions are only measurable if unequivocal disease progression is 
demonstrated). 
f. Patients with solid tumour indications in Part A (dose-escalation): 
• 
Sufficient archival tumour tissue samples. If the archival tissue is older than 
6 months at screening – or, if not available – a fresh pre-dose tumour 
biopsy is required. If the lesion is not accessible for a fresh tumour biopsy, 
a liquid biopsy may be used after confirmation with the Sponsor. 
g. Patients with solid tumours in the MTD/RP2D confirmatory cohort of Part A 
and in Part B:  
• 
 If the Notch status is unknown, patients with solid tumours should have 
sufficient archival biopsy tissue not older than 6 months prior to pre-
screening (or, if not available, a fresh tumour biopsy must be taken) in 
order to enable the selection of the patients. 
All solid tumour patients: tumour lesions accessible to biopsy and patient 
willing to provide a fresh tumour biopsy at pre-dose, one during treatment, 
and one at disease progression or when clinically indicated. In individual 
cases where the lesion is not accessible for a fresh tumour biopsy, a liquid 
biopsy may be used after confirmation with the Sponsor.  
h. Life expectancy of at least 3 months in the opinion of the investigator. 
2. Demography 
a. Men and women ≥ 18 years old on the day of signing informed consent. 
b. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
c. Patients able and willing to swallow capsules. 


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3. Organ function and laboratory results 
Patients must have the following laboratory values (obtained within 14 days of 
enrolment): 
a. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) 
b. Alkaline phosphatase (ALP) ≤ 2.5 x ULN; if liver function abnormalities are due to 
the underlying malignancy and known bone metastases, then ALP must be ≤ 5 x 
ULN 
c. Serum aspartate aminotransferase (AST/SGOT) and alanine aminotransferase 
(ALT/SGPT) ≤ 2.5 x ULN; if liver function abnormalities are due to the underlying 
malignancy and known hepatic metastases, then AST and ALT must be ≤ 5 x ULN 
d. Serum creatinine ≤ 1.5 x ULN; or if serum creatinine > 1.5 x ULN, then serum 
creatinine clearance (CrCl) ≥ 50 mL/min (estimated by Cockcroft-Gault formula) 
e. Potassium levels within normal limits or correctable with supplements 
f. Total calcium levels (corrected for serum albumin) within normal limits or 
correctable with supplements 
g. Magnesium levels within normal limits or correctable with supplements 
h. Phosphorus levels within normal limits or correctable with supplements 
i. 
Serum albumin concentration ≥ 30 g/L 
j. 
Patients with solid tumours must have: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L  
• 
Haemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L) 
• 
Platelet count ≥ 75 x 109/L (without platelet transfusion or growth factor 
support in the preceding 7 days) 
• 
Partial thromboplastin time (PTT) ≤ 1.5 x ULN and international normalised 
ratio (INR) ≤ 1.3 (unless the patient is receiving therapeutic anticoagulants) 
4. Contraceptive measures 
a. Women of childbearing potential (WOCBP, for definition see Section 6.2) must 
have a serum pregnancy test performed within a maximum of 7 days before start 
of study treatment, and a negative result must be documented before start of study 
treatment. 
b. Women of childbearing potential and men must agree to use at least two highly 
effective forms of contraception (i.e., two of the following – oral contraception, 
injectable contraceptives, mechanical contraception including a condom for the 
partner, or an intrauterine coil) and must continue using them throughout the entire 
clinical trial period and for 90 days post-treatment completion (duration of 


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3 ovulatory cycles). Contraception must start from the day of 1st administration of 
CB-103. 
c. Men whose partners could be of childbearing potential must routinely use a 
condom throughout the entire clinical trial period and for 90 days post-treatment 
completion (duration of sperm turnover). The partner should also use a reliable 
form of contraception such as the oral contraceptive pill or an intrauterine device. 
d. Azoospermic males and females with sterilisation (e.g. tubal ligation) are exempt 
from contraceptive requirements. 
e. Women capable of becoming pregnant who are continuously not heterosexually 
active are exempt from contraceptive requirements. However, they must still 
undergo pregnancy testing as described in inclusion criterion “4a”. 
5. Informed consent 
a. Ability to understand the patient information and informed consent form (ICF) and 
comply with the protocol-related procedures. 
b. Signed and dated written informed consent obtained prior to performing any study-
related procedure, including pre-screening (Part A - MTD/RP2D confirmatory 
cohort - and part B) and screening. 
 
 


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6.1.2 
Exclusion Criteria 
1. Medical History 
a. Patients with symptomatic CNS metastases who are neurologically unstable or 
require increasing doses of steroids to control their CNS disease. 
Note: Patients with controlled CNS metastases may participate in this study. The 
patient 
must 
have 
completed 
radiotherapy 
or 
surgery 
for 
CNS 
metastases > 2 weeks prior to study entry. Patients must be neurologically stable, 
having no new neurologic deficits on clinical examination, and no new findings on 
recent CNS imaging. If patients require steroids for management of CNS 
metastases, they must have been on a stable dose of steroids for two weeks 
preceding study entry. 
Note: Patients without clinical signs or symptoms of brain involvement are not 
required to have a computed tomography (CT)/ magnetic resonance imaging (MRI) 
scan of the brain. 
Note: T-ALL/T-LBL patients with active CNS disease defined as the presence of 
CNS disease at diagnosis, and/or presence of CNS involvement-related symptoms, 
e.g. related to cranial nerve involvement, may not be included. 
b. Hypersensitivity to any of the excipients of the finished drug CB-103. 
c. Patients with unresolved nausea, vomiting, or diarrhoea of CTCAE grade ˃ 1 
d. Impairment of GI function or presence of GI disease that may significantly alter the 
absorption of CB-103 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhoea, malabsorption syndrome, or small bowel resection) 
e. History of second or other primary cancer with the exception of 
• 
Curatively treated non-melanomatous skin cancer 
• 
Curatively treated cervical cancer or breast carcinoma in situ 
• 
Other primary solid tumour treated with curative intent and no known active 
disease present and no treatment administered during the last 2 years 
2. Exclusionary concurrent medical conditions 
a. Impaired cardiac function or clinically significant cardiac diseases, including any 
one of the following: 
1. Clinically significant cardiac disease including congestive heart failure (NYHA 
class III or IV), arrhythmia or conduction abnormality requiring medication, or 
cardiomyopathy  
2. Clinically uncontrolled hypertension (systolic blood pressure ≥160 mmHg or 
diastolic blood pressure ≥100 mmHg) 


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3. Complete left bundle branch block 
4. Right bundle branch block + left anterior hemiblock  
5. Mandatory use of a cardiac pacemaker 
6. Congenital long QT syndrome 
7. History or presence of sustained or symptomatic ventricular tachyarrhythmia  
8. Presence of atrial fibrillation 
9. Clinically significant resting bradycardia (< 50 bpm) 
10. Corrected QTcF > 450 ms for males and > 470 ms for females at the screening 
ECG 
11. QRS ≥ 110 ms 
12. History of symptomatic congestive heart failure 
13. Left ventricular ejection fraction (LVEF) < 50%. History of absolute decrease 
in LVEF of ≥ 15 absolute percentage points, or ≥ 10 absolute percentage 
points and crossing from > lower limits of normal (LLN) to < LLN on prior anti-
cancer therapy (e.g. anti-HER2 therapy, anthracyclines), even if asymptomatic 
14. Angina pectoris ≤ 6 months prior to starting study drug 
15. Acute myocardial infarction (MI) ≤ 6 months prior to starting study drug 
b. General conditions or other clinically significant diseases, including any one of the 
following: 
1. Haemorrhagic, embolic, or thrombotic stroke within 6 months prior to the first 
planned CB-103 treatment  
2. For patients with solid tumours: prior bone marrow/haematopoietic stem cell 
transplant.  
Note: For T-ALL patients prior allogenic bone marrow/haematopoietic stem 
cell transplant is allowed if they have no current GvHD and patients are off 
immunosuppressive therapy. 
3. Known infection with human immunodeficiency virus (HIV); or hepatitis B or C 
requiring treatment 
4. Any active infection requiring the use of parenteral anti-microbial agents or 
that is > Grade 2 
5. Non-malignant interstitial lung disease or pneumonitis 
6. Dyspnoea of any cause requiring supplemental oxygen therapy and dyspnoea 
at rest due to complications of advanced malignancy and co-morbidities 
7. Significant traumatic injury or major surgery (major surgery means opening of 
a body cavity, e.g., thoracotomy, laparotomy, laparoscopic organ resection, 


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and major orthopaedic procedures, e.g. joint replacement, open reduction and 
internal fixation) within 14 days of scheduled dosing day 1. 
8. Other concurrent severe and/or uncontrolled medical conditions (e.g. 
uncontrolled diabetes, active or uncontrolled infection) that could cause 
unacceptable safety risks or compromise compliance with the protocol. 
3. Prior Therapy 
a. In patients with solid tumours, cytotoxic chemotherapy within 3 weeks (6 weeks for 
nitrosoureas and mitomycin C) of the scheduled first dose of CB-103 on day 1. 
b. In T-ALL/T-LBL patients, prior anti-cancer therapy less than 2 weeks prior to 
starting therapy or 5 half-lives (whichever is longer) with the following exceptions: 
1. Up to 5 days of glucocorticoids (10 mg/m2 dexamethasone or equivalent/day) 
in combination with up to 3 doses of cyclophosphamide (200 mg/m2/day) are 
allowed as standard prephase treatment up to 1 day before start of study 
treatment 
2. Mercaptopurine may be dosed up to 5 days prior to first dose of CB103 
3. Vinca alkaloids may be dosed up to 5 days prior to first dose of CB103 
4. Prophylactic IT chemotherapy may be dosed up to 3 days prior to first dose of 
CB103. 
c. Prior cumulative doxorubicin exposure of ≥ 500 mg/m2 
d. Prior cumulative epirubicin exposure of ≥ 900 mg/m2 
e. Any investigational treatment (including NOTCH signalling inhibitors and prior 
treatments with CB-103) within 4 weeks of scheduled CB-103 dosing day 1. 
f. Concurrent enrolment in another therapeutic clinical trial involving ongoing therapy 
with any investigational or marketed product or placebo. 
g. Radiation therapy within 2 weeks of scheduled CB-103 dosing day 1, unless the 
radiation comprised a limited field to non-visceral structures (e.g. a limb bone 
metastasis). 
h. Immunotherapy (including interferons, interleukins, immune-conjugates, immune 
checkpoint inhibitors), biological therapies (including monoclonal antibodies, 
antibody drug conjugates or other engineered proteins), targeted small molecules 
(including but not limited to kinase inhibitors), hormonal therapies within 3 weeks 
of scheduled CB-103 dosing day 1. 
i. 
Unresolved toxicity CTCAE grade > 1 from previous anti-cancer therapy or 
radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia, or other 
adverse event associated with leukemic involvement), or incomplete recovery from 


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previous surgery, unless agreed by the Sponsor and the Principal Investigator and 
documented. 
4. Concomitant medications 
a. Drugs which prolong QT interval, either with a known or a conditional/ possible risk 
to induce Torsades de Pointes (a list of drugs is given in Appendix 4 of the 
protocol). However, in case of a life-threatening infection, in the best interest of the 
patient, concomitant treatment with the study drug and the relevant anti-infectious 
drug, though this may be included in the list given in Appendix 4, can be continued 
with closer monitoring. 
b. Patients receiving warfarin and phenytoin that cannot be discontinued at least one 
week prior to start of treatment with CB-103 and for the duration of the study. 
c. Anticoagulants: Patients receiving coumarin-type anticoagulants who cannot 
discontinue at least one week prior to start of treatment and for the duration of the 
study. Low molecular weight heparin and direct oral anticoagulants are permitted.  
5. Demography 
a. Patients who are pregnant or breast feeding. 
6. Others 
a. Patients who are unable or unwilling to comply with all study requirements for 
clinical visits, examinations, tests, and procedures. 
6.2 
CRITERIA FOR WOMEN OF CHILDBEARING POTENTIAL 
A woman is considered to be of childbearing potential (WOCBP) unless she meets at least 
one of the following criteria: 
• 
Previous 
bilateral 
salpingectomy, 
bilateral 
salpingo-oophorectomy 
or 
hysterectomy. 
• 
Premature ovarian failure confirmed by a specialist. 
• 
XY genotype, Turner syndrome, uterine agenesis. 
• 
Postmenopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
6.3 
NUMBERING OF PATIENTS AND INVESTIGATIONAL SITES 
Each patient in the study is uniquely identified by a 6-digit patient number which is a 
combination of his/her 3-digit centre number and 3-digit patient number.  
The site number is assigned by the Sponsor (or its delegate) to the investigational site. 


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The patient number will be assigned when the case book is created in the eCRF after the 
informed consent is obtained. 
 
 


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7. 
STUDY TREATMENT 
7.1 
FORMULATION 
The Investigational Medicinal Product (IMP) CB-103 will be provided in the form of 
capsules for oral treatment. More detailed information on the oral formulation of CB-103 
can be found in the Investigator’s Brochure. 
Capsules with different drug strengths will be provided, e.g. 5, 10, 20, 50 and 100 mg each. 
All drug supplies should be stored in a secure, temperature-controlled area, which can be 
accessed only by the pharmacist, the Investigator, or another duly designated person. The 
investigational sites will be supplied with study drug according to the sites’ needs. Patients 
should be given a sufficient supply to last until their next study visit. Detailed storage 
conditions will be provided on the medication label and on the Pharmacy Manual. 
The respective CB-103 doses will be given as fixed dose in milligrams (mg). 
7.2 
PACKAGING, LABELING AND HANDLING 
IMP packaging will be overseen by the Sponsor Clinical Trial Supplies department or 
delegate and will bear a label with the identification required by local law, the protocol 
number, drug identification and dosage.  
The packaging and labelling of the study medication will be performed in compliance with 
Good Manufacturing Practices (GMP) and any other or local applicable regulations. The 
qualified individual responsible for dispensing the study drug will prepare the correct drug 
product according to the individual specific dose allocated to the individual patient. This 
individual will also record study drug batch number received by each patient during the 
study. 
Upon arrival of investigational products at the investigational site, site personnel should 
check for damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the Monitor upon discovery.  
7.3 
IMP STORAGE AND DISPENSING 
The Investigator is responsible for safe and proper handling and storage of the study drug 
at the investigational site and for ensuring that the study drug is administered only to 
patients enrolled in the study and in accordance with the protocol. 
IMP must be kept in a locked temperature-controlled area, which can be accessed only 
by the pharmacist, the Investigator, or another duly designated person. The investigational 
sites will be supplied with study drug according to the sites’ needs. Patients should be 
given sufficient supply to last until their next study visit.  
Further details on storage conditions and instructions are provided in the Pharmacy 
Manual and the Investigator’s Brochure.  


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7.3.1 
IMP Accountability 
All IMP (CB-103) required for completion of this study will be provided by the Sponsor. 
The investigational site will acknowledge receipt of IMP and confirm the shipment 
condition and contents. Any damaged shipments will be replaced.  
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of drug dispensed, used, dosages administered, returned, and intervals between 
visits will be maintained during the study.  
IMP accountability will be performed on a regular basis by the study staff and will be 
checked by the study monitor during site visits and at the completion of the study. 
Returned IMP should be stored separately from IMP that needs to be dispensed. All 
records and drug supplies must be available for inspection by the study monitor at every 
monitoring visit.  
IMPs will either be disposed of at the investigational site according to the investigational 
site’s institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation. The investigational site’s method of IMP destruction must be 
agreed upon by the Sponsor. Local or institutional regulations may require immediate 
destruction of used IMP for safety reasons. In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned, destroyed and provided that adequate storage and integrity of the drug has been 
confirmed.  
The investigational site must obtain written authorisation from the Sponsor before any IMP 
is destroyed, and IMP destruction must be documented on the appropriate form.  
Written documentation of IMP destruction must contain the following:  
• 
Identity of investigational product[s] destroyed. 
• 
Quantity of investigational product[s] destroyed. 
• 
Date of destruction. 
• 
Method of destruction. 
• 
Name and signature of responsible person [or company] who destroyed 
investigational product[s]. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the investigational site should be recorded on the Drug Inventory Log. 


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7.4 
DOSAGE AND TREATMENT SCHEDULE 
CB-103 will be administered orally as a continuous once daily (QD) dosing during the 
treatment period of Part A (escalation) and Part B (expansion) until disease progression, 
unacceptable toxicity or until the Investigator’s decision or the patient’s refusal. As soon 
as clinical safety and PK data become available, it is possible that an alternate dosing 
(e.g. twice daily [BID], intermittent) may be implemented. 
For the purpose of scheduling and evaluations, a treatment cycle is defined as 28 days 
throughout the whole study. For Part A (escalation), the DLT period is defined as the 1st 
cycle of CB-103 dosing with a duration of 28 days. Eleven provisional dose levels are 
defined for the dose escalation (see Table 3 in Section 7.4.2), as well as one dose level 
with a 30% lower dose than the 1st dose level if the first dose level is not well tolerated. 
Patients will be instructed to swallow the CB-103 capsules whole with a glass of water 
(approx. 200 mL) on an empty stomach at least 1 hour before breakfast. Capsules should 
not be chewed prior to swallowing. Capsules that are broken, cracked, or otherwise 
damaged should not be ingested. 
• 
In case of the once-daily dosing schedule, when self-administering the drug at home,  
the patients will be instructed to self-administer CB-103 in the morning, on an empty 
stomach at least 1 hour before taking breakfast and at approximately the same time 
each day without treatment breaks, until they experience unacceptable toxicity, 
disease progression or withdrawal from the study.  
• 
In case a BID dosing schedule is implemented, when self-administering the drug at 
home, the first capsule should be taken on an empty stomach at least 1 hour before 
breakfast. The second capsule should be taken within 8 to 12 hours of the first intake 
and at least 1 hour before or 2 hours after the evening meal.  
• 
On the day of the study visits the patients should come to the site fasted and will be 
instructed to not take the dose of CB-103 at home since it will be administered at the 
site. 
Regardless of the dosing schedule, the timing of CB-103 intake and the timing of meals 
should be recorded in the patient diary. The information on the actual dosing times will be 
transferred into the eCRF.  
The Investigator should instruct the patient to record daily administration of the IMP in their 
patient diaries (paper format). If a patient misses a daily dose and notices this the next 
day after the scheduled day, they must be instructed not to “make it up” or double the next 
days’ dose. If a patient vomits any time after taking a dose, they must be instructed not to 
“make it up”, but to resume subsequent doses the next day as prescribed. The information 
on dosing and any missing doses should be noted by the patient in the diary. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the concerned eCRF forms (PK Sampling form and Study Drug 


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Adjustment form). Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in the following section. 
7.4.1 
Justification of Starting Dose in Dose Level 1 
Phase I, Part A – dose escalation 
The starting, FIH dose for CB-103 at dose level 1 of the dose escalation, will be 15 mg 
(fixed dose) and will be administered on a continuous daily schedule. The starting dose is 
selected based on the results from the non-GLP and GLP-compliant safety pharmacology 
and toxicology studies in rats and dogs, as well as, the standard criteria for an anticancer 
drug were applied. The key toxicokinetic parameters from the 28-day GLP studies in rats 
and dogs used to derive the safety margins are given in Section 2.5.4.  
The starting dose of 15 mg is expected to achieve an exposure (AUC0-24) in humans of 
approximately 600 µg*h/mL (see Section 2.5.3, assuming, almost complete bioavailability 
in humans). This is comparable to 1/10th of the exposure at the highest non-severely toxic 
dose (HNSTD) in rats (AUC0-24 in males at 30 mg/kg/day on day 28: 5980 µg*h/mL). Rats 
are more sensitive to CB-103 than dogs and the expected exposure in humans at the 
starting dose is below 1/10th of the exposure at the HNSTD in dogs (AUC0-24 at 8.6 
mg/kg/day, day 28: 8970 µg*h/mL in males and 13100 µg*h/mL in females). The signs of 
toxicity at the HNSTD in the 28 day GLP toxicology studies are mild and reversible and a 
safety factor of 10 is considered reasonably safe. The expected average plasma 
concentration after 15 mg repeated administration is approximately 25 ng/mL and 
therapeutic plasma levels (IC50 1 µM = 242 ng/mL) can therefore be achieved in a limited 
number of dose escalation steps. 
The predicted plasma levels and AUC0-24 values in humans assumes almost complete 
bioavailability. If CB-103 is not completely bioavailable in humans, the concentration will 
be lower and the safety margins even larger. For more details on the PK of CB-103 and 
selection of the starting doses please refer to the Investigator’s Brochure. 
7.4.2 
Dose Escalation and Maximum Exposure 
The design of this FIH study – with the inclusion of the BLRM – allows flexible dose 
escalation based on observation of DLTs, review of the entire safety data and 
pharmacokinetics in patients, and it aims to achieve CB-103 plasma concentrations in the 
range of the IC50 (1 µM = 242 ng/mL) as quickly as possible to increase the chances of 
benefit for the patients. 
The provisional dose escalation levels are given in the table below. 


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Table 3 
Provisional dose escalation levels 
Dose level 
Proposed dose (mg) b 
Increment from 
previous dose (%) 
-1a 
10 mg 
(30% decrease) 
1 
15 mg 
Starting dosec 
2 
30 mg 
100 % 
3 
60 mg 
100 % 
4 
120 mg 
100 % 
5 
180 mg 
50 % 
6 
240 mg 
33 % 
7 
320 mg 
25 % 
8 
400 mg d 
25 % 
a Dose level -1 represents a dose that may be evaluated if dose level 1 is poorly 
tolerated. No dose de-escalation below this level is planned for this study. If 
dose-level -1 is poorly tolerated the study may be terminated. 
b It is possible for some dose levels to be skipped or additional dose levels to be 
added during the course of the study. 
c If the first PK assessments in humans suggest a major deviation from the 
expected AUC at the starting dose, the dose of CB-103 in the next dose level 
might be adapted accordingly. 
d CB-103 doses higher than 400 mg may be allowed depending on the observed 
safety, PK and PD, and based on the recommendation of the two-parameter 
BLRM. 
 
Initially, a daily dosing schedule will be used since the expected half-life in humans is 
sufficiently long to ensure coverage with CB-103 for 24 hours. As soon as clinical safety 
and PK/PD data become available it may be preferable to change the administration of 
CB-103 (e.g. BID or intermittent schedule). The change of the dosing schedule will be 
discussed by the CRC and decided by the Sponsor, with the new dose and dosing 
schedule applied to the next patient cohort. The decision to change the dose and/or dose 
schedule will be based on the totality of safety, PK, biomarker, preliminary efficacy and 
other data available to be reviewed and discussed by the CRC and Sponsor. Evaluation 
of safety, PK, preliminary efficacy, PD and biomarker data at the new dose schedule 
selected (BID or intermittent dosing) will be performed. 


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7.4.3 
Criteria for Dose Escalation and Determination of the Maximum 
Tolerated Dose  
Phase I, Part A – Escalation 
Definition of MTD and RP2D 
For any given schedule, the MTD is the highest dose of CB-103 if the following criteria are 
fulfilled: the posterior probability of the true DLT rate in the target interval [0.16 – 0.33] of 
the MTD is above 0.50 and 6 patients have been treated at the MTD/RP2D  confirmatory 
cohort of the treated patients in the first 28 days of CB-103 treatment under that schedule. 
If the MTD cannot be reached in the dose escalation part of the study and the therapeutic 
dose range of CB-103 with the IC50 being reached, the RP2D will be determined at a dose 
below or equal to the MTD, based on the PD, PK, safety and potential efficacy data, upon 
review of all study data by the CRC and Sponsor. Adverse events and laboratory 
abnormalities considered to be DLTs are defined in Section 7.4.4 on DLT Assessments. 
Estimation of MTD / RP2D 
A two-parameter BLRM employing the EWOC principle will be used during the escalation 
phase for selection of doses to investigate and for estimation of the MTD. The general 
plan is that cohorts of patients will receive escalating doses of CB-103 until the MTD is 
reached. Each cohort will consist of newly enrolled patients. 
Estimation of the MTD during the escalation phase of the study will be based upon the 
estimation of the probability of DLT in cycle 1 in patients in the DDS. If MTD cannot be 
reached in the dose escalation part, the RP2D will be determined based on the review of 
DLTs, adverse events/serious adverse events, laboratory, PK and PD data and selected 
as the dose resulting in the best therapeutic window for CB-103. 
At all decision time points, the adaptive BLRM permits alterations in the dose increments 
based on the observed toxicities. It will be possible for some dose levels to be skipped or 
additional, intermediate dose levels or dosing schedules to be added during the course of 
the study. 
Dose escalation will in general not exceed a 100% increase from the current dose being 
studied with the exemption of the dose escalation following the starting dose of 15 mg 
CB-103 where the next dose of CB-103 in the next dose level might be adapted if the 
exposure of CB-103 (AUC0-24) is much lower than the expected value of approximately 
600 µg*h/mL which was determined to be safe from the non-clinical GLP safety and 
toxicology studies in rats and dogs. If clinically relevant toxicity CTCAE ≥ grade 2 is 
observed and suspected to be related to CB-103 in > 1 patient within the current cohort, 
the escalation to the next cohort will be restricted to ≤ 50% of the current dose. Cohorts 
may be expanded at any dose level below the highest dose deemed unacceptable in order 
to better understand safety, tolerability, PK or PD. 
Dose decisions during escalation are however not limited to the provisional dose levels 
provided in Table 3. Based on the recommendation of the BLRM regarding the highest 


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dose that may not be exceeded at any decision point during escalation and the maximum 
increase in dose allowed by the protocol, intermediate doses may be administered to 
subsequent new cohorts of patients. This includes doses lower than the starting dose or 
an intermediate dose between the current and next (lower or higher) provisional dose and 
different schedules. To further characterise the safety (e.g. specific suspected treatment-
related adverse events) or PK/PD of CB-103 a dose that is considered acceptably safe, 
i.e., shown to be lower than any potential MTD, may be expanded.  
Dose escalation may be terminated at any time based on emerging safety concerns 
without establishing the MTD. 
The DLT period starts from the administration of the first oral dose until 28 days after the 
first oral dosing (1st cycle of CB-103). Intermediate dose levels of CB-103 may be explored, 
e.g. in case of MTD. 
During the MTD/RP2D confirmatory cohort, if in specific subgroups (e.g., by indication or 
ethnicity) a higher rate of toxicities occurs or the PK profile of CB-103 is different, dose 
adjustments in such subgroups may be decided. 
Phase IIA, Part B - Expansion 
The enrolment into the Part B expansion cohorts for the selected cancer indications will 
begin after the MTD/RP2D is determined in Part A and reviewed by the CRC. CB-103 will 
be administered orally at the MTD/RP2D with the dosing schedule being determined in 
Part A (QD, BID or intermittent). 
7.4.4 
Dose-Limiting Toxicity (DLT) 
DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated 
to disease progression, inter-current illness, or concomitant medications, that occurs 
≤ 28 days following the first dose of CB-103 (Cycle 1) and that meets any of the following 
criteria shown in the table below. Clinically relevant toxicities will be evaluated according 
to the National Cancer Institute (NCI)/National Institutes of Health (NIH) CTCAE version 
4.03. 
For the purpose of dose-escalation decisions, only DLTs occurring during the first cycle of 
treatment will be necessarily considered in the binary logistic regression model. 
Refer to the study synopsis “Dose limiting Toxicity” section for the DLTs criteria.  
 
 


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7.4.5 
Dose Modifications, Dose Delays and Treatment Discontinuation 
Every effort should be made to administer CB-103 at the planned dose and schedule. In 
the event of treatment-related toxicities and DLT with CB-103, dose or schedule 
adjustments are required and have to be undertaken by the Investigator in the best interest 
of the patient to continue therapy. In the event of multiple toxicities, the dose modification 
should be based on the worst toxicity observed (according to the NCI CTCAE, v4.03). Any 
adjustment to the CB-103 dose should be documented in the eCRF. 
Dose adjustments and interruptions criteria are described in the following sections. 
Depending on the type, severity and timing of the events, the Investigator will determine 
and decide on dose reductions and resumption of treatment. The following rules have to 
be followed:  
• 
After Cycle 1 / Day 1, a continuous treatment interruption of more than 14 days will 
result in discontinuation of the patient from the study. Interruption of treatment not 
related to CB-103 may not require discontinuation; in such a case treatment 
continuation must be discussed with the Sponsor.  
• 
Patients with a continuous treatment delay for more than 7 days during cycle 1 in 
Part A of the study (DLT period) that is not due to a drug-related AE, will be 
considered non-evaluable for DLT and will need to be replaced accordingly. 
• 
Doses of CB-103 held or missed will not be made up (i.e., cycles will not be 
prolonged beyond the 28th calendar day in order to make up any missed doses). 
• 
If doses of CB-103 are missed or forgotten to be taken for more than three 
sequential dosing events and if this happens more than once, this will result in 
discontinuation of the patient from the study. Dose delays as outlined above to 
recover from adverse events are allowed. 
• 
If a treatment interruption continues beyond Day 28 of the current cycle, then the 
day when treatment is restarted will be counted as Day 1 of the next cycle.  
• 
During cycle 1 in Part A (DLT period), any dose adjustments must be discussed 
with and approved by the Sponsor. 
• 
One dose reduction is allowed per patient. In case the patient shows clinical benefit 
a 2nd dose reduction might be allowed, but this needs to be agreed upon on a case-
by-case basis with the Sponsor. Section 7.4.6.1  describes the CB-103 dose 
modifications for the haematologic and non-haematologic toxicities not clearly 
attributed to disease. 
If a patient concurrently experiences both haematological and non-haematological 
toxicities, then dose modifications for CB-103 should follow the most conservative 
approach, as outlined in Section 7.4.6.1.1, depending on the specific hematologic and 
non-hematologic toxicities. 


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Patients who discontinue from the study for a treatment-related adverse event or an 
abnormal laboratory value, must be followed up until fully recovered, according to the 
judgement of the Investigator. 
Intra-patient dose escalation 
Intra-patient dose escalations for CB-103 must be approved by the Sponsor and will be 
only allowed on a case-by-case basis, upon evaluation and discussion between the 
Investigator and the Sponsor. The following criteria have to be fulfilled for a patient under 
consideration: 
‒ Intra-patient dose escalation can occur only when the next higher dose has 
been cleared by the CRC. Additional safety data collected will not be included 
in DLT assessment and discussions for dose escalation.   
‒ Intra-patient dose escalation will be implemented on the first day of the cycle. 
7.4.6 
Follow-up for Dose-Limiting Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value, must be followed at least once a week for 
4 weeks, and subsequently at 4-week intervals, until resolution or stabilisation of the event, 
whichever comes first. 
7.4.6.1 
Follow-up Evaluations and Dosing Modifications for Toxicities 
The follow-up evaluations for toxicities apply during or beyond cycle 1 in Part A, and 
throughout Part B of the study. 
The following sections outline the specific dose modifications for CB-103 for haematologic 
and non-haematologic toxicities and should be followed by the Investigator accordingly. 
7.4.6.1.1 
Haematologic Toxicities for Solid Tumour Patients 
If > CTCAE grade 3 neutropenia or > CTCAE grade 3 thrombocytopenia have been 
demonstrated, testing for these parameters must be repeated at least twice a week until 
resolution to < CTCAE grade 1 neutropenia or < CTCAE grade 1 thrombocytopenia, to 
allow for re-treatment and then at least weekly until either resolution or until stabilisation. 
 


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Table 4 
Dose modifications for haematologic toxicities 
Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless 
otherwise specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Haematologic toxicities: 
Neutropenia (ANC) 
 
Grade 1 (ANC < LLN - 1.5 x 
109/L) & Grade 2 (ANC < 1.5 - 
1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 
109/L) 
Omit dose administration until resolved to ≤ grade 1, 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose administration until resolved to ≤ grade 1, then ↓ 1 
dose level 
Grade 3 Febrile neutropenia 
(ANC < 1.0 x 109/L with a 
single temperature of >38.3°C 
or a sustained temperature of 
≥38°C for more than one hour) 
Omit dose administration until resolved, then ↓ 1 dose level 
Thrombocytopenia 
 
Grade 1 (PLT < LLN - 75 x 
109/L) 
Maintain dose level 
Grade 2 (PLT < 75 - 50 x 
109/L) & Grade 3 (PLT < 50-25 
x 109/L) 
Omit administration dose until resolved to ≤ grade 1, then: 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit administration dose until resolved, then ↓ 1 dose level 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
 
7.4.6.1.2 
Renal Toxicities 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be repeated 
at least twice a week until resolution to < CTCAE grade 1, to allow for initiation of re-
treatment and then at least weekly until either resolution or until stabilisation. 
If proteinuria or haematuria > CTCAE grade 2 or serum creatinine > 2.0 x ULN has been 
demonstrated, a 24-hour urine collection must be obtained for total protein and total 
creatinine must be repeated at least weekly until either resolution to baseline value to 
allow for initiation of re-treatment, or until stabilisation. Whenever a measured CrCl is 
obtained, a serum creatinine value should be obtained within < 72 hours of the urine 
collection. 
 


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Table 5 
Dose modifications for renal toxicities 
Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless 
otherwise specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Renal toxicities: 
Serum creatinine 
 
(< 2 x ULN) 
Maintain dose level 
(2 - 3 x ULN) 
Omit dose administration until resolved to ≤ grade 1, 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (> 3.0 - 6.0 x ULN) & 
Grade 4 (> 6.0 x ULN) 
Omit dose administration and discontinue patient from study 
treatment 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
 
7.4.6.1.3 
Hepatic Toxicities 
If bilirubin > CTCAE grade 2 or AST/ALT > CTCAE grade 3 has been demonstrated, these 
parameters must be repeated at least twice a week until resolution to < CTCAE grade 1 
(or baseline if liver metastases were present at baseline), to allow for initiation of re-
treatment and then at least weekly until either resolution or until stabilisation. 
Patients with total bilirubin > ULN (any duration) should have fractionation of bilirubin into 
total/direct or indirect/direct components and any additional work-up as clinically indicated 
by these results. Follow-up of hyperbilirubinaemia should proceed as per the guidelines 
above, irrespective of the results of fractionation. 


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Table 6 
Dose modifications for hepatic toxicities 
Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless 
otherwise specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Hepatic toxicities: 
Bilirubin 
 
Grade 1 (< 1.5 x ULN) 
Maintain dose level 
Grade 2 (1.5 - 3 x ULN) 
Omit dose administration until resolved to ≤ grade 1, 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose administration until resolved to ≤ grade 1, then ↓ 1 
dose level 
Grade 4 (> 10.0 x ULN) 
Omit dose administration and discontinue patient from study 
treatment 
AST or ALT 
 
Grade 1 (> ULN – 3.0 x ULN) 
& Grade 2 (>3.0 - 5.0 x ULN) 
without increase in total 
bilirubin >2 x ULN 
Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN) 
without increase in total 
bilirubin >2 x ULN 
Omit dose administration until resolved to ≤ grade 1 (or ≤ 
grade 2 in case of liver metastasis), then 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (> 20.0 x ULN) 
without increase in total 
bilirubin >2 x ULN 
Omit dose administration until resolved to ≤ grade 1, then ↓ 1 
dose level 
 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
 


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7.4.6.1.4 
Ocular/Vision-related Toxicities 
For toxicities related to visual symptoms related to CB-103, refer to the following table. 
Table 7 
Dose modifications for ocular/vision-related toxicities 
 Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless 
otherwise specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Visual symptoms 
Grade 1 
Maintain dose level 
Grade 2 
Omit dose administration until resolved to ≤ grade 1 (or 
baseline), then continue treatment with CB-103 at the current 
dose level 
If visual symptoms ≥ Grade 2 recur upon re-exposure to CB-
103 and if is intolerable by patient, discontinue patient from 
study 
Grade 3 
Omit dose administration and discontinue patient from study 
Grade 4 
Omit dose administration and discontinue patient from study 
 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
 
7.4.6.1.5 
Cardiac Toxicities 
As in non-clinical studies with CB-103, QT prolongation was observed at higher doses and 
ECG changes in patients may be observed, therefore, intensive cardiac monitoring is 
implemented into this study with central management and review of multiple ECGs and 
Holter ECGs at selected timepoints. Furthermore ECHO/MUGA scans and cardiac 
markers will be assessed at selected time points. For toxicities related to QTc prolongation, 
refer to Table 8 below. For all other cardiac toxicities, please follow the non-laboratory 
recommendations seen in Section 7.4.6.1.7. 
Table 8 
Dose modifications for cardiac toxicities 
Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless otherwise 
specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Cardiac - Prolonged QTcF interval2 
During Cycle 1:  
 
Absolute QTcF< 480 ms 
Maintain dose level and ECG monitoring as per visit 
schedule. 


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Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless otherwise 
specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Cardiac - Prolonged QTcF interval2 
QTcF > 480 ms 
and < 500 ms 
Maintain dose level. ECG monitoring assessments 
should be increased as indicated (e.g. hourly until no 
QTcF > 480 ms).  
During any Cycle: 
 
Grade 3 or QTcF ≥ 500 ms as 
identified by the Investigator on the 
ECG. 
Omit dose administration. Monitor patient with frequent 
ECGs as indicated (e.g. hourly) until the QTcF has 
returned to ≤ 480 ms. Further monitoring as clinically 
indicated. Exclude other causes of QTc prolongation such 
has hypokalaemia, hypo-magnesaemia and blood 
oxygenation status. Once QTcF prolongation has 
resolved, and if the QTcF prolongation was confirmed by 
central reading, patients may be re-treated at one lower 
dose level at the Investigator’s discretion. 
ECG monitoring must continue throughout the treatment 
period as follows: 
• ECG monitoring assessments should be performed for 
2 additional cycles at higher frequency as clinically 
indicated 
• If the ECGs obtained in the first additional cycle after 
dose reduction are without any QTcF prolongation, 
then ECG monitoring in subsequent cycles will be 
continued as per the visit schedule. 
• If the patient had an absolute QTcF ≥ 480 ms and 
< 500 ms, then ECG monitoring at a higher frequency 
will be continued for all subsequent cycles. 
• Patients who experience absolute QTcF ≥ 500 ms 
after one dose reduction will be discontinued from 
study. 
Note: 
• If QTcF ≥ 500 ms result is observed in a patient during 
the study treatment, this event will be considered as a 
DLT. If Torsades de Pointes are observed in a patient, 
the patient will be discontinued from the study. 
• Whenever QTcF ≥ 500 ms result is observed, a 
plasma sample for determination of CB-103 
concentration should be obtained and the time of 
sample collection noted. 
 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
2 Exclude other causes of QTcF prolongation such has hypokalaemia, hypomagnesaemia and 
blood oxygenation status. Patients who develop hypokalaemia or hypomagnesaemia during the 
study should receive electrolyte replacement as soon as possible and should not receive further 
CB-103 dosing until the respective electrolytes are documented to be within normal limits. 


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7.4.6.1.6 
Gastro-Intestinal Toxicities (Diarrhoea, Nausea) 
In non-clinical studies in different species (dog, rat, mouse), CB-103 administered at 
different doses and administration schedules did not show any gastro-intestinal toxicities, 
e.g. diarrhoea, weight loss. However, as other NOTCH inhibitors (GSIs, mABs) have 
shown diarrhoea as their major DLT, there might be a risk for CB-103 to also develop 
gastro-intestinal toxicities. In the event that diarrhoea is observed in clinical trial patients, 
the following algorithm for CB-103 dose modifications should be followed. Furthermore, 
Sections 7.4.7.2 to 7.4.7.4 provide a management plan for the occurrence of diarrhoea 
with a description of measures and treatment suggestions. 
Table 9 
Dose modifications for gastro-intestinal toxicities 
Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade1 unless 
otherwise specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Gastro-intestinal toxicities 
Grade 1 
Maintain dose level 
Grade 2 
(see Sections 7.4.7.2 to 7.4.7.4 
for treatment algorithm) 
Omit dose administration until recovery to Grade ≤ 1 or 
baseline then continue at current dose level if grade 2 toxicity 
persisted for ≤ than 7 days. 
If grade 2 toxicity persisted for more than 7 days decrease 
dose by 1 dose level after resolution to Grade 0 or baseline 
Grade 3 
(see Section 7.4.7.2 to 7.4.7.4 
for treatment algorithm) 
Omit dose administration until recovery to Grade ≤ 1 or 
baseline then decrease the next scheduled dose by 1 dose 
level 
Grade 4 
(see Section 7.4.7.2 to 7.4.7.4 
for treatment algorithm) 
Omit dose administration until recovery to Grade ≤ 1 or 
baseline then decrease the next scheduled dose by 1 dose 
level 
In the event Grade 4 toxicity lasts > 24 hours despite maximal 
medical attention discontinue treatment. 
If grade 4 toxicity lasts < 24 hours reduce dose by 1 dose 
level at next cycle 
If toxicity recurs discontinue treatment. 
All grades 
At the first sign of abdominal cramping, loose stools, or onset 
of diarrhoea, the patient should be treated according to 
Sections 7.4.7.2 to 7.4.7.4 according to the recommended 
treatment algorithm. 
Omit dose administration of CB-103 for ≥ CTCAE grade 2 
diarrhoea only if diarrhoea could not be controlled despite the 
use of optimal anti-diarrhoea treatments. 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
 


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7.4.6.1.7 
Non-Laboratory Toxicities 
Patients who experience non-laboratory toxicities related to CB-103 must be evaluated at 
least once a week following demonstration of the toxicity until resolution of the toxicity to 
allow for re-treatment, stabilisation of the toxicity, or study treatment completion.  
Table 10 
Dose modifications for non-laboratory toxicities 
Dose Modifications for CB-103 post cycle 1 
Worst Toxicity 
CTCAE Grade1 unless 
otherwise specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Non-laboratory adverse events 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose administration until resolved to ≤ grade 1, then ↓ 1 
dose level 
Grade 4 
Omit dose administration and discontinue patient from study 
 
1 Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
7.4.7 
Diarrhoea and Nausea Management Plan 
Although no signs of gastro-intestinal toxicities (e.g., diarrhoea) were observed in the non-
clinical safety and toxicology studies in different species (dog, rat, mouse) treated with 
CB-103 at different doses and administration schedules, the occurrence of diarrhoea 
cannot be excluded.  
There is no a priori prophylaxis for nausea, vomiting, and/or diarrhoea. Any of these 
symptoms constitute DLT only if they reach Grade ≥3 severity in Cycle 1 despite the 
following adequate supportive care measures: 
• 
Nausea and/or emesis: 
o Metoclopramide +/- meclozine 
o Dexamethasone 2 mg p.o. in case of Grade 3 nausea/emesis 
• 
Diarrhoea: 
o Loperamide 4 mg p.o. as needed 
CAUTION: 
• 
Serotonin-antagonists for the 5-HT3-receptor (e.g., ondansetron, granisetron) 
must NOT be used. 
• 
Metoclopramide and loperamide are drugs associated with Torsades de Pointes 
(TdP) BUT only under certain conditions OR by creating conditions that facilitate 
or induce TdP. Therefore, (i) the patient must be advised accordingly, (ii) the usage 
of other concomitant QT-prolonging drugs must be carefully considered, (iii) the 


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use of metoclopramide or loperamide should be closely monitored and (iv) the 
patient’s electrolyte status followed and promptly corrected. 
• 
ECGs that may be taken during the concomitant administration of metoclopramide 
or loperamide must be repeated if they remain abnormal after a wash-out period 
from these agents. 
• 
The intake of these agents should be kept as separated as possible from CB-103 
intake (at least up to 4 hours before and from 2 hours after CB-103 intake). 
Table 11 
NCI CTCAE version 4.03 grading of diarrhoea, nausea and vomiting for 
patients without colostomy 
Toxicity 
0 
1 
2 
3 
4 
Diarrhoea1 
None 
Increase of 
< 4 stools per 
day over 
baseline; mild 
increase in 
ostomy output 
compared to 
baseline 
Increase of 4 - 6 
stools per day 
over baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline 
Increase of ≥7 
stools per day 
over baseline; 
incontinence; 
hospitalisation 
indicated; 
severe increase 
in ostomy 
output 
compared to 
baseline; 
limiting self-care 
ADL 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Nausea 
None 
Loss of appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant weight 
loss, dehydration 
or malnutrition; 
inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, or 
hospitalization 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, 
or 
hospitalization 
indicated 
- 
Vomiting 
None 
1 - 2 episodes 
(separated by 5 
minutes) in 
24 hrs 
3 - 5 episodes 
(separated by 5 
minutes) in 
24 hrs 
≥ 6 episodes 
(separated by 5 
minutes) in 
24 hrs; tube 
feeding, TPN or 
hospitalization 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
 
1 Definition: A disorder characterised by frequent and watery bowel movements. 
Web address: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 


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7.4.7.1 
First Report of Diarrhoea 
• 
Obtain history of onset and duration of diarrhoea 
• 
Description of number of stools and stool composition (e.g. watery, blood, mucus 
in stool) 
• 
Assess patient for fever, abdominal pain, cramps, distension, bloating, nausea, 
vomiting, dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, 
dehydration) 
• 
Medication profile (i.e., to identify any diarrhoeagenic agents) 
• 
Dietary profile (i.e., to identify diarrhoea-enhancing foods) 
Proactively look for occurrence of diarrhoea after start of CB-103 treatment. Call patients 
at home, if necessary, to detect diarrhoea early during the first 8 weeks. If no problems 
occur, instruct the patient to call when a problem does arise. 
7.4.7.2 
Management of Diarrhoea 
General measures: 
• 
Stop all lactose-containing products, alcohol 
• 
Stop laxatives, bulk fibre (e.g., Metamucil®, Procter & Gamble), and stool softeners 
(docusate sodium; Colace, Roberts) 
• 
Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte® (Ross), 
Gatorade (Quaker), broth) 
• 
Eat frequent small meals (e.g., bananas, rice, apple sauce, Ensure®, toast) 
• 
Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with 
fibre) 
It is recommended that patients be provided loperamide tablets. It is mandatory that 
patients are instructed on the use of loperamide at cycle 1 in order to manage signs or 
symptoms of diarrhoea at home. Patients should be instructed to start oral loperamide 
(initial administration of 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) at the 
first sign of loose stool or symptoms of abdominal pain. These instructions should be 
provided at each cycle and the investigational site should ensure that the patient 
understood the instruction. At the beginning of each cycle, each patient should be 
specifically questioned regarding any experience of diarrhoea or diarrhoea related 
symptoms. If symptoms were experienced, then the investigational site should question 
the patient regarding the actions taken for these symptoms. 


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7.4.7.3 
Treatment of Diarrhoea Grade 1 or 2 
Diarrhoea grade 1 or 2 will be treated with standard loperamide (initially at first 
administration 4 mg, then 2 mg every 4 hours [maximum of 16 mg/day] or after each 
unformed stool). 
12-24 hours later: 
Diarrhoea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide after 12-hours diarrhoea-free interval 
 
Diarrhoea unresolved 
Persisting diarrhoea grade 1 or 2 will be treated with addition of opium tincture, 
dihydrocodeine tartrate tablets/injections and start early on with corticosteroids which is 
the recommended treatment for the development of goblet cell metaplasia seen with other 
NOTCH inhibitors. Treatment should be accompanied by monitoring the patient’s 
condition (to rule out dehydration, sepsis, ileus), medical check and selected workup if 
patient does not need hospitalisation (see Section 7.4.7.5 for diarrhoea work-up). Observe 
patient for response to antidiarrheal treatment and may also consider treatment with high 
dose corticosteroids.  
Persisting diarrhoea grade 3 or 4 may be treated with hospitalisation, high dose 
loperamide (initially 4 mg, then 2 mg every 2 hours), addition of opium tincture or 
dihydrocodeine tartrate tablets/injections and with high dose corticosteroids to potentially 
inhibit the development of the goblet cell metaplasia seen with other NOTCH inhibitors. 
Furthermore, start of i.v. fluids, parenteral nutrition and antibiotics as needed with 
monitoring of patients’ condition (to rule out dehydration, sepsis, ileus), medical check and 
workup (perform appropriate additional testing) should be started immediately. Observe 
patient for response. 
After 12-24 hours: 
Diarrhoea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide and/or other treatment after 12-hours diarrhoea-free 
interval 


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Diarrhoea unresolved 
• 
If diarrhoea still persisting (NCI CTC grades 1 and 2), after 2 x 24 hours with high 
dose loperamide, opiates and corticosteroids then admit to hospital and employ 
measures as for grade 3 and 4 until diarrhoea resolved. 
• 
If diarrhoea still persisting and progressed to NCI grades 3 and 4, employ 
measures described below. 
7.4.7.4 
Treatment of Diarrhoea Grade 3 or 4 
Severe diarrhoea grade 3 or 4 may be treated with hospitalisation, high dose loperamide 
(initially 4 mg, then 2 mg every 2 hours, addition of opium tincture or dihydrocodeine 
tartrate tablets/injections as well as early start of administration of corticosteroids as being 
the recommended treatment for goblet cell metaplasia observed in patients treated with 
other NOTCH inhibitors. Furthermore, start of i.v. fluids, parenteral nutrition and antibiotics 
as needed with monitoring of patients’ condition (to rule out dehydration, sepsis, ileus), 
medical check and workup (see Section 7.4.7.5 for diarrhoea work-up). Observe patient 
for response.  
After 12-24 hours: 
• 
If diarrhoea persisting administer high dose corticosteroids and consider 
subcutaneous (s.c.) Sandostatin/octreotide (100-500 μg three times daily [TID]) 
• 
Continue i.v. fluids, parenteral nutrition and antibiotics as needed 
• 
If diarrhoea grade 3 or 4 still persists patients should receive besides 
corticosteroids opium tincture or dihydrocodeine tartrate injections s.c. or 
intramuscular (i.m.) 
• 
If diarrhoea grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 μg 
TID) should be administered. 
• 
To control and/or resolve diarrhoea, next cycle of treatment should be delayed by 
1 or 2 weeks. Treatment should be continued only when diarrhoea resolved. 
7.4.7.5 
Diarrhoea Workup 
Perform appropriate tests (American Gastroenterological Association [AGA] Technical 
Review on the Evaluation and Management of Chronic Diarrhoea; Fine and Schiller, 1999). 
Spot stool analysis 
• 
Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• 
Blood 
• 
Faecal leukocytes (Wright's staining and microscopy) or 
• 
C. difficile toxin 


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• 
Faecal cultures such as Shigella and pathogenic E. coli - enterotoxigenic, 
enterohaemorrhagic etc., possibly Aeromonas, Pleisiomonas (if suspected 
exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis and thus great care and caution must be 
exercised in undertaking these invasive procedures. 
• 
Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy 
of proximal jejunum to assess extent of inflammatory jejunitis 
• 
Sigmoidoscopy - reassessment of colitis 
7.4.8 
Sample Size in Part A and Part B 
The sample size of Part A of the study depends on the number of patients to be enrolled 
in each dose level during the dose escalation with at least 3 and up to 6 patients enrolled 
per dose cohort. Depending on the BLRM, additional patients may be enrolled in some 
dose cohorts.  
The sample size of Part B will depend on the number of patients being enrolled in each 
expansion arm. For each expansion arm it is planned to have at least 10 patients enrolled 
and to continue enrolment in each arm to at least 20 patients based on an interim futility 
analysis. The table below shows the current calculation of sample size for Part A and Part 
B of the study. 
Table 12 
Sample size in Part A and Part B of this study 
Escalation 
Part A 
Dose Levels 
1-11 
MTD/RP2D 
confirmatory 
cohort 
Expansion 
Part B 
Total Study 
N (patients) 
55 pts* 
45 pts* 
100-140 pts 
200-240 pts** 
 
* Depending on the BLRM, additional patients may be enrolled in some dose cohorts. Based on 
the decision of the CRC approximately 45 patients in total may be enrolled in the MTD/RP2D 
confirmatory cohort to confirm safety before opening Part B.   
** Includes the eligible patients from the MTD/RP2D confirmatory cohort 
 
 
 


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7.5 
CONCOMITANT THERAPY 
7.5.1 
Permitted Concomitant Therapy 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
drugs (OTCs), approved dietary and herbal supplements, nutritional supplements and any 
non-medication interventions (e.g., individual psychotherapy, smoking cessation therapy, 
physical therapy and rehabilitative therapy) used by a patient within 14 days of the planned 
1st dose administration of CB-103. All concomitant medications taken within 14 days prior 
to planned first dose administration, as well as all new and ongoing concomitant 
therapy(ies) must be reported to the Investigator and recorded on the eCRF along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
Any diagnostic procedure and all medication administered to manage adverse events 
during the study will be according to standard of care and at the discretion of the 
Investigator and must be recorded on the Adverse Event eCRF with the exception of 
prohibited medications included in Section 7.5.2 below. 
Patients who use oral or injectable contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use, which should be recorded. Dosing should 
always be used in the dose-range according to the approved local prescribing information. 
Stable doses of medications administered for chronic diseases (e.g. hypertension) are 
allowed. The use of low molecular weight heparin (as an anticoagulant) is permitted.  
7.5.2 
Prohibited Concomitant Therapy 
Refer to the “LIST OF PROHIBITED MEDICATIONS" in the synopsis.  
 


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8. 
VISIT SCHEDULE AND STUDY ASSESSMENTS  
8.1 
DESCRIPTION OF STUDY ASSESSMENTS 
All examinations listed below will be performed according to the Schedule of Assessments 
outlined in Appendix 1 and Appendix 2. 
Phase I, Part A – Escalation: 
• 
All patients from each dose cohort in Part A will stay overnight at the hospital for 
1 night following their first CB-103 administration (C1D1) to allow for 24-hour PK 
sampling and ECG monitoring. During this time the patients will be closely 
monitored for safety. The overnight stays may not be required if reduced ECG and 
PK sampling is implemented. 
In case CB-103 is given BID, one more overnight hospital stays at Day 8 in cycle 
1 may be necessary to allow late samples collection. 
• 
Patients will then undergo daily visits for 2 days following the overnight monitoring 
on Day 1 at the hospital, and will get their CB-103 doses administered in the 
hospital. Patients will stay at the hospital for at least 3 hours following each 
administration to allow safety reporting. 
• 
Weekly visits to monitor safety and perform ECG monitoring and PK sampling are 
planned during the rest of the treatment period for the 1st cycle of CB-103 (28 
days). 
• 
Every 2 weeks visits to monitor safety and perform PK sampling are planned from 
cycle 2 until the completion of cycle 6. 
• 
EOT visit within 14 days after the last dose of CB-103 (within the 6 cycles period). 
• 
Safety follow-up visit (End-of-Study) for each patient within 28 days after the last 
dose of CB-103. 
• 
Survival follow-up (e.g. per telephone) for 1 year is planned every three months 
after the End-of-study visit or after the last treatment cycle (if outside of the 6 cycles 
period).  
• 
Further visits might be considered, depending on the health status of the patient, 
as determined by the treating Investigator of the respective investigational site.  
• 
More frequent laboratory safety tests (e.g., to closely monitor the liver function), 
are possible and can be performed outside the study site for those patients leaving 
far away, if necessary. The laboratory reference ranges from the local laboratories 
must be collected, and filed in the laboratory report together with the patients’ 
medical records. Care should be taken that any outliers possibly produced by the 
local laboratory findings are investigated at the study site. 


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Note: for those patients who may have the option to continue treatment after cycle 6, the 
subsequent visits are planned every 4 weeks if no medical issue or complication occurred 
in the previous cycles.  
Phase I, Part A - MTD/RP2D confirmatory cohort and Phase IIA, Part B – Expansion: 
For patients with solid tumours who are not hospitalized: 
• 
Patients will undergo daily visits for 3 days and will get their CB-103 doses 
administered in the hospital. Patients will stay for at least 3 hours following each 
administration of CB-103 to allow safety reporting with the exception of the first 
day where the patients should stay for up to 8 hours post-dose. 
In case CB-103 is given BID, one more overnight hospital stays at Day 8 in cycle 
1 may be necessary to allow late samples collection. 
• 
Weekly visits to monitor safety and perform ECG monitoring and PK sampling are 
planned during the rest of the treatment period for the 1st cycle of CB-103 (28 
days). 
• 
Every 2 weeks visits to monitor safety and perform PK sampling are planned from 
cycle 2 until the completion of cycle 6.  
• 
After cycle 6, subsequent visits are planned every 4 weeks if no medical issue or 
complication occurred in the previous cycles. 
• 
End-of-Treatment (EOT) visit within 14 days after the last dose of CB-103 (within 
the 12 cycles period). 
• 
Safety follow-up visit (End-of-Study) for each patient within 28 days after the last 
dose of CB-103. 
• 
Survival follow-up (e.g. per telephone) for 1 year is planned every three months 
after the End-of-Study or after the last treatment cycle (if outside of the 12 cycles 
period), and every six months thereafter for the 2nd year. 
• 
Further visits might be considered, depending on the health status of the patient, 
as determined by the treating Investigator of the respective investigational site. 
• 
More frequent laboratory safety tests (e.g., to closely monitor the liver function), 
are possible and can be performed outside the study site for those patients living 
far away, if necessary. The laboratory reference ranges from the local laboratories 
must be collected and filed in the laboratory report together with the patients’ 
medical records. Care should be taken that any outliers possibly produced by the 
local laboratory findings are investigated at the study site. 
For hospitalized patients with T-ALL/T-LBL: 
• 
Patient with T-ALL/T-LBL will undergo the same visit and monitoring schedule as 
outpatients with solid tumours. 


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Note: for those patients who may have the option to continue treatment after cycle 12, the 
subsequent visits are planned every 8 weeks if no medical issue or complication occurred 
in the previous cycles.  
8.1.1 
Eligibility Screening  
Patients are allowed to enter the study based on confirmation of the eligibility criteria (refer 
to inclusion and exclusion criteria in Section 6.1.1 and Section 6.1.2) at screening/baseline.  
The procedures for eligibility check, patient identification number assignments and 
coordination among the investigational site involved will be provided in a separate 
document prior to study start. 
8.1.2 
Information to be Collected on Screening Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but 
are not subsequently treated in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients. Minimal information will 
be entered into the clinical database and includes demography, screen failure reasons, 
eligibility criteria, and any serious adverse event which occurred after ICF signature during 
the screening period. 
8.1.3 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, use of alcohol and drugs of abuse, all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements). 
Demographic data will include year of birth, sex and self-reported race/ethnicity (collecting 
this information is essential in order to be able to evaluate the results of this study, for 
example, in the case of PK outliers or important between-patient differences in terms of 
treatment effect). 
Evaluation of the inclusion and exclusion criteria will be performed at the screening visit.  
8.1.4 
Disease History 
The patients’ disease history from the time of diagnosis (including surgeries, radiographic 
tumour progression, any biomarker information [e.g. tumour mutations like KRAS, BRAF 
and NRAS]) and details regarding anti-neoplastic treatments they have received in the 
past) will be collected at screening. The exact parameters to be collected will be outlined 
on the respective screening eCRF pages. 
8.2 
SAFETY ASSESSMENTS 
Safety assessments will consist of monitoring by Investigators and recording all adverse 
events, serious adverse events, and the regular monitoring of laboratory evaluations, 
physical examination, vital signs, weight, performance status evaluation, ECGs (standard 


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triplicates and Holter ECG) and repeat cardiac assessments, cardiac markers, ECHO or 
MUGA scan (if clinically required). Detailed description of the safety monitoring based on 
adverse events, serious adverse events, cardiac and laboratory monitoring as well as the 
requirements for the reporting of safety findings for the study and a description of the 
process for regulatory reporting is provided in Section 9, Safety Monitoring. 
8.2.1 
Adverse Events 
An adverse event for the purposes of this protocol is the appearance of (or worsening of 
any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after 
signing the informed consent even if the event is not considered to be related to the study 
drug(s). Please refer to Section 7.1 to Section 7.4 for the protocol-specific definitions of 
study drug and study treatment. 
Adverse events will be assessed according to CTCAE version 4.03. If CTCAE grading 
does not exist for an adverse event, the severity of mild, moderate, severe, life threatening 
and death, or grades 1 - 5, will be used. Adverse event monitoring should be continued 
for at least 4 weeks following the last dose of study treatment. 
Adverse events (but not serious adverse events) occurring before starting study treatment 
but after signing the ICF are recorded on the Medical History/Current Medical Conditions 
eCRF. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms, are considered clinically significant or require therapy 
(e.g., any haematologic abnormality that requires transfusion or cytokine treatment); and 
should be recorded on the Adverse Events eCRF under the signs, symptoms or diagnosis 
associated with them. In addition, isolated abnormal laboratory values that are considered 
clinically significant (e.g., cause study discontinuation or constitutes in and of itself a 
Serious Adverse Event) should be recorded on the Adverse Events eCRF. Serious 
adverse events occurring after signing the ICF are recorded on the Adverse Event eCRF. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
1. The severity grade (CTCAE grade 1-5) 
2. Its relationship to the study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication 
taken; 
non-drug 
therapy 
given; 
hospitalisation/prolonged 
hospitalisation) 


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5. Whether it is serious (For a description of serious adverse events, please refer to 
Section 9.1.2) 
Adverse events will be graded (wherever possible) using the NCI CTCAE version 4.03. 
It can be viewed electronically or downloaded and printed by visiting the following website: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
For consistency in adverse event grading, NCI CTCAE, version 4.03 must be used 
throughout the trial regardless of any subsequent versions of the CTC that may become 
available. 
All adverse events should be treated appropriately. Such treatment may include changes 
in study drug treatment including possible interruption or discontinuation, starting or 
stopping concomitant treatments, changes in the frequency or nature of assessments, 
hospitalisation, or any other medically required intervention. Once an adverse event is 
detected, it should be followed until its resolution, an assessment should be made at each 
visit (or more frequently, if necessary) of any changes in its severity, its suspected 
relationship to the study drug(s), any of the interventions required to treat it, and its 
outcome. 
Information from non-clinical studies with the investigational drug CB-103 about common 
side effects seen in the species treated with CB-103 on various doses and dosing 
schedules (e.g. dog, rat, mouse) has been taken into account to evaluate the potential 
adverse events which can be expected in patients in this FIH study and a list of these 
potential adverse events can be found in the Investigator’s Brochure or will be 
communicated between updates to the Investigator’s Brochure in the form of Investigator 
Notifications. This information will be included in the patient informed consent and should 
be discussed with the patient during the study as needed. 
Adverse event monitoring should be continued in the safety follow-up period for ≥ 28 days 
following the last dose of study drug. In this period of time following last dose of CB-103 
all cancer medications/therapies given to the patient as subsequent therapy must be 
recorded in the eCRF Concomitant Medications page. 
8.2.2 
Physical Examination, Weight, Height and Vital Signs 
All examinations (physical examination, weight, height and vital signs) will be performed 
according to the standards at each institution. Physical examinations will be conducted as 
depicted in Appendix 1 and Appendix 2.  
In most cases, for all patient visits during the study, the examinations can be performed 
within 24 hours prior to the visit day. Information about the physical examination, weight, 
height, vital signs and any additional specific examinations performed at the 
investigational site or by a clinical expert must be present in the source documentation at 
the investigational site. Significant findings present prior to the start of study drug must be 
included in the relevant Medical History/ eCRF. Significant findings made after the start of 


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study drug which meet the definition of an adverse event must be recorded on the Adverse 
Event eCRF. 
8.2.2.1 
Weight and Height 
Body weight and height will be measured as outlined below with the time-points specified 
in the Schedule of Assessments (see Appendix 1 and Appendix 2). 
Weight will be measured at baseline, on Day 1 of each treatment cycle (with exemption of 
Cycle 1 Day 1 where baseline assessment is sufficient), at any unscheduled visit, at EOT 
and Safety Follow-up visits. Body weight will be measured to the nearest kilogram. 
Height need only be recorded once, at screening visit.  
8.2.2.2 
Physical Examinations 
Physical examinations will be performed at the indicated patient visit (see Appendix 1 and 
Appendix 2), even if administration of study medication is being withheld. More frequent 
examinations may be performed at the Investigator’s discretion, if medically indicated. If 
these baseline examinations are performed within 72 hours prior to the first administration 
of CB-103, they need not be repeated on Day 1 of Cycle 1, except for patients with T-
ALL/T-LBL who need to repeat the physical examination at C1D1. 
A complete physical examination should be performed according to the standards at each 
institution and must include an evaluation of the head, eyes (including pupil size and reflex 
status), ears, nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, genitourinary, and neurological systems.  
Any abnormality identified at baseline should be recorded on the General Medical History 
eCRF.  
Eye examinations will be performed by an ophthalmologist during screening, at EOT, and 
in case of abnormalities at the safety follow-up visit.  
An extended eye examination including invasive ophthalmologic assessments should be 
performed by an ophthalmologist during the treatment period, in case significant 
abnormalities are experienced by the patient or seen by the study doctor at the regular 
eye evaluation as part of the physical examinations. 
The following standard ophthalmological assessments performed by an ophthalmologist 
are recommended: 
1. Visual acuity test 
2. Intraocular pressure test 
3. Slit-lamp test 
4. Dilated fundus test 
5. Colour-vision (Ishihara-plate) test 
Additional assessments or tests may be conducted by an ophthalmologist as clinically 
indicated. Invasive ophthalmologic assessments such as electroretinography (ERG) may 


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be conducted if feasible, at the discretion of the site and may be conducted at the time 
when visual symptom(s) are reported (if any). 
For any significant abnormalities seen at the eye examination, all assessed parameters 
and findings should be documented in the respective eCRF pages and source documents. 
At clinical visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in the patient’s medical file. New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
8.2.2.3 
Vital Signs 
Vital signs (oral temperature, respiratory rate, sitting blood pressure, and sitting pulse/ 
heart rate) will be obtained while the patient is in a semi-supine/supine position after the 
patient has been resting for approximately 5 minutes. Vital signs should be measured prior 
to blood draw or at least 10 minutes after the last blood draw. 
Blood pressure and heart rate should be obtained in a quiet room at a comfortable 
temperature, with the patient's arm unconstrained by clothing or other material. The patient 
should be asked to remove all clothing that covers the location of cuff placement. All 
measurements will be obtained from the same arm and, with the appropriate cuff size, 
using a well-calibrated automatic instrument with a digital readout, throughout the study 
(the “ideal” cuff should have a bladder length that is 80% and a width that is at least 40% 
of arm circumference [a length-to-width ratio of 2:1]). The individual should be comfortably 
in a semi-supine/supine position. 
Blood pressure, heart rate, and body temperature (oral) will be recorded at the time-points 
specified in the Schedule of Assessments (see Appendix 1 and Appendix 2). Vital signs 
should be assessed on the scheduled day, even if study medication is being withheld. 
More frequent examinations may be performed at the Investigator’s discretion, if medically 
indicated. 
8.2.2.4 
ECOG Performance Status 
The ECOG performance status will be assessed at screening within 14 days before 
planned first dose administration. In addition, an ECOG performance status will be done 
at baseline and at the indicated visits as per the Schedule of Assessments. With the 
baseline assessment performed, the assessment does not need to be repeated on the 
day of the first administration (Day 1 / Cycle 1) (Part A and Part B). 
Performance status will be scored using the ECOG performance status scale index (see 
Table 13). 


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Table 13 
ECOG performance status scale 
Score 
Performance Status 
0 
Fully active, able to carry out all normal activity without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed 
or chair. 
5 
Dead 
8.2.3 
Cardiac Assessments 
The following cardiovascular assessments will be performed in Part A and Part B of the 
study as outlined in the Schedule of Assessments (see Appendix 1 and Appendix 2): 
• 
Blood pressure and heart rate (as part of vital signs performed at every visit, see 
Section 8.2.2.3 and Section 8.2.3.1) 
• 
Digital 12-lead ECG (in triplicate) and selected time points for 24 hour Holter ECGs 
• 
Evaluation of cardiac markers as part of the laboratory safety assessments 
• 
ECHO or MUGA for LVEF assessment will be done at the investigational sites at 
pre-defined time points during the study 
As ECG changes were observed in the non-clinical safety and toxicology studies in rats 
and dogs at the Cmax concentration of CB-103 and CB-103 might therefore have an 
influence on the QT interval and bear a risk of cardiotoxicity, intense, continuous cardiac 
monitoring including central management of ECGs and central review of all ECG data by 
cardiac experts will be included in the study for Part A (escalation) and depending on 
results of Part A also in Part B (expansion) as medically required.  
8.2.3.1 
Blood Pressure and Heart Rate 
As part of the assessment of vital signs, blood pressure and heart rate are determined as 
outlined in Section 8.2.2.3. 
8.2.3.2 
Electrocardiograms (ECG) and Holter Safety Monitoring 
12-lead ECG monitoring in triplicate will be conducted as part of the screening process to 
evaluate eligibility of the patient and subsequently used as standard procedure during the 
whole study. 3-lead Holter ECG monitoring with 24 hour ECG profiles will be performed at 
baseline and used as baseline assessment and subsequently at selected time points as 
method to detect arrhythmias (for the exact time points refer to Table 14, Table 15, 
Appendix 1 and Appendix 2). 
12-lead ECG monitoring in triplicates and Holter ECG Monitoring (24 hours) will be 
conducted in Part A component according to the following schedule: 


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Table 14 
Part A ECG schedule (once daily dosing regimen of CB-103) 
Cycle 
Day 
12-lead 
ECG (E) 
/ Holter 
(H) ECG 
Timing and details 
- 
Screening 
E 
Triplicate ECGs will be recorded to evaluate for 
potential exclusion criteria.  
Within 7 days 
prior to 1st dose 
Baseline 
H 
24 hours Holter recording will be recorded as baseline 
assessment. 
1 
1, 8 
E, H 
24 hours Holter ECG will be hooked up prior to dosing 
on Day 1 and 8 and returned the day after. 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when the 
PK samples are taken: 
• 
Day 1: pre-dose (-30’ and -60’), 0.5, 1, 2, 4, 
6, 8 hours post-dose, 12 hours post-dose 
and 24 hours post-dose  
• 
Day 8: pre-dose (up to 60 minutes), 0.5, 1, 2, 
4, 6 and 8 hours post-dose and 24 hours 
post-dose  
 
15, 22 
 
12-lead ECG should be obtained (in triplicate approx. 
1-2 minutes apart) at the same time when the PK 
sample is taken: 
• 
pre-dose (up to 60 minutes) and 1 hour post-
dose 
2 
1 
E, H 
24 hours Holter ECG will be hooked up prior to dosing 
on Day 1 and returned the day after.  
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when the 
PK sample is taken: 
• 
pre-dose (up to 60 minutes), 0.5, 1, 2, 4, 6, 
and 8 hours post-dose  
2 
15 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when the 
PK sample is taken (i.e., pre-dose, up to 60 minutes). 
3,4,5,6 
1 
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when the 
PK sample is taken. 
EOT 
Within 
14 days after 
last dose  
E, H 
24 hours Holter ECG and returned the day after. 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
After cycle 6 
1 
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
 
Note 1:  ECG and PK blood samples need to be obtained at the same time-points and the ECG should 
be performed just prior to the drawing of the blood.  
Note 2: Holter recording should start 1 to 2 hours before the CB-103 intake. 
 
In Part B component of the study (Phase IIA, expansion), 12-lead ECGs in triplicates 
and Holter ECG Monitoring (24 hours) should be performed according to the following 
schedule and may be adapted based on the results of the ECG monitoring in Part A of the 
study 


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Table 15 
Part B (Phase IIA, expansion) ECG schedule (once daily dosing regimen 
of CB-103) 
Cycle 
Day 
12-lead 
ECG (E) / 
Holter (H) 
ECG 
Timing and details 
- 
Screening 
E 
Triplicate ECGs will be recorded to evaluate for 
potential exclusion criteria.  
Within 7 days 
prior to 1st dose 
Baseline 
H 
24 hours Holter recording will be recorded as 
baseline assessment. 
1 
1, 8,15, 22 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the pre-dose time 
point. 
2 till 12 
1 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the pre-dose time 
point. 
EOT 
Within 14 days 
after last dose  
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
After cycle 12 
1 
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
 
Note: ECG should be performed just prior to the drawing of the blood.  
Digital ECGs should be transmitted to the central ECG CRO designated by Sponsor on 
the day that they are acquired. Paper copies of the ECGs should be timely reviewed by 
the Investigator for the purpose of general safety. The central ECG CRO should send 
alerts to the Investigator and Covance if any ECGs are detected with QTcF values of 
≥ 500 ms. 
Timing of ECGs may be modified based upon emerging PK data (as some ECGs are 
matched with the PK data). When matched with PK sampling all efforts should be 
made to perform the ECG before each PK sample drawing such that the PK sample 
is collected at the nominal time.  
A 15-minute window for ECG collection is allowed around each nominal ECG time 
point except for the 24 hour ECG time point, where a 1 hour window is allowed. 
The 12-lead ECG recordings must be obtained in triplicate (i.e., three high quality ECGs 
without artifacts/lead misplacement, recorded approx.1-2 minutes apart) in Part A and Part 
B of the study. The average of the three readings will be used to determine ECG intervals 
(e.g., PR, QRS, QT). Digital 12-lead ECG devices will be provided to each investigational 
site by the central ECG laboratory for the duration of the study. Digital ECG recording 
must be performed for all patients according to the study protocol schedule (see Appendix 
1 and Appendix 2). ECGs will be reviewed, signed and dated by the Investigator or 
designee and ECG print-outs must be filed with the source documentation. The data 
records will be sent to the CRO responsible for central cardiac reading. The conditions 
should be as close as possible to pre-dose time-points. Details for the ECG collection and 
transmission will be provided in the ECG manual provided by the ECG core laboratory. 


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For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings in a timely fashion. Paper or electronic copies will be kept as part of the 
patient’s permanent study file at the investigational site.  
ECG characteristics, including heart rate, QRS duration, and PR, QTcF and QT interval, 
will be recorded on the eCRF. 
For both Part A and Part B, changes to the ECG scheme may be implemented based on 
emerging data. Any adjustments will be recorded in the study file and the total number of 
ECGs taken from an individual patient within a cycle will not be exceeded.  
ECG Schedule for BID Twice Daily Dosing Regimen of CB-103  
In case of oral BID dosing regimen of CB-103 the ECG schedule during cycle 1 will be 
adjusted concomitantly to the adjusted PK sampling.  
The ECG schedule at screening and baseline and from cycle 2 and onwards is identical 
to the one described above for the once-daily dosing of CB-103. However, the time points 
are related to the 1st IMP intake unless otherwise indicated. 
 
 


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Table 16 
Part A (Phase I) ECG schedule – BID regimen 
Cycle 
Day 
12-lead (E) / 
Holter (H) 
ECG 
Timing and details 
- 
Screening 
E 
Triplicate ECGs will be recorded to evaluate for 
potential exclusion criteria.  
Within 7 days 
prior to 1st dose 
Baseline 
H 
24 hours Holter recording will be recorded as 
baseline assessment. 
1 
1, 8 
E, H 
24 hours Holter ECG will be hooked up prior to 
1st IMP dosing on Day 1 and 8 and returned the 
day after. 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when 
the PK samples are taken: 
• 
Day 1: pre-dose 1st IMP intake (-30’ and 
-60’), 0.5, 1, 2 and 4 hours post-dose  
• 
Day 1: pre-dose 2nd IMP intake (-30’ and 
-60’), 0.5, 1, 2 and 4 hours post-dose 
• 
Day 2: pre-dose 1st IMP intake (up to 
60 minutes prior to dose) 
• 
Day 8: pre-dose 1st IMP intake (-30’ and 
-60’), 0.5, 1, 2 and 4 hours post-dose  
• 
Day 8: pre-dose 2nd IMP intake (-30’ and 
-60’), 0.5, 1, 2 and 4 hours post-dose 
• 
Day 9: pre-dose 1st IMP intake (up to 
60 minutes prior to dose) 
1 
15 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when 
the PK samples are taken: 
• 
Pre-dose (up to 60 minutes) 1st IMP 
intake 
2 
1 
E, H 
24 hours Holter ECG will be hooked up prior to 
1st IMP dosing on Day 1 and returned the day 
after.  
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when 
the PK sample is taken: 
• 
pre-dose (up to 60 minutes), 0.5, 1, 2, 4, 
6, and 8 hours post-dose 1st IMP intake 
2 
15 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when 
the PK sample is taken (i.e., pre-dose, up to up to 
60 minutes 1st IMP intake). 
3,4,5,6 
1 
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the same time when 
the PK sample is taken (respect to the 1st IMP 
intake). 
EOT 
Within 
14 days after 
last dose  
E, H 
24 hours Holter ECG and returned the day after. 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
After cycle 6 
1 
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
 


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Table 17 
Part B (Phase IIA, expansion) ECG schedule – BID regimen 
Cycle 
Day 
12-lead (E) 
ECG 
Timing and details 
- 
Screening 
E 
Triplicate ECGs will be recorded to evaluate for 
potential exclusion criteria.  
Within 7 days 
prior to 1st 
dose 
Baseline 
H 
24 hours Holter recording will be recorded as 
baseline assessment. 
1 
1, 8,15 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the pre-dose time 
point of the 1st IMP intake. 
2 till 12 
1 
E 
12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart) at the pre-dose time 
point of the 1st IMP intake. 
EOT 
Within 14 days 
after last dose  
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
After cycle 12 
1 
E 
A 12-lead ECG should be obtained (in triplicate 
approx.1-2 minutes apart). 
 
8.2.3.3 
Cardiac Imaging – ECHO or MUGA 
An ECHO or MUGA should be performed at baseline (within 7 days of first treatment), at 
Day 8 Cycle 1, at Day 1 Cycle 3 and at EOT visit to assess LVEF. These assessments 
will be done locally and may be repeated at the Investigator’s discretion if there are signs 
or symptoms of cardiotoxicity. The ECHO or MUGA scans will be reviewed, signed and 
dated by the Investigator or designee in a timely fashion and print-outs must be filed with 
the source documentation. The data records will be sent to the CRO for collection and 
storage. Details for the ECHO and MUGA scans will be provided in a separate Laboratory 
Manual. 
8.2.3.4 
Cardiac Laboratory – Cardiac Markers 
Evaluation of cardiac markers will be included as part of the laboratory safety assessments 
and will be assessed at the time points provided in Appendix 1 and Appendix 2. Cardiac 
markers include troponin [Trop] I or Trop T and N-terminal propeptide BNP (NT-pro-BNP). 
These assessments may be repeated at the Investigator’s discretion if there are signs or 
symptoms of cardiotoxicity. 
8.2.4 
Laboratory Safety Assessments 
Laboratory safety tests shall be performed at time-points specified in the Schedule of 
Assessments (Appendix 1 and Appendix 2). 
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient’s safety. Where the clinical significance of abnormal 


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lab results is considered uncertain, screening lab tests may be repeated before enrolment 
to confirm eligibility.  
In the event of unexplained abnormal clinically significant laboratory test values, the tests 
should be repeated immediately and followed up until they have returned to the normal 
range and/or an adequate explanation of the abnormality is found. Results of clinical 
laboratory testing will be recorded on the eCRF. 
Samples for the following blood and urine laboratory tests will be collected as specified in 
the Schedule of Assessments (Appendix 1 and Appendix 2) and sent to the local 
laboratory for analysis.  
• 
Haematology: Haemoglobin, haematocrit, erythrocytes (RBC), reticulocyte count, 
platelets, leukocytes (WBC), differentials (counts): neutrophils, eosinophils, 
lymphocytes, monocytes, basophils. 
• 
Coagulation: prothrombin time (expressed as INR) and activated partial 
thromboplastin time (aPTT). 
• 
Blood chemistry: AST, ALT, total and conjugated bilirubin, ALP, gamma-glutamyl-
transferase (γ-GT), creatine phosphokinase (CPK), albumin, creatinine, urea nitrogen, 
total protein, sodium, chloride, calcium, bicarbonate, phosphate, potassium, 
triglycerides, total cholesterol, glucose, C-reactive protein (CRP),  lipase, urate and 
lactate dehydrogenase. 
• 
Serology: human immunodeficiency virus (HIV), hepatitis B (HBV) or C (HCV). 
• 
Pregnancy test: All women of childbearing potential (including those who have had 
a tubal ligation) will have serum or urine pregnancy tests at the time-points specified 
in the Schedule of Assessments (Appendix 1 and Appendix 2). Pregnancy tests will 
also be done whenever one menstrual cycle is missed during the active treatment 
period (or when potential pregnancy is otherwise suspected) to confirm the patient 
has not become pregnant during the study. 
• 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, red and 
white blood cells) and microscopic examination, if clinically significant positive results 
from the dipstick (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). 
• 
Cardiac markers: Trop I or Trop T and NT-pro-BNP. 


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8.3 
EFFICACY ASSESSMENTS 
Tumour assessments will be performed at baseline, during treatment period and at 
treatment completion at the time-points specified in the Schedule of Assessments 
(Appendix 1 and Appendix 2). All radiographic assessments for the different indications 
will be defined in the imaging manual and all radiographic images (x-ray, CT, PET-CT, 
MRI) will be collected and archived centrally. 
A chest X-ray must be performed at baseline and should be repeated if clinically indicated. 
If a chest CT is performed at baseline to assess tumour lesions, then a chest X-ray may 
not be required. If any brain involvement is suspected, a brain scan should also be 
performed at baseline to identify any brain metastasis and document them into the 
respective tumour assessment eCRFs. For selected cancer indications, positron emission 
tomography–computed tomography (PET-CT) scans are to be performed and used for the 
tumour assessments at baseline and, if positive, on C2D15 (before tumour biopsy). 
For the different solid tumour indications enrolled in the study, the following criteria for 
radiographic tumour response assessments will be used: 
• 
For solid tumours: Radiographic tumour response assessments will be based 
on CT/MRI scans throughout the study and response determined by Investigator 
based on the RECIST v1.1 criteria (Eisenhauer et al., 2009). Response criteria by 
response subcategory are provided in Appendix 7. The same imaging method 
used for tumour assessment at screening should be used throughout the study. 
• 
In addition, in some indications, CT scan will be replaced by PET-CT (or PET 
scan added to CT scan) at baseline (prior to tumour biopsy) and if positive, 
repeated on treatment at C2D15 (prior to tumour biopsy) to explore changes in 
metabolism of the tumour. See Section 8.6 and Appendix 9. 


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8.4 
PHARMACOKINETIC ASSESSMENTS 
Blood samples for determination of plasma concentrations of CB-103, and its potential 
metabolite(s) as applicable, will be collected as detailed in Appendix 1 and Appendix 2. 
Details regarding the collection, processing, storage and shipping of the blood samples 
will be provided in a separate Laboratory Manual. 
Part A pharmacokinetic sample collection (for patients on a once-daily dose 
regimen of CB-103) will be obtained on: 
Cycle 1 (total of 22 samples): 
• 
Day 1: pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose (± 5 minutes) and 12 hours post-
dose (± 15 minutes) 
• 
Day 2: 24 hours post Day 1 dose (± 60 minutes), before drug intake on Day 2 
• 
Day 3: pre-dose 
• 
Day 8: pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose (± 5 minutes) 
• 
Day 9: 24 hours post Day 8 dose (± 60 minutes), before drug intake on Day 9 
• 
Day 15: pre-dose and 1 hour post-dose (± 5 minutes) 
• 
Day 22: pre-dose and 1 hour post-dose (± 5 minutes) 
Cycle 2 (total of 8 samples): 
• 
Day 1: pre-dose, 0.5, 1, 2, 4, 6, and 8 hours post-dose (± 5 minutes) 
• 
Day 15: pre-dose 
Note: the pre-dose PK should be collected up to 1 hour of CB-103 intake. 
Cycle 3 till cycle 6 (total of 2 samples per cycle) 
• 
One sample at every visit (pre- or post-dose). The timing can be flexible as long as the 
time of prior drug intake and PK sampling is recorded exactly. 
 


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Part B pharmacokinetic sample collection will be obtained on: 
Cycle 1 (total of 22 samples): 
• 
Day 1: pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose (± 5 minutes) and 12 hours post-
dose (± 15 minutes)  
• 
Day 2: 24 hours post Day 1 dose (± 60 minutes), before drug intake on Day 2 
• 
Day 3: pre-dose 
• 
Day 8: pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose (± 5 minutes) 
• 
Day 9: 24 hours post Day 8 dose (± 60 minutes), before drug intake on Day 9  
• 
Day 15: pre-dose and 1 hour post-dose (± 5 minutes) 
• 
Day 22: pre-dose and 1 hour post-dose (± 5 minutes) 
Cycle 2 (total of 8 samples): 
• 
Day 1: pre-dose, 0.5, 1, 2, 4, 6, and 8 hours post-dose (± 5 minutes) 
• 
Day 15: pre-dose 
Cycle 3 till cycle 12 (total of 2 samples per cycle) 
• 
One sample at every visit (pre- or post-dose). The timing can be flexible as long as the 
time of drug intake and PK sampling is recorded exactly. 
For both Part A and Part B changes to the PK sampling scheme may be implemented 
based on emerging data. Any adjustments will be recorded in the study file and the total 
number of PK samples taken from an individual patient within a cycle will not be exceeded.  
All efforts will be made to obtain the PK samples at the scheduled nominal-time relative to 
the dosing. However, samples obtained within the specified deviation of the nominal time 
(see above time window) will be considered protocol compliant, and the exact time of the 
sample collection noted on the eCRF. If a scheduled blood sample collection cannot be 
collected for any reason, the missed sample time may be re-scheduled with agreement of 
clinical Investigators, patient and Sponsor. PK samples will be assayed for CB-103 using 
a validated analytical method in compliance with the standard operating procedures of the 
central PK laboratory. 
8.4.1 
PK Sample Collection for BID Dosing Regimens of CB-103  
In case an oral BID dosing regimen of CB-103 is implemented, the PK sampling scheme 
during cycle 1 will be adjusted to allow an evaluation of the concentration-versus-time 
curves after the morning and the evening dose on the first day of dosing (Day 1) and again 
after multiple days of administration (Day 8).  
The PK sampling scheme from cycle 2 and onwards is identical to that described above 
for the once-daily dosing of CB-103. However, the time points are related to the 1st IMP 
intake of a day unless otherwise indicated. 


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Part A and B of the study: Cycle 1 (total of 23 samples): 
• 
Day 1: pre-dose, 1st intake, 0.5, 1, 2, 4 hours post-1st intake (± 5 minutes) 
• 
Day 1: pre-dose, 2nd intake, 0.5, 1, 2, 4 hours post-2nd intake (± 5 minutes) 
• 
Day 2: pre-dose, 1st intake (up to 60 minutes prior to dose) 
• 
Day 8: pre-dose, 1st intake, 0.5, 1, 2, 4 hours post-1st intake (± 5 minutes) 
• 
Day 8: pre-dose, 2nd intake, 0.5, 1, 2, 4 hours post-2nd intake (± 5 minutes) 
• 
Day 9: pre-dose, 1st intake (up to 60 minutes prior to dose) 
• 
Day 15: pre-dose, 1st intake (up to 60 minutes prior to dose) 
For any other dose regimen (e.g., intermittent oral dosing) the PK sampling scheme may 
require further adaptations based on new emerging data. Any adjustments will be 
recorded in the study file and the total number of PK samples taken from an individual 
patient within a cycle will not be exceeded. 
8.4.2 
PK Sub-study 
It can be decided to explore certain dosing conditions and their effect on the PK of CB-
103 (e.g., influence of food, influence of co-medications such as acid reducing agents, 
influence of formulation changes such as additional excipients, i.v. formulation, tablets or 
drinkable solutions) in a sub-set of patients during Cycle 2. The PK assessments on Day 
1 of Cycle 2 will serve as reference and a second set of PK samples will be taken on Day 
2 of Cycle 2 under the testing conditions. The total number of PK samples during Cycle 2 
in this sub-set of patients will not exceed 20 samples. 
All the procedural details including PK sampling time points of the PK sub-study(ies) will 
be described in a Note to File and the concerned authorities/ethics will be informed 
accordingly. 
It is possible to initiate several PK sub-studies to test different dosing conditions (as above), 
but each patient will participate in only one sub-study.  
Refer to the Appendix 11 and Appendix 12 for the PK sub-studies already initiated. 
8.4.3 
PK in CSF 
In T-ALL/T-LBL patients, a CSF sample should be taken on or around cycle 1 day 28, if 
clinically feasible, to determine the intra-thecal concentration of CB-103. 
 
 


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8.5 
PHARMACODYNAMIC/BIOMARKER ASSESSMENTS 
8.5.1 
Tumour tissue in Patient with Solid Tumours 
The required fresh tumour tissue(s) will be assessed for various PD markers/biomarkers 
and a potential role for safety, PD and anti-cancer activity of CB-103 will be investigated. 
Samples will be processed and shipped as described in a separate Laboratory Manual. 
The timing of sampling may change, but the total number of samples will not increase. 
The respective time points for each tumour tissue sampling are provided in Appendix 1 
and Appendix 2. 
• 
For patients enrolled in Part A (escalation): fresh tumour biopsies are not 
mandatory; however, patients should be encouraged to participate. Sufficient archival 
tumour tissue samples not older than 6 months prior to screening will be required to 
characterise the NOTCH alterations in tumours retrospectively.  
• 
For patients enrolled in Part A (MTD/RP2D confirmatory cohort) and Part B 
(expansion):  fresh tumour biopsies will be collected from all patients enrolled at the 
timepoints defined in the Schedule of Assessments (Appendix 1 and Appendix 2). 
Sufficient archival tumour tissue samples are allowed, if not older than 6 months prior 
to pre-screening, to be used for the characterisation of NOTCH alterations for the pre-
screening of patients, however, a pre-dose fresh tumour tissue sample should be 
taken to confirm the NOTCH activation in tumour cells as well as to detect newly 
developed NOTCH and NOTCH-related pathway activation. 
8.5.2 
Hair follicles in patients with solid tumours 
Hair follicles collection will be obtained at the following time-points:  
• 
Cycle 1 Day 1: pre-dose and 1 hour  post-dose (± 10 minutes)  
• 
Cycle 2 Day 1 and Day 15: pre-dose and 1 hour  post-dose (± 10 minutes)  
• 
Day 1 of each subsequent cycle*: 1 hour post-dose (± 10 minutes) 
 
For the BID dosing regimen of CB-103 the hair follicles collection is as follows: 
• 
Cycle 1 Day 1: pre-dose 1st intake, and 1 hour (± 10 minutes) post-dose 2nd intake 
• 
Cycle 2 Day 1 and Day 15: pre-dose and 1 hour (± 10 minutes) post-dose 1st intake  
• 
Day 1 of each subsequent cycle*: 1 hour (± 10 minutes) post-dose 1st intake 
 
*up to cycle 6 Part A and up to cycle 12 Part B. After the dose-escalation portion of Part A of the study, hair 
follicles will be collected only for selected patient groups. 
Changes to the sampling scheme may be required based on the emerging data. Any 
adjustment will be recorded in the study file and the total number of samples taken will not 
be exceeded. 
The time of collection of the hair follicles should be captured in the patient’s record and in 
the specific sample requisition form to send to the concerned central laboratory along with 


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the samples. More details regarding the collection, processing, storage and shipping of 
the hair follicle samples will be provided in a separate Laboratory Manual. 
8.5.3 
Whole blood plasma and saliva 
Serial blood samples (whole blood, plasma) in all patients (and bone marrow samples in 
T-ALL/T-LBL patients, as indicated) will be obtained to measure NOTCH/NOTCH target 
gene expression as well as to investigate changes of gene expression by CB-103 
treatment in immune cell subsets, T- and B- lymphocytes. Serial blood samples will be 
obtained to measure several soluble markers (plasma). 
Whole blood and plasma will be obtained at the time points indicated in the Schedule of 
Assessments in Appendix 1 and Appendix 2. The collection time window is as follows: 
• 
Cycle 1 Day 1: pre-dose and 1 hour  post-dose (± 10 minutes)  
• 
Cycle 2 Day 1 and Day 15*: pre-dose and 1 hour post-dose (± 10 minutes)  
• 
Day 1 of each subsequent cycle: 1 hour post-dose (± 10 minutes) 
 
For the BID dosing regimen of CB-103 the samples collection is as follows: 
• 
Cycle 1 Day 1: pre-dose 1st intake, and 1 hour (± 10 minutes) post-dose 2nd intake 
• 
Cycle 2 Day 1 and Day 15*: pre-dose and 1 hour (± 10 minutes) post-dose 1st 
intake  
• 
Day 1 of each subsequent cycle: 1 hour (± 10 minutes) post-dose 1st intake 
* for T-ALL/T-LBL patients the collection at C2D15 in NOT requested.  
A sample of saliva together with one blood sample will be obtained from T-ALL/T-LBL 
patients to determine the Notch mutational status in leukaemic blasts prior to start of 
treatment. If the Notch status of the patient is unknown, the samples will be taken during 
pre-screening. If the Notch status is known, the samples will be taken at baseline.   
Changes to the sampling scheme may be required based on the emerging data. Any 
adjustment will be recorded in the study file and the total number of samples taken will not 
be exceeded. 
More details regarding the collection, processing, storage and shipping of the blood, 
plasma and saliva samples will be provided in a separate Laboratory Manual.  
8.6 
POSITRON EMISSION TOMOGRAPHY (PET) IN PATIENTS WITH 
BREAST CANCER OR T-ALL/T-LBL WITH EXTRAMEDULLARY 
DISEASE 
FDG-PET can identify sign of biological effect early, before tumour size is reduced. 
Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy 
(e.g., in lymphoma, non–small cell lung, and esophageal cancer) has been shown to 
correlate with prolonged survival and other clinical end points now used. These findings 
suggest that FDG-PET could facilitate drug development as an early marker of drug effect. 


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At baseline, and if positive at baseline, also at cycle 2 day 15, the FDG ([18F]-Fluoro-
Deoxy-Glucose) PET imaging will be performed with CT in place of the CT scan alone. 
PET-CT will be done for patients with breast cancer in the MTD/RP2D confirmatory cohort 
of Part A and for patients with T-ALL/T-LBL if clinically indicated. 
FDG-PET must be performed before taking the fresh tumour biopsies. Refer to Appendix 9 
for more details. 
8.7 
DRUG METABOLISM AND GENETICS  
Genotype testing will be performed in all patients in Part A and Part B to allow the 
determination of the haplotype of selected metabolic enzymes in order to identify 
differential metabolisers. For these assessments, an extra blood sample will be taken at 
screening and at Day 1 of the first cycle. Based on the results from the investigation of 
fast and slow metabolisers in Part A on certain enzymes, patients may be excluded from 
the population for Part B (expansion) of this study or the dosing in each patient may be 
adapted based on the determined metabolic status of each patient. 
8.8 
OPTIONAL BIOMARKER STUDIES ON ADDITIONAL OR 
REMAINING SAMPLES 
Remaining blood and/or tumour tissue samples may be used for DNA, RNA and/or 
protein-based analyses.  
8.9 
ASSAYS AND DIAGNOSTIC METHODS FOR 
CHARACTERISATION OF THE NOTCH PATHWAY 
Established diagnostic methods will be used for the characterisation of NOTCH signalling 
at study-entry screening in the confirmatory cohort of Part A and Part B of the study 
(expansion) to detect alterations and activation of the NOTCH pathway in tumour tissue 
samples, in order to select patients eligible for the study. For the dose escalation cohorts 
in Part A of the study, patient selection based on NOTCH activation is not required and 
their NOTCH activation status in tumours will be retrospectively assessed, therefore the 
results will not be used to determine patient eligibility for the study.  
Where NOTCH testing is not done locally, a central laboratory will have diagnostic 
methods established for the assessment of alterations of the NOTCH pathway.  
Details on the criteria used for determining a patient to qualify as NOTCH positive (NOTCH 
pathway activation) will be provided in a separate Laboratory Manual for the diagnostic 
methods used in this study. 


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8.10 
TIMING OF STUDY ASSESSMENTS 
8.10.1 
Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before performing 
any study-related procedures. The ICFs for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the investigational site. 
All screening and pre-treatment assessments must be completed and reviewed to confirm 
that patients meet all eligibility criteria. The Investigator will complete the Eligibility Check 
List form after completing the screening procedures as detailed in the Patient Registration 
Plan.   
Screening, baseline and pre-treatment assessments will be performed between 1 to 
28 days prior to Day 1 (according to the Schedule of Assessments in Appendix 1 and 
Appendix 2). Patients cannot commence the enrolment procedure until all the entry criteria 
have been fulfilled. Where the clinical significance of an abnormal screening test result 
(laboratory or any other tests) is considered uncertain, the test should be repeated to 
confirm the result. 
8.10.2 
Assessments during Treatment 
Patients who enrolled in the lower dose cohorts in this study and (i) who had completed 
treatment as specified and discontinued the study,* or (ii) who have not been dosed for 
other reasons besides ineligibility, may be allowed to be re-screened  and to be re-enrolled 
into higher dose level cohorts in the study, upon a case-by-case level discussion and 
documented agreement with the Sponsor.  
*patients that had tolerated treatment well and experienced temporary benefit from treatment (e.g. long-term 
stable disease) in the lower dose cohorts and could be expected to benefit from treatment again at higher 
dose.  
These patients are to be seen as “new” subjects. Therefore, informed consent must be 
obtained and they will have to undergo all study-related procedures starting from 
screening; a previous analysis of an archival tumour tissue biopsy does not need to be 
repeated. The inclusion/exclusion criteria apply. 
The assessments to be performed during the treatment period are given in Appendix 1 
and Appendix 2. 
8.10.3 
Assessments at Study Completion 
Patients who complete the study will be followed-up for survival (Appendix 1 and Appendix 
2). 
8.10.4 
Assessments at Unscheduled Visits 
Assessments as listed in Appendix 1 and Appendix 2 (as deemed necessary by the 
Investigator and/or Sponsor/delegate CRO in particular for safety) and any other additional 


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examinations and assessments deemed necessary, can be performed at unscheduled 
visits at the discretion of the investor and Sponsor/delegate CRO. 
8.11 
PATIENT, STUDY, AND SITE DISCONTINUATION 
8.11.1 
Patient Discontinuation 
The Investigator has the right to discontinue a patient from treatment with CB-103 or 
withdraw a patient from the study at any time. In addition, patients have the right to 
voluntarily discontinue study drug or withdraw from the study at any time for any reason. 
The date and reason for discontinuation must be documented in the eCRF. Reasons for 
discontinuation of study drug or withdrawal from the study may include, but are not limited 
to, the following: 
• 
Patient withdrawal of consent at any time. 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardise 
the patient’s safety if he or she continues in the study. 
• 
Investigator or Sponsor determines it is in the best interest of the patient. 
• 
Patient non-compliance. 
8.11.1.1 
Discontinuation from Study Drug and Withdrawal from the Study 
Patients must discontinue the study drug if they experience any of the following: 
• 
Pregnancy 
• 
Unable to continue to comply with study requirements 
Patients who discontinue study treatment before completing the study should be 
scheduled for an EOT and safety follow-up visits within 14 days and 28 days (respectively) 
after discontinuing study treatment, at which time all of the assessments listed for the EOT 
and safety follow-up visits will be performed. An end of treatment eCRF should be 
completed, giving the date and reason for stopping the study treatment. Patients who 
discontinue study drug in Part A prematurely during the DLT period will be replaced, unless 
the reason for discontinuation is a DLT. 
Every effort should be made to obtain information on patients who withdraw from the study. 
The Investigator should inquire about the reason for withdrawal, requests the patient to 
return for a final visit, if applicable, and follow-up with the patient regarding any unresolved 
adverse events. The primary reason for withdrawal from the study should be documented 
in the eCRF. 
Patients will not be followed for any reason after consent from participation in the study 
has been withdrawn. 
When a patient voluntarily withdraws from the study, or is withdrawn by the Investigator, 
the reason for withdrawal should be reported in the eCRF. Samples collected until the 


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date of withdrawal will be analysed, unless the patient specifically requests for these to be 
discarded or local laws require their immediate destruction.  
Patients who withdraw prematurely in Part A of the study during the DLT period from the 
study for any other reason besides a DLT will be replaced. For Part B, discontinued 
patients will be replaced if they do not have at least one post-baseline efficacy assessment 
and did not discontinue due to clinical progression. 
Criteria for withdrawal from the study are given in Section 9.2.4. 
8.11.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events indicates a potential health hazard to 
patients. 
• 
Patient enrolment is unsatisfactory. 
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 
The Sponsor has the right to replace an investigational site at any time. Reasons for 
replacing a site may include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the ICH guideline for GCP 
 


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9. 
ASSESSMENT OF SAFETY 
9.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest, measurement 
of protocol‑specified safety laboratory assessments, measurement of protocol-specified 
vital signs, ECGs, and any other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 9.4. 
9.1.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient administered a pharmaceutical product, 
regardless of causal attribution. An adverse event can therefore be any of the following: 
• 
Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 9.3.5.10. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., invasive screening 
procedures such as biopsies). 
9.1.2 
Serious Adverse Events  
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death). 
• 
Life-threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death). 
• 
Requires or prolongs inpatient hospitalisation (see Section 9.3.5.10). 


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• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions). 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug or to a mother whose partner was exposed to study drug. 
• 
Significant medical event in the Investigator's judgment (e.g., may jeopardise the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria (e.g., NCI CTCAE v4.03 criteria; see Section 9.3.3); the event itself may 
be of relatively minor medical significance (such as severe headache without any further 
findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Pregnancy of a female patient or of the female partner of a male patient is not reported as 
a serious adverse event and are reported on a specific Clinical Trial Pregnancy Reporting 
Form immediately, within 24 hours to the Sponsor (see description in Section 9.4.3). 
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after becoming aware of the event; see 
Section 9.4.2 for reporting instructions). 
9.1.3 
Non-Serious Adverse Events of Special Interest  
Not applicable in Part A. Based on the results from Part A, non-serious adverse events of 
special interest [AESI]) might be defined for Part B of the study. These AESIs are required 
to be reported by the Investigator to the Sponsor immediately (i.e., no more than 24 hours 
after becoming aware of the event; see Section 9.4 for reporting instructions). 
9.2 
SAFETY PLAN 
9.2.1 
Safety Precautions 
Safety will be assessed by close monitoring and timely assessment of adverse events, 
serious adverse events, DLTs, laboratory parameters, robust cardiovascular assessments 
(blood pressure, heart rate, ECG, periodical Holter ECG monitoring, ECHO or MUGA, 
cardiac markers), the patient’s medical condition (physical examination), and general 
well-being and activities of daily life (ECOG performance status). The CTCAE v4.03 will 
be used. 


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Safety will be evaluated by: 
• 
Adverse events (according to CTCAE v4.03), AESIs in Part B if applicable, serious 
adverse events and adverse events leading to discontinuation or death 
• 
The results of safety laboratory test, physical examination, vital signs, 12-lead 
ECGs, Holter Monitoring, LVEF and ECOG performance status 
• 
Drug exposure, including dose intensities and dose modifications 
9.2.2 
Dose-Limiting Toxicity (DLT) 
Refer to Section 7.4.4. 
9.2.3 
Cardiac Monitoring 
Cardiovascular assessments will be performed as outlined in the Schedule of 
Assessments (Appendix 1 and Appendix 2), and as detailed in Section 8.2.3. 
9.2.4 
Criteria for Withdrawal from the Study 
Patients will be withdrawn from the study if the following criteria are met: 
• 
Unequivocal disease progression 
• 
Death 
• 
Intervening illness that prevents further administration of treatment 
• 
Unacceptable adverse events 
• 
Intercurrent cardiac disease, especially drop in LVEF < 40% or drop > 15% from 
baseline (if LVEF with > 15% drop is still > 55% a second measurement after 
1 week would be allowed before discontinuing the patient) 
• 
Intercurrent interstitial lung disease or pneumonitis 
• 
Patient non-compliance  
• 
Pregnancy 
• 
The patient decides to withdraw from study or is lost to follow-up 
• 
General or specific changes in the patient's condition that render the patient not 
eligible for further treatment in the judgment of the Investigator 
• 
If a patient experiences a DLT 
• 
If a patient requires a continuous dose delay of more than 14 days (Part A and 
Part B) from the intended day of the next scheduled dose of CB-103  
• 
If a patient is non-compliant and misses or forgets more than 3 sequential dosings 
on more than 1 occasion 


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9.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all adverse events (see Section 9.1.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 9.4 to 9.5.  
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 9.1.2 for seriousness criteria), severity (see 
Section 9.3.3), and causality (see Section 9.3.4). 
Follow-up by the Investigator may be required until the event or its sequelae resolve or 
stabilise at a level acceptable to the Investigator, and Sponsor concurs with that 
assessment. As part of ongoing safety reviews conducted by the Sponsor, any non-
serious adverse event that is determined by the Sponsor to be serious will be reported by 
the Sponsor as a serious adverse event. To assist in the determination of case 
seriousness further information may be requested from the Investigator to provide clarity 
and understanding of the event in the context of the clinical trial. 
9.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in 
the patient’s medical records. Adverse events will then be reported on the Adverse Event 
eCRF as follows: 
From informed consent until the initiation of study drug, only serious adverse events 
related to study procedures. Any other adverse events occurring in this period should be 
only recorded on the Medical History. 
After initiation of study drug, all adverse events regardless of relationship to study drug, 
will be reported until 4 weeks after the last dose of study drug. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 9.6. 
9.3.2 
Eliciting Adverse Event Information 
Investigators are advised to use a consistent method of non-directive questioning to elicit 
adverse event information at all patient evaluation time‑points. Some examples of 
non-directive questions are: “How have you felt since your last clinic visit?” or “Have you 
experienced any changes to your health since your last visit?” 
9.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.03) will be used to 
assess adverse event severity. Table 18 will be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE. 


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Table 18 
Adverse event severity grading scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated. 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily livinga 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; or 
limiting self-care activities of daily livingb,c,d 
4 
Life-threatening consequences or urgent intervention indicatede 
5      Death related to AEe 
Abbreviations: NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
Based on the NCI CTCAE (v4.03), which can be found at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding 
one's self, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event (Section 9.4.2 for reporting instructions), per the definition of a serious adverse event in 
Section 9.1.2. 
d Grade ≥ 2 skin or subcutaneous, pharyngeal/laryngeal or mucosal reaction, clinically relevant 
retinal abnormalities detected by OCT should be reported as Adverse Events of Special Interest, 
as indicated in Section 9.1.3. 
e Grade 4 and Grade 5 events must be reported as serious adverse events (Section 9.4.2 for 
reporting instructions), per the definition of serious adverse events in Section 9.1.2. 
 
9.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the information about the 
investigational drug and its non-clinical effects described in the Investigator Brochure, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether or not an adverse event is considered to be related to the 
study drug, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug. 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug. 
• 
Known association of the event with the study drug or with similar treatments. 
• 
Known association of the event with the disease under study. 


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• 
Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event. 
• 
Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event. 
9.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
9.3.5.1 
Diagnosis versus Signs and Symptoms 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases). However, if a constellation 
of signs and/or symptoms cannot be medically characterised as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF. If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that corresponds 
to the starting date of the first symptom of the eventual diagnosis. 
9.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of severe 
or serious secondary events. However, medically significant adverse events occurring 
secondary to an initiating event that are separated in time should be recorded as 
independent events on the Adverse Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
• 
If a severe GI haemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 


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9.3.5.3 
Reporting of Progression of Disease 
Progression of the underlying malignancy should not be captured as an (S)AE (including 
fatal AEs). Clinical symptoms may be reported as AEs, if the symptom cannot be 
determined as exclusively due to the progression of the underlying disease or does not fit 
the expected pattern of progression for the disease under study. If a new malignancy 
appears, it will be considered an AE. 
9.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time-points. If the initial severity of a persistent adverse event worsens, 
the entry in the Adverse Event eCRF should be marked as resolved and a new separated 
entry with the worsening severity should be added. If the event becomes serious, the 
Adverse Event eCRF should be updated to reflect this. 
A recurrent adverse event is one that resolves between patient evaluation time-points and 
subsequently recurs. Each recurrence of an adverse event should be recorded separately 
on the Adverse Event eCRF. 
9.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• 
Results in a medical intervention (e.g., potassium supplementation for 
hypokalaemia) or a change in concomitant therapy. 
• 
Clinically significant in the Investigator’s judgment. 
 
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event. 
9.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• 
Results in a medical intervention or a change in concomitant therapy. 
• 
Clinically significant in the Investigator’s judgment. 
Medical and scientific judgment should be exercised in deciding whether an isolated vital 
sign abnormality should be classified as an adverse event. 


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9.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( >  3 × ULN) in combination with either an elevated 
total bilirubin ( >  2  ×  ULN) or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinaemia is considered to be an indicator of severe liver injury (Hy’s Law). 
Therefore, Investigators must report as a serious adverse event the occurrence of either 
of the following: 
• 
Treatment-emergent ALT or AST >  3 × ULN in combination with total 
bilirubin >  2 × ULN (Hy’s Law). In the event of suspected Hy’s Law CB-103 
administration has to be put on hold immediately and permanent discontinuation 
of treatment should be considered. 
• 
Treatment-emergent ALT or AST >  3 × ULN in combination with clinical jaundice. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 9.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after becoming 
aware of the event) as a serious adverse event (see Section 9.4.2). 
9.3.5.8 
Deaths 
Deaths that occur during the protocol-specified Adverse Event reporting period that are 
attributed by the investigator solely to the progression of the underlying cancer, will be 
recorded on the EoT/EoS pages in the eCRF and not as an Adverse Event. All other 
deaths that occur during the protocol-specified adverse event reporting period (see 
Section 9.3.1), regardless of relationship to study drug, must be recorded on the Adverse 
Event eCRF and immediately, within 24 hours reported to the Sponsor (see Section 9.4.2).  
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded on the Adverse Event 
eCRF. Generally, only one such event should be reported. The term “sudden death” 
should only be used for the occurrence of an abrupt and unexpected death (i.e., due to 
presumed cardiac causes in a patient with or without pre-existing heart disease). If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of death 
later becomes available, “unexplained death” should be replaced by the established cause 
of death. 
9.3.5.9 
Pre-existing Medical Conditions 
A pre-existing medical condition is a condition which is listed in Medical History and/or has 
an onset prior to the date the informed consent is obtained. 
A pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 


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that the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
9.3.5.10 Hospitalisation or Prolonged Hospitalisation  
Any adverse event that results in hospitalisation or prolonged hospitalisation should be 
documented and reported as a serious adverse event (per the definition of serious adverse 
events in Section 9.1.2), except as outlined below. 
The following hospitalisation scenarios are not considered to be serious adverse events: 
• 
Hospitalization for treatment of T-ALL/T-LBL 
• 
Hospitalisation for respite care. 
• 
Planned hospitalisation required by the protocol (e.g., tissue biopsy). 
• 
Hospitalisation for a pre-existing condition, i.e. hospitalisation that was planned 
prior to the study. 
The following hospitalisation scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalisation for an adverse event that would ordinarily have been treated in an 
out-patient setting had an outpatient clinic been available 
• 
Admission to emergency room that does not result in hospitalisation.  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as adverse events. However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an adverse event. 
For example, an acute appendicitis that begins during the adverse event reporting period 
should be reported as the adverse event, and the resulting appendectomy should be 
recorded as the treatment of the adverse event. 
9.3.5.11 
Overdose 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. Administration of the 
precise dosage must always be ensured. 
Any study drug overdose of study drug should be noted on the Study Drug Administration 
eCRF. 
All adverse events associated with an overdose of study drug should be recorded on the 
Adverse Event eCRF. If the associated adverse event fulfils serious criteria, the event 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after becoming 
aware of the event; see Section 9.4). 
In the case of study drug overdose, it is at the discretion of the Investigator to consider 
hospitalization of the patient for observation of at least 24 hours with frequent cardiac 
monitoring (frequent ECG, cardiac markers), repeated physical examinations, laboratory 


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tests as indicated and as usually performed locally, as well as any other specialised 
examinations deemed necessary to ensure the safety of the patient. Depending on the 
amount of study drug taken in excess of the planned dose and according to the symptoms 
observed in the patient, measures may also include admission to an intensive care unit 
and measures to empty the stomach if the timing of the administration enables study drug 
removal from the stomach before it becomes fully absorbed. 
9.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR 
TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to Covance Pharmacovigilance immediately; under no circumstances should 
reporting take place more than 24 hours after the Investigator becomes aware of the event. 
The following is a list of events that the Investigator must report to Covance 
Pharmacovigilance within 24 hours after becoming aware of the event, regardless of 
relationship to study drug: 
• 
Serious adverse events 
• 
Non-serious adverse events of special interest 
• 
Pregnancies 
The Investigator must report new significant follow-up information for these events to 
Covance Pharmacovigilance immediately (i.e., no more than 24 hours after becoming 
aware of the information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IEC/IRB. 
9.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours a day, 7 days a week. The Medical Monitor contact details for all investigational 
sites are listed in the separate document “Administrative and Contact Information & List 
of Investigators”. 


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9.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 9.1.2 and 9.1.3), Investigators should record all case details that can be 
gathered on the Serious Adverse Event eCRF page and submit to Covance 
Pharmacovigilance within 24 hours of awareness. Details on the reporting of these 
adverse events are described in the separate eCRF Completion Guidelines. 
In case of system failure or any reason why electronic reporting is not possible, the paper 
Serious Adverse Event Reporting Form must be completed and forwarded to Covance 
Pharmacovigilance, no more than 24 hours after becoming aware of the event. Any safety 
information reported by paper must be retrospectively added to the eCRF as soon as 
access has been restored.  
Contact details for Covance Pharmacovigilance are as follows: 
Email: GlobalSAEInbox@covance.com 
Fax (Part A & B planned countries):  Spain:   
+34 (0) 800-529-34043 
 
 
 
 
 
Netherlands: +31 (0) 800-529-34043 
 
 
 
 
 
Switzerland: 
+41 (0) 800-529-34043 
 
 
 
 
 
Germany:  
+49 (0) 800-529-34043 
 
 
 
 
 
UK:  
 
+44 (0) 800-529-34043 
 
 
 
 
 
France: 
+33 (0) 800-529-34043 
 
 
 
 
 
US:  
 
+1 888 726 8416 
When using the Freephone Universal International Freephone Number (UIFN) numbers 
listed above, they must be dialled using the international prefix from the country the fax is 
being sent from. The exception is for the UK where the 44 pre-fix may not be required. 
Most countries require the first zero to be dropped, but this depends on local fax number 
conventions.  
9.4.3 
Reporting Requirements for Pregnancies 
9.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 90 days after the last dose 
of study drug. A Clinical Trial Pregnancy Reporting Form should be completed by the 
Investigator and submitted to Covance Pharmacovigilance within 24 hours after becoming 
aware of the pregnancy. Pregnancy should not be recorded on the Adverse Event eCRF. 
The Investigator should discontinue study drug and counsel the patient, discussing the 
risks of the pregnancy and the possible effects on the foetus. Monitoring of the patient 
should continue until conclusion of the pregnancy. 


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9.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant during the study or within 90 days after the last dose of 
study drug. A Clinical Trial Pregnancy Reporting Form should be completed by the 
Investigator and submitted to Covance Pharmacovigilance within 24 hours after becoming 
aware of the pregnancy. Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
drug. 
9.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to Covance Pharmacovigilance immediately 
(i.e., no more than 24 hours after becoming aware of the event; see Section 9.4.2). 
Any induced abortion due to maternal toxicity and/or embryo-foetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after becoming aware of the event; 
see Section 9.4.2). 
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form. 
9.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to Covance Pharmacovigilance 
immediately (i.e., no more than 24 hours after becoming aware of the event; Section 9.4.2). 
9.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
9.5.1 
Investigator Follow-Up 
The Investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the Investigator, the patient is lost to 
follow-up, or the patient withdraws consent. Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilisation cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 


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All pregnancies reported during the study should be followed until pregnancy outcome and 
reported according to the instructions provided in Section 9.4.3. 
9.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or its designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
9.6 
POST-STUDY ADVERSE EVENTS 
The Investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 4 weeks after the last dose of study 
drug). If the Investigator becomes aware of any other serious adverse event occurring 
after the end of the adverse event reporting period, if the event is believed to be related to 
prior study drug treatment, the event should be reported directly to the Sponsor or its 
designee. 
9.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to Investigators, IECs/IRBs, and 
applicable health authorities based on applicable legislation. If the new information may 
adversely affect the safety of patients or the conduct of the study, a “Dear Doctor Letter” 
is sent to the sites with further instructions that may differ from the protocol or even instruct 
the sites to stop IMP treatment. The patients are timely informed by the investigator and 
the communication documented on medical records along with the confirmation whether 
the patient is willing to remain in the study. If any information in the ICF needs to be 
changed, it must be re-approved by the IEC/IRB and the patient must be re-consented. 
 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
CB-103 Investigator's Brochure 
Section 6 of the Investigator's Brochure contains the reference safety information (RSI) 
of CB-103 to be used for assessing expectedness of a respective adverse event and 
serious adverse event. The RSI of CB-103 in the Investigator’s Brochure will be 
updated based on new findings occurring in the clinical study, however for the 
assessment of expectedness for a specific event, only the approved current version 
of the Investigator’s Brochure should be used. 


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The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the Investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An aggregate report of any clinically relevant imbalances that do not favour the test 
product will be submitted to Health Authorities. 
 


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10. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP) covering Part A and Part B 
of this study. The SAP will provide all data handling rules, including the management of 
missing values and the handling of data for withdrawn patients. The SAP will also outline 
protocol deviation criteria. Any deviations from the planned analyses specified or 
populations defined within the SAP will be justified in writing and presented within the final 
clinical study report (CSR) for Part A and for Part B. 
The clinical database locks, for Part A and Part B respectively, will occur after all data for 
the respective part of the study are reconciled (i.e., “cleaned”) for all patients who 
participate in the dose escalation Part A for the Part A CSR and in the expansion Part B 
at the MTD/RP2D for the Part B CSR. Two CSRs will be generated for this study, one for 
Part A (dose escalation) and one for Part B (dose expansion). The SAPs for each part of 
the study will be finalised and signed before the database lock.  
In all tables, listings and figures of Part A, the dose-escalating cohorts will be reported 
from the lowest to the highest dose. In the Part B of the study expansion arms will be 
reported by indication. Where appropriate, for efficacy assessment, in addition those 
patients analysed by “NOTCH+” status who received what becomes identified as the 
MTD/RP2D during Part A and B, will be combined and summarised under the same dose 
level. 
10.1 
ANALYSIS SETS 
The safety set will consist of all patients who received at least one dose of CB-103 and 
had at least one post-baseline safety assessment (where the statement that a patient had 
no adverse event on the Adverse Events eCRF constitutes a safety assessment). The 
safety set will be the primary population for all efficacy and safety related endpoints except 
determination of the dose-DLT relationship. 
The dose-determining set (DDS), which is the analysis set used for determination of the 
MTD, will consist of all patients in the safety set, who have (a) experienced DLT at any 
time during Cycle 1, and/or (b) met the minimum treatment and safety evaluation 
requirements without experiencing DLT within Cycle 1, as described below. 
For all dose levels, from starting dose to the respective dose escalation levels, 3-6 patients 
will be enrolled and treated with CB-103 according to a staggered inclusion scheme to 
ensure adequate time for safety observation between inclusions, and before dose 
escalation. Depending on the BLRM, additional patients may be enrolled in some dose 
cohorts. The minimum treatment and safety evaluation requirements will have been met 
if, in Cycle 1, the patient has been treated with the planned dose of CB-103 for ≥ 21 days 
(≥ 75% of the planned dose; minimum exposure criterion), was observed for ≥ 28 days 
following the Cycle 1 Day 1 dose, and has completed the required safety evaluations for 
Cycle 1. Patients who do not meet these minimum treatment and safety evaluation 


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requirements will be regarded as ineligible for inclusion in the DDS. Unless they 
experienced a DLT, patients will be replaced until the minimum number of 3 patients 
required for evaluation is reached. 
The DDS will be used in the BLRM to estimate the dose-DLT relationship. 
The PK set consists of all patients who have at least received one dose of study drug and 
have at least one post-dose PK measurement. 
Patients who were screened and have signed the informed consent but did not receive 
any treatment will be listed including reason for screen failure and any serious adverse 
event that is related to study procedure. These patients will not be part of any summary 
table except for summarising disposition. 
10.1.1 
Missing Data/Discontinuation 
Due to the dose escalation design of Part A and the exploratory design of Part B of the 
study no missing imputation of missing values will be done for any analysis. Reasons for 
discontinuation of the study and the study treatment will be listed and summarised. 
Currently no drop-outs are foreseen. However, if patients in the escalation phase do not 
fulfil the minimum treatment and safety evaluation requirements and discontinue for a 
reason other than DLT, they will be replaced. For Part B, discontinued patients will be 
replaced if they do not have at least one post-baseline efficacy assessment and did not 
discontinue due to clinical progression. 
10.2 
DEMOGRAPHICS, MEDICAL HISTORY, PRIOR MEDICATION AND 
OTHER BASELINE CHARACTERISTICS 
Demographic characteristics, prior anti-cancer therapies and surgeries, medical history, 
prior medication and other baseline data will be listed and summarised using descriptive 
statistics for numerical data and contingency tables for categorical data. Medical history 
and prior medication will be listed. Prior anti-cancer therapies will be coded by World 
Health Organization (WHO) Anatomical, Therapeutic and Chemical (ATC) terms and 
summarised. Prior cancer surgeries will be summarised. 
10.3 
STUDY TREATMENT 
The actual dose received and the duration of CB-103 as well as the dose intensity (actual 
dose received/actual duration) will be listed and summarised by cycle and overall using 
descriptive statistics.  
10.4 
CONCOMITANT MEDICATION 
Concomitant medication and significant non-drug therapies after the start of study 
treatment will be listed and summarised by WHO ATC term in contingency tables. 


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10.5 
PRIMARY ANALYSIS 
10.5.1 
Part A (Escalation) 
10.5.1.1 
Bayesian Logistic Regression Model for Dose Escalation 
Determination 
An adaptive BLRM guided by the EWOC principle will be used in the dose escalation. The 
use of Bayesian response adaptive models for Phase I studies has been advocated by 
the EMA guideline on small populations (2006) and by (Rogatko et al., 2007) and is one 
of the key elements of the FDA’s Critical Path Initiative. 
10.5.1.2 
Dose-Finding of Single Agent CB-103 
A 2-parameter BLRM (Neuenschwander et al., 2008) will be used for dose escalation. 
Standardised doses will be used such that one of the doses (d*) equals 1, e.g., doses are 
rescaled as d/d*. As a consequence, α is equal to the odds of the probability of toxicity 
at d*. All information currently available about the dose-DLT relationship of CB-103 is 
summarised in a prior distribution. For this study, this includes pre-clinical data about the 
starting dose and predicted MTD of CB-103 within different animal species. This prior 
distribution is then updated after each cohort of patients with all of the DLT data available 
in the DDS from the current trial. Once updated, the distribution summarises the probability 
that the true rate of DLT for each dose lies in the following categories: 
• 
[0,16%) under-dosing 
• 
[16%,33%) targeted toxicity 
• 
[33%,100%] excessive toxicity 
The EWOC principle (Babb et al., 1998, Neuenschwander et al., 2008) mandates that any 
dose of CB-103 that has more than a 25% chance of being in the excessive toxicity 
category is not considered for the next dose cohort. After a clinical synthesis of the 
available toxicity information (including adverse events that are not DLTs), PK, PD, and 
efficacy information as well as the recommendations from the Bayesian model, the CRC 
will determine the dose regimen for the next cohort at a dose-escalation teleconference. 
In case that another regimen is evaluated during the study, a separate 2-parameter logistic 
regression will be used for the assessment of the respective DLT rates. However, all data 
that are available from the other regimen (or regimens) before “First Patient First Visit” 
(FPFV) for the new regimen has happened will be incorporated into an informative, meta-
analytic predictive (Neuenschwander et al 2015) prior distribution. This prior distribution 
will be mixed with a weakly informative prior distribution to hedge against a potential prior-
data conflict. 
The frequency of DLTs will be tabulated by dose for patients in the dose escalation phase 
and information about the DLTs will be listed by dose.  


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10.5.1.3 
Bayesian Logistic Regression Model for MTD Determination 
The objective of the design is to determine the MTD defined as the highest dose with less 
than 25% risk of the true DLT rate being above 33%. The Part A dose-finding will be 
guided by a Bayesian 2-parameter logistic regression model with overdose control. These 
designs have been shown to be superior regarding the precision of MTD determination 
compared to 3+3 designs and have been particularly endorsed by the FDA.  
The model is formulated as follows: 
logit(p(d)) = log(α) + β*log(d/d*), 
where logit(p) = log(p/(1-p)). p(d) represents the probability of having a DLT in the first 
cycle at dose d, d* = 150 mg is the reference dose, allowing for the interpretation of α as 
the odds of a DLT at dose d*, and θ = (log(α), log(β)) with α, β > 0 is the parameter vector 
of the model. 
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of two 
multivariate normal distribution, i.e. 
π(θ) = φ1π1(θ) + φ2I2(θ)  
with  
φi, i = 1, 2 the prior mixture weights (φ1+ φ2 = 1) 
and  
πi(θ) = MVN(μi, Σi) 
the multivariate normal distribution of the i-th component with mean vector μi and 
covariance matrix Σi, with 
 
Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.  
Prior derivation 
For the current study, data from the pre-clinical animal studies were available. Therefore, 
the following prior will be used: A combination of the observed toxicity data from a study 
in rats further supported by data from a study in dogs.  
Prior from rat data: 
Based on the IMPD, the starting dose of CB-103 will be 15 mg, which is expected to 
achieve an exposure (AUC0-24) in humans of approximately 600 µg*h/mL. This exposure 
is comparable with 1/10th of the exposure at the HNSTD (30 mg/kg/day) in male rats. It is 
therefore highly unlikely that a DLT would occur at this dose, leading to the prior 
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assumption that the median DLT rate at 15 mg is 0.1%. On the other hand, assuming 
dose-proportionality in humans, a dose of 150 mg would approximately have an exposure 
of 6000 µg*h/mL, i.e., the same as the exposure at the HNSTD in rats. Using a cautious 
approach, the median DLT rate at d*= 150 mg was therefore assumed 25%. 
Prior from dog data: 
Based on the IMPD, the exposure at 1/10th of the HNSTD (8.6 mg/kg/day) in (male) dogs 
is approximately 9000 µg*h/mL, which we assume would correspond to a human dose of 
15*9000/600 = 225 mg. A cautious approach was chosen again, using a median 25% DLT 
rate at d = 225 mg. 
Table 19 
Summary of prior distribution 
Prior Component 
Mixture Weight 
Mean vector 
STD vector 
Correlation 
1: Rat 
0.500 
-1.122, 0.299 
1.98476, 0.9906 
-0.0004715777 
2: Dog 
0.500 
-1.682, -0.101 
1.9847620  
0.9906 
-0.0004715777 
 
A summary of the prior probabilities of DLT at different doses, as well as the corresponding 
probability of under-, targeted and overdosing, are shown in Table 20. Graphically, the 
prior medians with accompanying 95% credible intervals are shown in Figure 6. As can 
be seen from both Table 20 and Figure 6, the prior medians of the DLT probabilities are 
in line with the prior medians derived from the two animal studies, and the uncertainty 
around the medians is large, showing the low amount of in-men information this prior 
provides. 
Table 20 
Prior probabilities of DLT at selected doses 
Dose 
Probability of true DLT rate in 
 
 
Quantiles 
 
[0–0.16) 
[0.16–0.33) 
[0.33–1] 
Mean 
STD * 
2.5% 
50% 
97.5% 
10 mg 
0.857 
0.069 
0.075 
0.077 
0.162 
0 
0.008 
0.647 
15 mg 
0.832 
0.079 
0.089 
0.089 
0.173 
0 
0.012 
0.685 
30 mg 
0.775 
0.101 
0.123 
0.118 
0.197 
0 
0.025 
0.757 
60 mg 
0.688 
0.129 
0.182 
0.165 
0.228 
0 
0.057 
0.828 
120 mg 
0.524 
0.178 
0.298 
0.253 
0.266 
0.003 0.144 
0.898 
180 mg 
0.384 
0.186 
0.429 
0.347 
0.3 
0.006 0.256 
0.954 
240 mg 
0.31 
0.171 
0.519 
0.418 
0.324 
0.008 0.352 
0.986 
320 mg 
0.26 
0.153 
0.588 
0.479 
0.339 
0.011 0.449 
0.998 
400 mg 
0.229 
0.141 
0.63 
0.52 
0.345 
0.013 0.525 
0.999 
Doses printed in bold type meet the overdose criterion, P(overdose) < 0.25.  
* STD = standard deviation.  
 


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Figure 6 
Prior medians and 95% credible intervals. 
 
 
The MTD may be considered reached if one of the following criteria is fulfilled: 
1. 
The posterior probability of the true DLT rate in the target interval (16%-33%) of the 
MTD above 50%  
OR 
2. 
At least 6 patients have been treated at MTD, including the MTD/RP2D confirmatory 
cohort  
Statistical model assessment 
The single agent model was assessed using two different metrics: 
1. 
Hypothetical data scenarios: for various potential data constellations as they could 
occur in the actual trial, the maximal next doses as allowed by the model and by the 
100% escalation limit are investigated. Data scenarios thus provide a way to assess 
the “on-study” behaviour of the model. 
2. 
Simulated operating characteristics: these illustrate for different assumed true dose-
toxicity relationships, how often a correct dose would be declared as MTD by the 
model. They are a way to assess the “long-run” behaviour of the model. 
In summary, the model showed very good behaviour as assessed by these metrics. More 
details can be found in Appendix 10. 
10.5.2 
Part B (Expansion) 
Once the MTD/RP2D is determined, enrolment into Part B (expansion) can be started by 
enrolling patients into several expansion arms for selected cancer indications. All patients 
in Part B will need to have tumours characterised by alterations and over-activation of the 
NOTCH signalling pathway (mutations, translocations, over-expressions).  


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For the primary analysis of the expansion arms a Bayesian hierarchical exchangeable 
binomial design will be used. The assumption of the model is that the true response rate 
in each of the preliminary indications for the Part B expansion arms is fully exchangeable. 
For these indications the response criteria for success is a point estimate (from the model) 
above 25%. 
The T-ALL/T-LBL indications are assumed to be only partially exchangeable with other 
indications. The success criteria for this indication is a point estimate (from the model) 
above 40%. 
A robust hierarchical model (Neuenschwander et al., 2015) will be used for the analysis 
of the response rate 𝑝𝑝𝑘𝑘 in the different indications 𝑘𝑘= 1, … , 𝐾𝐾. The number of responders 
in each indication follows a binomial likelihood function. For exchangeable indications (𝑘𝑘=
1, … , 𝐾𝐾−1) it is assumed that 
 
 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝𝑘𝑘)~ 𝑁𝑁(𝜇𝜇, 𝜏𝜏2) 
 
 
On the other hand, for the partially (or non-) exchangeable indication 𝐾𝐾 we use the mixture  
 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝𝐾𝐾)~ 𝑁𝑁(𝜇𝜇, 𝜏𝜏2) with probability 𝜋𝜋 ,  
 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝𝐾𝐾)~ 𝑁𝑁(𝑚𝑚, 𝑠𝑠2) with probability 1 – 𝜋𝜋 
setting 𝑚𝑚= 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(0.3) and 𝑠𝑠= 2.2. 
Further, the following weakly informative priors (Friede et al., 2016; Friede et al., 2017) 
are used: 
 
𝜇𝜇 ~ 𝑁𝑁(𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(0.2), 2.52) 
 
𝜏𝜏 ~ 𝐻𝐻𝐻𝐻(1) 
For these exchangeable indications, the advantage of this model is the fact that borrowing 
information across indications improves the precision of the estimators of the response 
rate. On the other hand, for the possibly different indication, the mixture 
approach hedges for a too-optimistic assumption about similarity. Therefore, 
the described approach captures the design adequately. 
Other characterisations of the posterior distribution will be evaluated as appropriate. The 
final analysis will take place after the last expansion arm was closed for futility or the last 
patient of the last expansion arm had the final end-of-study visit. 
10.6 
SECONDARY ANALYSES 
The following sections describe the secondary analyses that will be performed for Part A 
(escalation) & Part B (expansion) of this study. 


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10.6.1 
Safety Analyses 
10.6.1.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary will be 
applied for the coding of AEs. NCI-CTCAE toxicity Grades will be utilised for classifying 
severity. 
Adverse events, related adverse events, serious adverse events and related serious 
adverse events, adverse events with NCI CTCAE Grades ≥ 3, related adverse events with 
NCI CTCAE Grades ≥ 3, adverse events leading to premature discontinuation, 
interruptions or discontinuation of study drug or dose modification will be analysed 
descriptively utilising corresponding MedDRA System Organ Classes (SOCs) and 
Preferred Terms (PTs).  
Deaths within 28 days after the last dose and the corresponding reasons will be 
summarised. Also, all deaths overall will be summarised. 
10.6.1.2 
Safety Laboratory 
Laboratory values will be graded by NCI CTCAE version 4.03, if no grading exists values 
will be classified into low/normal/high based on laboratory normal ranges. Each parameter 
will be presented by descriptive statistics at each visit including change from baseline 
(screening). Shift tables for CTCAE grades and normal ranges will be presented. All 
laboratory values will be listed. A separate listing for abnormal lab values (Grade 3 and 
higher, and low/high values) will be presented. 
10.6.1.3 
Vital Signs 
Vital signs will be summarised by descriptive statistics at each visit including change from 
baseline will be presented and a listing will be provided.  
10.6.1.4 
Electrocardiogram 
Centrally read ECG data will be listed overall and a separate listing for any clinically 
significant finding in ECG values will be provided. Change from baseline in QT intervals 
by cohort will be summarised for each visit as well as change from baseline in all other 
ECG parameters. Also, the worst change from baseline will be summarised. The 
frequency and percentage of patients with notable ECGs and newly occurring qualitative 
ECG abnormalities will be tabulated by cohort.  
10.6.2 
Efficacy Analyses 
Overall response rate: 
For solid tumours, overall response rate as defined by achieving confirmed complete 
response (CR) and/or partial response (PR) will be presented by percentage rates and 
95% confidence intervals. For changes in solid tumour size waterfall plots will be 


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presented. For all response assessments, swimmers plots will be presented. All response 
assessments will be listed. 
In T-ALL/T-LBL, overall response rate defined as achieving confirmed Complete 
Remission (CR) and/or Complete Remission with Incomplete Hematologic Recovery (CRi) 
will be presented by percentage rates and 95% confidence intervals (CI). 
Clinical benefit rate for solid tumours at Month 3, 6, and 9, and for T-ALL/T-LBL at 
1, 2, and 3 months, and every 2 months from Month 3 to Month 9: 
Clinical benefit rate as defined by achieving complete response and/or partial response 
and/or stable disease (SD) will be presented by percentage rates and 95% confidence 
intervals. Waterfall plots will be presented.  
‒ 
For solid tumour indications:  Clinical benefit rate (CR + PR + SD), assessed by 
RECIST 1.1. 
Duration of response: The duration of response defined as time from first assessment 
of PR or CR in solid tumours or CR/CRi in T-ALL/T-LBL to follow-on first assessment of 
PD or relapse will be summarised by descriptive statistics including median duration of 
response and respective 95% CIs. Duration of response will also be listed. 
Progression free survival (PFS) and overall survival (OS): 
Time from first treatment received until disease progression/overall survival will be 
summarised by Kaplan-Meier estimates, median PFS/OS and respective 95% CIs. 
Patients with no event will be censored at the last available tumour assessment for PFS 
and at the last timepoint known alive for OS. 
10.6.3 
Pharmacokinetic Analyses 
CB-103 concentrations will be determined by a validated high-performance liquid 
chromatography (HPLC) tandem mass spectrometry (LC/MS/MS) method and the 
following PK parameters of CB-103 including:  Cmax, tmax, Cmin, Clast, tlast, AUC0-8, AUC0-24, 
AUC0–∞, Vd/F, Vss/F, CL/F, t1/2 and AR. All pharmacokinetic parameters will be calculated 
from the curves constructed from the individual patients. Non-compartmental analysis will 
be performed using Phoenix WinNonlin version 6.3 (Pharsight Corporation, Mountain View, 
CA, USA). 
No formal statistical analysis beyond descriptive statistics is planned. For each PK 
parameter, individual and mean data and summary statistics (including number of patients, 
arithmetic mean, geometric mean, standard deviation [StD], confidence value [CV], 
median, Min and Max) will be presented (note that for time to maximum plasma 
concentration [tmax] and time to last measurable plasma concentration [tlast] no geometric 
means will be calculated). 


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10.6.4 
Pharmacokinetic / Pharmacodynamic Analyses 
With the PK timepoints collected, a population PK model will be built and then used to 
estimate individual AUCs or CL/F of CB-103. CB-103 AUC, as well as the observed Cmax, 
will then be tested for association with signs of efficacy and safety. If an observable trend 
exists, a PK/PD model will be developed to evaluate the exposure-response relationship 
between CB-103 plasma exposure and outcome measures. Demographic and clinical 
data (ethnicity, current age, body weight, sex, disease status, etc.) will be utilised to assess 
interpatient variability in the PK and PK/PD relationships. 
10.7 
EXPLORATORY ANALYSES 
10.7.1 
Additional PK, metabolite, PD markers, Genomic, 
Pharmacogenetics, and Protein Analyses, CB-103 metabolic 
expressions 
Exploratory PK assessments, plasma (or other matrix, e.g., urine) levels of metabolite(s), 
PD markers (genes, proteins) in tumour tissue biopsies and in whole blood, plasma 
samples and hair follicles, genotypes, protein expression and circulating tumour DNA in 
blood samples will be analysed as required by the Sponsor or by a delegated Laboratory 
or investigational site. A separate analysis plan and report for such assessments will be 
written. 
10.7.2 
Biomarker Analyses  
Summary statistics of PD, mechanistic and tumour profiling biomarkers will be reported by 
dose group and may be examined for possible correlations with CT/MRI/PET-CT efficacy 
endpoints. Additional analyses include comparing PD modulation with exposure.  
10.7.3 
CSF Exposure of CB-103 in Haematological Malignancies 
Summary statistics of the CB-103 concentration in CSF will be reported in selected 
patients with haematological malignancies. The concentrations in CSF will be compared 
with serum concentrations. 
10.8 
INTERIM ANALYSES 
10.8.1 
Part A (Escalation) 
Each dose escalation step is considered to be an interim analysis. The BLRM will be 
updated with the respective number of patients treated and the number of DLTs observed 
in the last cohort. The updated model will then give a statistical recommendation for the 
next escalation step. However, a risk-benefit assessment that includes a comprehensive 
analysis of safety and available clinical information will be done to decide on the next 
escalation steps. The aggregate safety data from the additional patients in the MTD/RP2D 
confirmatory cohort will be continuously reviewed at least on a quarterly basis for all 
CTCAEs ≥ grade 3, all SAEs, all clinically significant laboratory abnormalities and 


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available safety data, from all patients receiving RP2D, to confirm that the proposed dose 
for the expansion part is safe and well tolerated. 
10.8.2 
Part B (Expansion) 
Interim analyses will be triggered each time 10 patients in an arm have completed their 
first response assessment, this includes patients from the MTD/RP2D confirmatory cohort 
of Part A that qualify for any of the extension arms. An interim analysis will include all 
patients enrolled at, or prior to the cut-off (set by the completion of the 10th patient), and 
will be conducted once all patients have completed sufficient assessments to be 
categorised under the response endpoint, or have withdrawn from study. All arms that 
remain open to recruitment, and for which the minimum data efficacy requirements have 
been met, will be assessed for futility. For the interim and final analyses, a hierarchical 
model will be used. This model leads to more precise estimates of the indication-specific 
treatment effects as compared to those from stratified analyses. Details of the model can 
be found above and further descriptions are given in Appendix 10. The results of the 
interim analyses will be non-binding. Safety criteria will also be evaluated to decide of the 
continuation of the study arms. Since this is a non-comparative multiple arm study no 
adjustment for multiple testing is made.   
10.9 
SAMPLE SIZE 
10.9.1 
Part A - Dose Escalation and Dose Confirmation 
For all dose levels, from starting dose to the respective dose escalation levels, 3-6 patients 
will be enrolled and treated with CB-103 according to a staggered inclusion scheme to 
ensure adequate time for safety observation between inclusions, and before dose 
escalation. During the study, a minimum of 3 patients evaluable for the DDS will be treated 
per dose cohort until determination of the MTD or RP2D. Depending on the BLRM, 
additional patients may be enrolled in some dose cohorts. Approximately 11 dose cohorts 
are considered for this study with at least 3 patients per dose cohort. It is estimated that 
approximately 55 patients will be enrolled taking into account the drop-outs and additional 
patients enrolled for some of the dose groups. Based on the decision of the CRC 
approximately 45 patients in total may be enrolled on the MTD/RP2D confirmatory cohort 
to confirm safety before opening Part B. 
10.9.2 
Part B - Dose Expansion, Stratified by Indication 
Part B of the study will consist of one or several expansion arm(s) with selected tumour 
indications. For the analysis of the expansion arms a Bayesian Hierarchical binomial-
design will be applied with enrolment of at least 10 patients into each arm. With 10-20 
patients enrolled into each expansion arm it is estimated that about 100-140 patients 
(pending of the number of arms) will need to be recruited. Patients from the MTD/RP2D 
confirmatory cohort of Part A that qualify for any of the expansion arms will be included 
into the analyses of Part B and will contribute to the total sample size per arm. 


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20 patients per Indication arm will give sufficient evidence to determine early signs of 
clinical benefit. Assuming a true response rate of 30% for exchangeable and partially-
exchangeable indications (based on response criteria) the lower limit of the credible band 
for the point estimate would be greater equal to 19%.  
The following indications for patients with NOTCH activated pathway are considered and 
grouped into the respective expansion arms: 
1. Adenoid cystic carcinoma (ACC) 
2. Triple Negative Breast Cancer (TNBC) 
3. Breast Cancer (ER+/-, HER2+/-) 
4. Osteosarcoma, Malignant glomus tumour 
5. GI cancers (resistant to oxaliplatin or irinotecan-based therapy colorectal cancer, 
hepatocellular carcinoma) 
6. r/r T-ALL/T-LBL 
7. Any other cancer (haematologic or solid) with confirmed Notch pathway 
activation (basket arm) 
 
Table 21 
Sample size consideration for potential indications 
 
Indication 
 
1.ACC 
 2.TNBC 
3.Breast 
Cancer 
4. Osteosarcoma, 
Malignant glomus 
tumour  
5.GI 
 
 
n/N 
Median; 
(CI) 
n/N 
Median; 
(CI) 
n/N 
Median; 
(CI) 
n/N 
Median; (CI) 
n/N 
Median; 
(CI) 
 
strong 
homogenicity 
6/20 
30% 
 (18%- 
43%) 
6/20 
30% 
 (18%- 
43%) 
6/20 
30%  
(18%- 
47%) 
6/20 
30%  
(18% - 43%) 
6/20 
30% 
(18%- 43%) 
 
The indications considered for the expansion arms in Part B might be adapted and/or 
additional arms added by a protocol amendment based on the outcome of Part A and 
further findings from non-clinical studies with CB-103 and the planned interim analysis, 
this might increase the planned sample size. 
 


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11. 
DATA COLLECTION AND MANAGEMENT 
11.1 
DATA QUALITY ASSURANCE 
Delegated CRO Covance will be responsible for data management of this study, including 
quality checking of the data. Investigational sites will be responsible for data entry into the 
Electronic Data Capture (EDC) system. 
A comprehensive validation check program will verify the data. Discrepancies will be 
flagged automatically in the system at the point of entry or will be added manually for 
resolution by the Investigator. 
CRO Covance will produce a Data Management Plan that describes the quality checking 
to be performed on the data. Laboratory data will be sent directly to CRO Covance, using 
CRO`s standard procedures to handle and process the electronic transfer of these data. 
System backups for data stored by CRO Covance and records retention for the study data 
will be consistent with CRO Covance`s standard procedures. 
11.2 
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an online EDC system. The data collected in the 
source documents is entered onto the study eCRF. A complete electronic audit trail will 
maintain a record of initial entries and changes made; reasons for change; time and date 
of entry; and user name of person authorising entry or change. For each patient enrolled, 
an eCRF must be completed and electronically signed by the investigational site 
Investigator or authorised delegate from the study staff (as per 21 CFR Part 11). If a patient 
withdraws from the study, the reason must be noted on the eCRF. If a patient is withdrawn 
from the study because of a treatment‑limiting adverse event, thorough efforts should be 
made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports. 
All eCRF entries, corrections, and alterations must be made by the Investigator or other, 
authorised, investigational site personnel and only by individuals who have received 
training on the EDC system. Site staff may be allowed access to the system only after 
training is completed. Training must be documented and a log of all EDC users and their 
rights within the system be maintained. 
11.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (i.e., source data) entered into the eCRFs by authorised site personnel are accurate, 
complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical 


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and office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico‑technical departments involved in 
a clinical trial. 
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy 
for retention of records described in Section 11.4. 
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor or its designee direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IEC/IRB review. The investigational site must 
also allow inspection by applicable Health Authorities. 
All source document forms should be completed to ensure the entries are ALCOAC, and 
must be legible. Errors should be crossed out but not obliterated, or is documented by 
means of a comprehensive audit trail the correction inserted (if necessary, the reason 
must be noted), and the change initialled and dated by the Investigator, sub-Investigator, 
or study nurse. 
All source documents will be retained by the investigational site. Photocopies of completed 
source documents will be provided only if essential (i.e., for regulatory purposes) at the 
request of the Sponsor. In accordance with ICH GCP, the location of data identified as 
source data will be specified on the Source Document Identification List. 
11.4 
RETENTION OF RECORDS AND DOCUMENTS 
To enable evaluations and/or audits from regulatory authorities or Sponsor, the 
Investigator agrees to keep records and documents pertaining to the conduct of this study, 
including the identity of all participating patients (sufficient information to link records, e.g., 
CRFs and hospital records), all original signed ICFs, copies of all CRFs, laboratory test 
results, serious adverse event forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, 
meeting minutes, telephone calls reports). According to the EU Clinical Trial Regulation 
536/2014, unless other Union law requires archiving for a longer period, the Sponsor and 
the investigator shall archive the content of the clinical TMF for at least 25 years after the 
end of the clinical trial. However, the medical files of subjects shall be archived in 
accordance with national law. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements, respecting the data confidentiality, 
must be made between the Investigator and Sponsor to store these documents outside 
the site, so that they can be retrieved in case of a regulatory inspection. 


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After that retention period, the documents may be destroyed, subject to local regulations. 
No records/documents may be disposed of without the written approval of the Sponsor. 
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
If the site is using an electronic/computerised system to store patient medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 
or equivalent standard) and if the monitor has been provided personal and restricted 
access to study patients only, to verify consistency between electronic source data and 
the eCRF during monitoring visits. 
If the site is using an electronic/computerised system to store patient medical records but 
it could not be confirmed that the system is validated, the site is requested to print the 
complete set of source data needed for verification by the monitor. The printouts must be 
numbered, stapled together with a coversheet, signed and dated by the 
Investigator/delegate to confirm that these certified copies are exact copies having the 
same information as the original patient’s data. The printouts will be considered as the 
official clinical study records.  
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor must verify and confirm that copies generated from electronic/computerised 
system are ALCOAC. If it were not possible for the monitor to observe this process, it 
would not be possible to rely on the site’s certified copies and therefore the site cannot be 
selected for the clinical study.  
The site master file must be stored in a secure and access-restricted area during and after 
the study. It must be kept by the site for as long as needed to comply with any applicable 
rules and regulations (ref. EU Clinical Trial Regulation 536/2014 when coming into force). 
If the site needs to transfer the site master file to another location and/or if site facility can 
no longer store the site master file the Investigator must inform the Sponsor immediately.  
The site master file will contain all the essential documents that are required to always be 
up-to-date and filed at site as per ICH GCP Section 8. If the Investigator will change, or if 
the site will relocate, the monitor must be notified as soon as possible. 
 


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12. 
ETHICAL CONSIDERATIONS 
12.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, and the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). Studies conducted in 
the United States or under a US Investigational New Drug (IND) application will comply 
with US FDA regulations and applicable local, state, and federal laws. Studies conducted 
in the European Union (EU)/European Economic Area (EEA) will comply with the EU 
Clinical Trial Directive (2001/20/EC) and when coming into force the EU Clinical Trial 
Regulation (536/2014). In Germany, the requirement to secure approval from and provide 
notification to the BfS respectively, pursuant to §§ 31 ff. StrlSchG, will have been met. 
12.2 
INFORMED CONSENT 
12.2.1 
Patient Informed Consent Forms 
The ICF and pre-screening ICF (collectively, the “Consent Forms”) will be provided to each 
investigational site. The pre-screening ICF applies only to the MTD/RP2D confirmatory 
cohort (Part A) and to the Phase IIA (expansion) part of the study.  
The final IEC/IRB-approved Consent Forms must be provided to the Sponsor for Health 
Authority submission purposes according to local requirements. 
For US only, according to HIPAA regulations, the individual institution may require that the 
Informed Consent and/or HIPAA Acknowledgement/Authorization Form be reviewed by 
their Privacy Board. In the instance of a Privacy Board review, approval must be received 
on the Informed Consent Form and Subject Acknowledgment/Authorization Form prior to 
initiating any study related procedures. 
It is the responsibility of the Investigator/delegate to obtain informed consent according to 
ICH GCP guidelines and local regulations from each individual participating in this study 
and/or legal representative. 
The Investigator/delegate will obtain a voluntary written consent from each patient after 
an appropriate explanation of the aims, methods, anticipated benefits, risks and any other 
aspect of the study relevant to the patient’s decision to participate. Consent Forms and all 
verbal study related information must be in a language fully comprehensible to the 
prospective patient.  
Patients will be informed that they are free not to participate in the study and that they may 
withdraw consent to participate at any time. They will be told which alternative treatments 
are available if they refuse to take part and that such refusal will not prejudice future 
treatment. Site staff authorised to participate to the consent process and/or to obtain 


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consent from the patient and/or legal representative will be listed on Sponsor Delegation 
of Authority form. A study physician must always be involved in the consent process. 
A written “Patient Information Sheet” will be given to each patient to complete the verbal 
information. This written form should be reviewed orally with the patient. Patient must be 
given ample opportunity to inquire about details of the study.  
The Consent Forms must be signed and dated by the Investigator and the patient (or the 
patient’s legally authorised representative) before any exposure to a study-related 
procedure, including screening tests for eligibility. The Consent Forms must also be signed, 
personally dated and timed (if appropriate) by the authorised site staff listed on the 
Delegation of Authority form. A copy of the signed and dated Consent Forms is given to 
the patient and/or legal representative; the original is filed in the site documentation. 
The medical records for each patient shall document the informed consent process 
including study reference, patient number, date/time (if applicable) when the patient was 
first introduced to the clinical study, date and time (if applicable) of consent, who 
consented the patient and any additional person present during the consent process (e.g., 
patient’s family member), copy of the signed ICF given to the patient / legal representative. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IEC/IRB-approved Consent Forms must be provided to the 
Sponsor for Health Authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IEC/IRB policy) during their participation in the study. For any updated or revised Consent 
Forms, the medical records for each patient shall document the informed consent process 
and that written informed consent was obtained using the updated/revised Consent Forms 
for continued participation in the study. 
A copy of each signed and dated Consent Form must be given to the patient. The originals 
must remain in each patient’s study file or in the site file and must be available for 
verification by study monitors at any time. 
12.2.2 
Exploratory Biomarker Sub-Study Consent Form 
Exploratory biomarker sub-studies   will be integrated in the main consent form. If a patient 
opts not to participate in such sub-studies , this in no way affects the patient’s ability to 
participate in the main research Study. 
12.3 
ETHICS AND GOOD CLINICAL PRACTICE 
Cellestia, delegate CRO Covance and the Investigators will ensure that the study is 
conducted in full compliance with ICH GCP Guidelines, the principles of the “Declaration 
of Helsinki” and with the laws and regulations of the country in which the research is 
conducted.  


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12.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted to the IEC/IRB by the Investigator or by CRO delegated by 
Cellestia (as required) of each participating investigational site/country and reviewed and 
approved by the IEC/IRB before the study is initiated. In addition, any patient recruitment 
materials must be approved by the IEC/IRB. 
Approval from the committee must be documented in a dated letter, clearly identifying the 
study, the documents reviewed, and the date of approval. 
The Investigator is responsible for providing written summaries of the status of the study 
to the respective investigational site/country IEC/IRB annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IEC/IRB. 
Investigators are also responsible for promptly informing the IEC/IRB of any protocol 
amendments (see Section 13.5). 
In addition to the requirements for reporting all adverse events to Sponsor or delegate 
CRO Covance, Investigators must comply with requirements for reporting serious adverse 
events to the local health authority and IEC/IRB. Investigators may receive written safety 
reports or other safety-related communications from the Sponsor or delegate CRO 
Covance. Investigators are responsible for ensuring that such reports are reviewed and 
processed in accordance with Health Authority requirements and the policies and 
procedures established by their IEC/IRB, and archived in the site’s study file. 
12.5 
CONFIDENTIALITY 
Sponsor and delegate CRO Covance maintain confidentiality standards by coding each 
patient enrolled in the study through the assignment of a unique patient identification 
number. Therefore, patient names and other personal identifiers are not included in the 
datasets that are transmitted to Sponsor or delegate CRO Covance. 
Patient medical information obtained from this study is confidential and may only be 
disclosed to third parties as permitted by the ICF (or separate authorisation for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the EMA, US FDA and other national and local Health Authorities, 
Sponsor monitors, auditors, representatives, and collaborators, and the IEC/IRB for each 
investigational site, as appropriate. 
By signing this protocol, the Investigator agrees to keep all information provided by the 
Sponsor and delegate CRO Covance in strict confidence, and to request similar 
confidentiality from his or her staff and the IEC/IRB. Study documents provided by 


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Cellestia or delegate CRO Covance (including Investigator’s Brochures [IBs], protocols, 
eCRFs, and other protocol-related documents) will be stored appropriately to ensure their 
confidentiality. The information provided by the Sponsor or delegate CRO Covance to the 
Investigator may not be disclosed to others without direct written authorisation from 
Sponsor or the delegate CRO Covance, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial. 
12.6 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor and the delegate CRO Covance with sufficient, 
accurate financial information in accordance with local regulations to allow Sponsor and 
the delegate CRO Covance to submit complete and accurate financial certification or 
disclosure statements to the appropriate Health Authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for one 
year after completion of the study. 
 


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13. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
13.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IEC/IRB approval. In addition, at the end of the 
study, the Investigator will receive the patient data, which includes an audit trail containing 
a complete record of all changes to the data.  
13.2 
SITE AUDIT AND INSPECTIONS 
Investigational site visits will be conducted by the Sponsor (or an authorised 
representative) or by the delegate CRO Covance for audit of study data, patients’ medical 
records, and eCRFs. The Investigator will permit national and local Health Authorities, 
Cellestia and delegate CRO Covance monitors, representatives, and collaborators, and 
IECs/IRBs to inspect facilities and records relevant to this study. 
13.3 
MONITORING 
Sponsor or delegate CRO Covance’s monitor must contact and visit the Investigator 
regularly, and must be allowed, on request, to have access to all study-related documents 
and facilities used in the study, as well as all source documents needed, to verify the 
entries on the eCRFs; provided that patient confidentiality is maintained in agreement with 
local regulations.  
On all documents submitted to the Sponsor or delegate CRO Covance, patients must not 
be identified by their names and date of birth, but by patient number only. The Investigator 
must keep a patient identification log showing the patient number, the patient’s name, date 
of birth, and address or any other locally accepted identifiers. Documents identifying the 
patients (e.g., patients’ signed ICFs) must not be sent to Sponsor or delegate CRO 
Covance, and must be kept by the Investigator in strict confidence. 
The Investigator and sub-Investigators agree to cooperate with the monitor(s) to ensure 
that any issues detected in the course of these monitoring visits are resolved. If the patient 
is hospitalised or dies in a hospital other than the investigational site, the Investigator is 
responsible for contacting that hospital in order to document the serious adverse event. 
An initiation visit will be performed before the first patient is screened. Following the 
initiation visit, a copy of the completed initiation visit report and follow-up letter will be 
provided to the Investigator and filed in the Investigator site file. 
Monitoring visits and contacts will occur at regular intervals thereafter, and a close-out visit 
will be performed after study database closure. 


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A close-out visit will be performed for any initiated site when there are no more active 
patients and all follow-up issues have been resolved. In case a site does not enrol any 
patients, the close-out visit may be performed prior to study database closure at the 
discretion of Sponsor. 
13.4 
PUBLICATION OF DATA BY INVESTIGATORS AND PROTECTION 
OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. However, 
to ensure against inadvertent disclosure of Confidential Information or Unprotected 
Inventions, the Investigator will provide the Sponsor with an opportunity to review any 
proposed publication or any other type of disclosure before it is submitted or otherwise 
disclosed. 
Study results will be documented in a CSR that will be signed by Sponsor representatives 
and the Investigator or its designee. The Investigator will have the opportunity to review 
the analysis of the data and to discuss the interpretation of the study results with the 
Sponsor prior to publication. The Sponsor or its delegate will post results from its clinical 
studies on external/national registries, as required by law. 
The Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to the 
Sponsor at least 30 days before they are submitted for publication or otherwise disclosed.  
The Investigator will, on request, remove any previously undisclosed Confidential 
Information (other than the study results themselves) before disclosure. 
If the study is part of a multi-centre study, the Investigator agrees that the first publication 
is to be a joint publication covering all investigational sites. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of 
the study at all participating sites, the Investigator is free to publish separately, subject to 
the other requirements outlined in this section. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. The list of authors of any 
publication of study results may include representatives of Sponsor, and will be 
determined by mutual agreement. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, unless agreed otherwise. 
Publication of study results is also provided for in the Clinical Study Agreement between 
Sponsor/the delegate CRO Covance and the institution. In this section the defined terms 
shall have the meanings given to them in the Clinical Study Agreement. 


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13.5 
PROTOCOL AMENDMENTS 
Any change to a protocol must be considered to be an amendment if the documents have 
already been submitted to IECs/IRBs or Health Authorities. An amendment could therefore 
occur before or after the approval of these documents by IECs/IRBs or Health Authorities. 
Each amendment must be documented in writing and approved by Sponsor. 
Changes to the Core Patient Information and Informed Consent requested by IECs/IRBs 
are not considered to be formal amendments, as long as they do not significantly change 
the core document or affect the protocol. 
13.5.1 
Substantial Amendments 
A substantial amendment is required for significant changes not stipulated by the protocol 
(e.g., new data affecting the safety of patients, and changes to the objectives or endpoints 
of the study, eligibility criteria, study assessments) with or without the need to modify the 
Core Patient Information and Informed Consent. 
Any substantial protocol amendments will be submitted to the IEC/IRB and to regulatory 
authorities in accordance with local regulatory requirements. Approval must be obtained 
from the IEC/IRB and regulatory authorities (as required according to local regulations) 
before implementation of any changes, except for those changes deemed necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements. 
 
 


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14. 
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Buonamici S., Trimarchi T., Ruocco M.G., et al. (2009). CCR7 signalling as an essential 
regulator of CNS infiltration in T-cell leukaemia. Nature, 459(7249), 1000-1004. 
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Curran E., Stock, W. (2015). How I treat acute lymphoblastic leukemia in older 
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De Angelo DJ., Yu D., et al. (2007) Nelarabine induces complete remissions in adults with 
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Appendix 1 
Schedule of Assessments for Part A  
Table 1 
Schedule of Assessments (Part A) 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT
29 
Safety 
follow-
up30 
After Cycle 
6 
(28-day 
cycles, 
until PD or 
toxicity) 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Overnight hospital stays 
 
  
 
X3 
 
 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent4 
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test6 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Vital Signs and body 
measurement 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body height (cm) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
ECOG perf. Status7 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination8 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Body temperature 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Respiratory rate 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
 
 
 


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May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT
29 
Safety 
follow-
up30 
After Cycle 
6 
(28-day 
cycles, 
until PD or 
toxicity) 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Cardiac Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Heart rate 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG9 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
Holter monitoring9 
 
 
X9 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
ECHO or MUGA for LVEF 
assessment9 
 
 
X9 
 
 
 
X 
 
 
 
 
 
 
 
X9a 
 
X 
 
 
X 
Cardiac serum markers10 
 
 
X10 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmological exams11  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X12 
 
 
Clinical chemistry13 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Hematology13 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Coagulation13 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
PK profile blood 
sampling14 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
PK sub-study  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood sampling for 
genotype testing 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool sample15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT
29 
Safety 
follow-
up30 
After Cycle 
6 
(28-day 
cycles, 
until PD or 
toxicity) 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Chest X-ray 16 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessment 
(PFS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival follow-up 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Safety assessment incl. 
AE/SAEs 18 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Assessments  
(Solid Tumours only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumour biopsies19  
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumour biopsies20 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Liquid biopsy 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Tumour assessment  
(CT/MRI/PET-CT) 21 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X22 
X 
 
X22 
X 
Hair follicles 23 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Whole blood, plasma23a 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Other Assessments 
(T-ALL/T-LBL only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy 
and/or aspirate24  
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Lumbar puncture25 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CSF sample26 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Tumour assessment  
(PET-CT)27 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X  
 
X 
 
X  
X 


Clinical Study Protocol 
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May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Six cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT
29 
Safety 
follow-
up30 
After Cycle 
6 
(28-day 
cycles, 
until PD or 
toxicity) 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 (DLT Period) 
Cycle 2 
Cycles 3 to 6 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS-A 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 
30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Liquid biopsy 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
Whole blood, plasma28 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Whole blood and Saliva 
X* 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: BL, baseline; CT, computed tomography; CSF, cerebrospinal fluid; DLT, Dose limiting toxicity; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOS-A, End of Study Part A; EOT, End of Treatment; F-up; Follow-up; ICF, Informed Consent Form; LVEV, left ventricular ejection fraction; MRI, 
magnetic resonance imaging; MUGA, multigated acquisition; PD, pharmacodynamics; PE, physical examination; PET-CT, positron emission tomography–computed tomography; 
PK, pharmacokinetic; SAE, serious adverse event; SCR, screening. 
* Pre-screening: it applies ONLY to the MTD/RP2D confirmatory cohort for patients whose Notch pathway activation status is not known; the patient must sign the pre-screening 
consent form. For solid tumour patients: if there is no sufficient archival tumour sample available or if older than 6 months prior to the pre-screening, a fresh pre-dose tumour 
biopsy is to be obtained. For T-ALL/T-LBL patients: when Notch status in unknown the whole blood and saliva will be collected at pre-screening, otherwise at BL to confirm the 
Notch status.  
1 
Visit windows: DLT treatment phase (first cycle): ± 0 day; cycles 2-6: ± 3 days. After cycle 6, visits are planned every 4 weeks (± 7 days) if no medical issue or complication 
occurred in the previous cycles. 
2 
Screening: may be performed in one or more visits.  
3 
Overnight stays at C1D1: it may not be required if reduced ECG&PK sampling is implemented. 
4 
Informed Consent: must be obtained prior to undergoing any study-related procedure. 
5 
Medical history (including relevant disease history) 
6 
Pregnancy test: for women of childbearing potential only. The serum pregnancy test must be performed within a maximum of 7 days of first CB-103 administration. The urine 
pregnancy test will also be done whenever one menstrual cycle is missed during the active treatment period (or when potential pregnancy is otherwise suspected) to confirm 
the patient has not become pregnant during the study. 
7 
ECOG: performance scale is available in Table 13 of the protocol. ECOG performance status will be assessed within 14 days prior to the first administration of CB-103, during 
the screening period. 
8 
Physical examination: will be performed at the screening, baseline and at the indicated patient visit, even if administration of study medication is being withheld. More 
frequent examinations may be performed at the Investigator’s discretion, if medically indicated. If the baseline examinations are performed within 72 hours prior to the 
first administration of CB-103, they need not be repeated on C1D1, except for patients with T-ALL/T-LBL who need to repeat the PE at C1D1. 


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9  
12-lead ECG: at each time point, three consecutive high-quality (without artefacts/lead misplacement) 12-lead ECGs will be performed approx.1-2 minutes apart. Refer to Table 
14 and Table 16 of the protocol for further details. ECG and PK blood samples need to be obtained at the same time-points and the ECG should be performed just prior to the 
drawing of the blood. A 15-minute window for ECG collection is allowed around each nominal ECG time point except for the 24 hour ECG time point, where a 1 hour window 
is allowed. 
9 
Holter monitoring: 3-lead Holter ECG monitoring with 24 hours ECG profiles. Refer to Table 14 and Table 16  of the protocol for the scheduling and further details. At BL allowed 
from Day -7. Holter recording should start 1 to 2 hours before the CB-103 intake. 
9 
ECHO/MUGA: allowed from Day -7. It may be repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity.  
9a  Between cycles 3 and 6 the ECHO/MUGA is only requested on C3D1. 
10  Cardiac markers: allowed from Day -7. They will be performed locally and may be repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
11  Ophthalmological exams: they will be performed by an ophthalmologist/eye doctor at screening, End of Treatment and when clinically indicated. Refer to Section 8.2.2.2 
12  Ophthalmological exams: will be done at the safety follow-up if the patient had ocular symptoms during the treatment phase 
13  Clinical chemistry/Haematology/coagulation will be performed locally; at screening (within 14 days of C1D1), and at the indicated visits. Refer to Section 8.2.4 of the protocol 
for the testing required. May be performed within a window of ± 24 hours during the DLT period and throughout all treatment cycles. 
14  PK time sampling: blood sampling will be collected as per the schedule and time window indicated in Section 8.4 of the protocol. Changes to the PK sampling scheme may be 
required based on emerging data. In case of twice daily intake of CB-103 the sampling schedule is slightly adjusted for cycle 1 (refer to Section 8.4.1) 
15  Stool specimen collection: only one sample is to be possibly collected during cycle 2 and 3. 
16  Chest X-ray: a baseline chest x-ray should be performed and be repeated if clinically indicated. If a chest CT is performed at baseline to assess tumour lesions, then a chest 
X-ray may not be required. 
17  Survival follow-up: it is planned for one year, every three months, after the End-of-Study visit or after the last treatment cycle (if outside of the 6 cycles period). 
18  Between the signature of the ICF and the initiation of CB-103, only the SAEs caused by study-related procedures will be reported; any other AEs will be only recorded on the 
Medical History in the eCRF. After initiation of CB-103, all AEs/SAEs will be reported until four weeks after the last dose of CB-103. 
19  Archival tumour biopsy tissue (Solid Tumour): for the patients enrolled in Part A (dose-escalation) it should be not older than 6 months prior to screening and if not available a 
pre-dose fresh tumour biopsy must be taken. If the lesion is not accessible for a fresh tumour biopsy, a liquid biopsy may be used after confirmation with the Sponsor. 
20  Fresh tumour biopsy (Solid Tumour): mandatory in the MTD/RP2D confirmatory cohort of Part A of the study; to be collected pre-dose at BL, then on-treatment at C2D15 ± 3 
days and at disease progression or when clinically indicated. The pre-dose fresh biopsy is not required if already obtained during the pre-screening. In individual cases, where 
the lesion is not accessible for a fresh tumour biopsy, a liquid biopsy may be used after confirmation with the Sponsor 
21 Tumour assessments (Solid Tumours): will be performed at baseline, then 6 weeks after the first administration of CB-103 (i.e., day 15 of cycle 2) then see note 22. For breast 
cancer patients  enrolled in the MTD/RP2D confirmatory cohort (refer to Appendix 9) the CT scan will be replaced with PET-CT (or add PET) at baseline (and if positive, also 
at C2D15, before tumour biopsy).  A time window of ± 3 days is allowed for the tumour assessments. A wider time window is allowed only at baseline however assessments 
should be performed as close as possible to the 1st drug administration and if feasible, not later than 2 weeks prior to the 1st drug administration. 
22 Tumour assessments (Solid Tumours): after cycle 2 will be performed, every 8 weeks and after cycle 6 every 12 weeks until EOT or disease progression/overall survival. The 
response will be determined as per the RECIST 1.1 and, if applicable, with confirmation as per RECIST.  
23  Hair follicles (Solid Tumour): samples will be collected for solid tumour indications only as per the schedule and time window indicated in Section 8.5.2. In the MTD/RP2D 
confirmatory cohort they will be collected only on selected patient groups. 
23a  Whole blood, plasma (Solid Tumour): samples will be collected as per the schedule and time window indicated in Section 8.5.3.  
24  Bone marrow biopsy and/or aspirate (T-ALL/T-LBL): a bone marrow biopsy and/or aspirate will be obtained to assess bone marrow cellularity and to determine the percentage 
of leukemic blasts, including assessment of minimal residual disease (MRD) to confirm remission status. At the baseline assessment, bone marrow biopsy and/or aspirate is 
within 2 weeks and no less than 1 day before the first dose of CB-103. Then patients are assessed for disease response by bone marrow biopsy and/or aspirate on day 29. If 
the blasts in bone marrow are <5% but marrow is hypocellular (cellularity ≤15%) on day 29 (±3 days), then a repeat bone marrow biopsy and/or aspirate is obtained 1 week 


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later to assess response; if residual leukaemia is present, repeated bone marrow biopsy and/or aspirate will be obtained per 28 days until CR or CRi. A response (CR or CRi) 
must be confirmed no less than 28 days from the first evidence of response by bone marrow core biopsy as indicated. In case of CR or CRi confirmed by bone marrow biopsy 
and/or aspirate on 2 bone marrow biopsy and/or aspirate assessments no less than 28 days apart (the interval between assessments), bone marrow biopsy and/or aspirate 
assessment may be increased to every 8 weeks until to PD or EOS (whichever is earlier). 
25  Lumbar puncture (T-ALL/T-LBL) for prophylactic intrathecal therapy: if prophylactic intrathecal therapy is foreseen by the treating physician, a lumbar puncture may be performed 
up to 3 days before the first dose of CB-103, and, depending on the response of the patient, may be repeated at the discretion of the treating physician at the end of the first 
cycle of treatment with CB-103, and at the end of any subsequent cycle of treatment with CB-103, if more than one is warranted. 
26  CSF sample (T-ALL/T-LBL): in patients in whom a lumbar puncture is done (e.g., for intrathecal prophylaxis) a CSF sample should be taken on or around cycle 1 day 28, if 
clinically feasible, to determine the exposure of CB-103 in the CSF. 
27  Tumour assessments (T-ALL/T-LBL): only for patients with extramedullary disease or as clinically indicated a PET-CT will be performed at baseline and if positive, also at 
C2D1, C3D1 and thereafter as clinically indicated. A time window of ± 3 days is allowed for the tumour assessments. A wider time window is allowed only at baseline; however, 
assessments should be performed as close as possible to the 1st drug administration and if feasible, not later than 2 weeks prior to the 1st drug administration.   
28  Whole blood, plasma (T-ALL/T-LBL): samples will be collected as per the schedule and time window indicated in Section 8.5.3.  
29 EOT: within 14 days after the last administration of CB-103. All participating patients must complete this visit even if they have had to prematurely discontinue treatment with 
CB-103. 
30  Safety Follow-up: within 28 days after the last dose of CB-103. All patients must have this visit, even if they have prematurely discontinued CB-103 treatment. 
 
 
 


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Appendix 2 
Schedule of Assessments for Part B (Expansion)  
Table 2 
Schedule of Assessments (Part B) 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Twelve cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT26 
Safety 
follow-
up27 
After cycle 
12 (28-day 
cycles, 
until PD or 
toxicity)28 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 
Cycle 2 
Cycles 3 to 12 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Overnight hospital stays 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent3 
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test5 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Vital Signs and body 
measurement 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body height (cm) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
ECOG perf. Status6 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination7 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Body temperature 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 


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May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Twelve cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT26 
Safety 
follow-
up27 
After cycle 
12 (28-day 
cycles, 
until PD or 
toxicity)28 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 
Cycle 2 
Cycles 3 to 12 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Respiratory rate 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
 
 
 
Cardiac Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Heart rate 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG8 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
Holter monitoring8 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA for LVEF 
assessment8 
 
 
X8 
 
 
 
X 
 
 
 
 
 
 
 
X8a 
 
X 
 
 
X 
Cardiac serum markers9 
 
 
X9 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmological 
exams10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X11 
 
 
Clinical chemistry12 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Hematology12 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Coagulation12 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
PK profile blood 
sampling13 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
PK sub-study 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood sampling for 
genotype testing 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Period 
Pre-
screening* 
Screening 
Baseline 
Twelve cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT26 
Safety 
follow-
up27 
After cycle 
12 (28-day 
cycles, 
until PD or 
toxicity)28 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 
Cycle 2 
Cycles 3 to 12 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Chest X-ray14 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessment 
(PFS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival follow-up15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Safety assessment incl. 
AE/SAEs16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Assessments  
(Solid Tumours only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumour biopsies 
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumour biopsies17 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Liquid biopsy 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Tumour assessment  
(CT/MRI/PET-CT)18 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X19 
X 
 
X19 
X 
Hair follicles20 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Whole blood, plasma20a 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Other Assessments 
(T-ALL/T-LBL only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy 
and/or aspirate21 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Lumbar puncture 22 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CSF sample23 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Tumour assessment  
(PET-CT)24 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X  
X 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
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May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Study Period 
Pre-
screening* 
Screening 
Baseline 
Twelve cycle treatment period 
(28-day cycles, until PD or toxicity) 
EOT26 
Safety 
follow-
up27 
After cycle 
12 (28-day 
cycles, 
until PD or 
toxicity)28 
Un-
scheduled 
visit 
 
 
 
 
Cycle 1 
Cycle 2 
Cycles 3 to 12 
 
 
Cycle n 
 
Visit No.1 
- 
SCR2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
8a 
8b 
9 
10 
… 
EOT 
EOS 
Cycle n 
UNSCHED 
Study Day1 
- 
- 
- 
1 
2 
3 
8 
9 
15 
22 
29 30 
36 
43 
57 
... 
 
 
 
 
Day of cycle 
- 
-28 to -4 
-3 to -1 
1 
2 
3 
8 
9 
15 
22 
1 
2 
8 
15 
1 
15 
 
 
1 
 
Liquid biopsy 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
Whole blood, plasma25 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Whole blood, Saliva 
X* 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CT, computed tomography; CSF, cerebrospinal fluid; DLT, Dose limiting toxicity; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative 
Oncology Group; EOS, End of Study; EOT, End of Treatment; F-up; Follow-up; LVEV, left ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multigated 
acquisition; PD, pharmacodynamics; PE, physical examination; PET-CT, positron emission tomography–computed tomography; PK, pharmacokinetic; SAE, serious adverse event; 
SCR, screening; BL, baseline; ICF, Informed Consent Form. 
 * Pre-screening:  the patient whose Notch pathway activation status is not known must sign the pre-screening consent form. For solid tumour patients: if there is no sufficient 
archival tumour sample available or if older than 6 months prior to the pre-screening, a fresh pre-dose tumour biopsy is to be obtained. For T-ALL/T-LBL patients: when Notch 
status in unknown the whole blood and saliva will be collected at pre-screening, otherwise at BL to confirm the Notch status.  
 
1 
Visit windows: treatment phase cycles 1-6: ± 3 days. After cycle 6 visits are planned every 4 weeks (± 7 days) if no medical issue or complication occurred in the previous 
cycles. 
2 
Screening: may be performed in one or more visits.  
3 
Informed Consent: must be obtained prior to undergoing any study-related procedure. 
4 
Medical history (including relevant disease history) 
5 
Pregnancy test: for women of childbearing potential only. The serum pregnancy test must be performed within a maximum of 7 days of first CB-103 administration. The urine 
pregnancy test will also be done whenever one menstrual cycle is missed during the active treatment period (or when potential pregnancy is otherwise suspected) to confirm 
the patient has not become pregnant during the study. 
6 
ECOG: performance scale is available in Table 13 of the protocol. ECOG performance status will be assessed within 14 days prior to the first administration of CB-103, during 
the screening period. 
7 
Physical examination: will be performed at the screening, baseline and at the indicated patient visit, even if administration of study medication is not being held. More 
frequent examinations may be performed at the Investigator’s discretion, if medically indicated. If the baseline examinations are performed within 72 hours prior to the 
first administration of CB-103, they need not be repeated on C1D1, except for patients with T-ALL/T-LBL who need to repeat the PE at C1D1. 
8 
12-lead ECG: at each time point, three consecutive high-quality (without artefacts/lead misplacement) 12-lead ECGs will be performed approx.1-2 minutes apart. Refer to Table 
15 and Table 17 of the protocol for further details. ECG and PK blood samples need to be obtained at the same time-points and the ECG should be performed just prior to the 
drawing of the blood. A 15-minute window for ECG collection is allowed around each nominal ECG time point except for the 24 hour ECG time point, where a 1 hour window 
is allowed. 


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8 
Holter monitoring: 3-lead Holter ECG monitoring with 24 hours ECG profiles. Refer to Table 15 and Table 17 of the protocol for the scheduling and further details. At BL allowed 
from Day -7. 
8 
ECHO/MUGA: At BL allowed from Day -7. These assessments may be repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
8a Between cycles 3 and 12 the ECHO/MUGA is only requested on C3D1. 
9 
Cardiac markers: At BL allowed from Day -7. They will be performed locally and may be repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
10 Ophthalmological exams: they will be performed by on ophthalmologist/eye doctor at screening, End of Treatment and when clinically indicated. Refer to Section 8.2.2.2. 
11 
Ophthalmological exams: will be done at the safety follow-up if the patient had ocular symptoms during the treatment phase. 
12 Clinical chemistry/Haematology/coagulation: will be performed locally; at the screening (within 14 days of C1D1), and at the indicated visits. Refer to Section 8.2.4 of the 
protocol for the testing required. May be performed within a window of ± 24 hours throughout all treatment cycles. 
13 PK time sampling: blood sampling will be collected as per the schedule and time window indicated in Section 8.4 of the protocol. Changes to the PK sampling scheme may be 
required based on emerging data.  In case of twice daily intake of CB-103 the sampling schedule is slightly adjusted for cycle 1 (refer to Section 8.4.1) 
14 Chest X-ray: a baseline chest x-ray should be performed and be repeated if clinically indicated. If a chest CT is performed at baseline to assess tumour lesions, then a chest 
X-ray may not be required. 
15 Survival follow-up: it is planned for one year, every three months, after the End-of-Study visit or after the last treatment cycle (if outside of the 12 cycles period), then every 6 
months for the second year. 
16 Between the signature of the ICF and the initiation of CB-103, only the SAEs caused by study-related procedures will be reported; any other AEs will be recorded on the Medical 
History in the eCRF. After initiation of CB-103, all AEs/SAEs will be reported until 4 weeks after the last dose of CB-103. 
17 Fresh tumour biopsy (Solid Tumour): to be collected pre-dose during the screening/BL period, then on-treatment at C2D15 ± 3 days and at disease progression or when 
clinically indicated.  The pre-dose fresh biopsy is not required if obtained during the pre-screening. If the lesion is not accessible for a fresh tumour biopsy, a liquid biopsy may 
be used after confirmation with the Sponsor. 
18  Tumour assessments (Solid Tumours): will be performed at baseline, then 6 weeks after the first administration of CB-103 (i.e., day 15 of cycle 2), then see note 19. For breast 
cancer patients  enrolled in the MTD/RP2D confirmatory cohort (refer to Appendix 9) the CT scan will be replaced with PET-CT (or add PET) at baseline (and if positive, also 
at C2D15, before tumour biopsy). A time window of ± 3 days is allowed for the tumour assessments. A wider time window is allowed only at baseline however assessments 
should be performed as close as possible to the 1st drug administration and if feasible, not later than 2 weeks prior to the 1st drug administration. 
19 Tumour assessments (Solid Tumours): after cycle 2 will be performed, every 8 weeks and after cycle 6 every 12 weeks until EOT or disease progression/overall survival. The 
response will be determined as per the RECIST 1.1 and, if applicable, with confirmation as per RECIST. 
20 Hair follicles (Solid Tumour): samples will be collected for solid tumour indications only and only in selected patient groups as per the schedule and time window indicated in 
Section 8.5.2. 
20a  Whole blood, plasma (Solid Tumour): samples will be collected as per the schedule and time window indicated in Section 8.5.3.  
21 Bone marrow biopsy and/or aspirate (T-ALL/T-LBL): a bone marrow biopsy and/or aspirate will be obtained to assess bone marrow cellularity and to determine the percentage 
of leukemic blasts, including assessment of minimal residual disease (MRD) to confirm remission status. At the baseline assessment by bone marrow biopsy and/or aspirate 
is within 2 weeks and no less than 1 day before the first dose of CB-103.  
 
Then Patients are assessed for disease response by Bone marrow biopsy and/or aspirate on day 29,if the blasts in bone marrow <5% but marrow is hypocellular (cellularity ≤ 
15%) on day 29 (±3 days), then a repeat bone marrow biopsy and/or aspirate is obtained 1 week later to assess response; if residual leukaemia is present, repeated bone 
marrow biopsy and/or aspirate will be obtained per 28 days  until to CR or Cri. A response (CR or Cri) must be confirmed no less than 28 days from the first evidence of 
response by bone marrow core biopsy as indicated. In case of CR or Cri confirmed by bone marrow biopsy and/or aspirate on 2 bone marrow biopsy and/or aspirate 
assessments no less than 28 days apart the interval between assessments, bone marrow biopsy and/or aspirate assessment may be increased to every 8 weeks until to PD 
or EOS (whichever is earlier). 
22 Lumbar puncture (T-ALL/T-LBL) for prophylactic intrathecal therapy: if prophylactic intrathecal therapy is foreseen by the treating physician, a lumbar puncture may be performed 
up to 3 days before the first dose of CB-103, and, depending on the response of the patient, may be repeated at the discretion of the treating physician at the end of the first 
cycle of treatment with CB-103, and at the end of any subsequent cycle of treatment with CB-103, if more than one is warranted. 
23 CSF sample (T-ALL/T-LBL): In patients in whom a lumbar puncture is done (e.g., for intrathecal prophylaxis) a CSF sample should be taken on or around cycle 1 day 28, if 
clinically feasible, to determine the exposure of CB-103 in the CSF. 


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EudraCT No. 2017-001491-35 
 
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May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
24  Tumour assessments (T-ALL/T-LBL): only for patients with extramedullary disease or as clinically indicated a PET-CT will be performed at baseline and if positive, also at 
C2D1, C3D1 and thereafter as clinically indicated. A time window of ± 3 days is allowed for the tumour assessments. A wider time window is allowed only at baseline however 
assessments should be performed as close as possible to the 1st drug administration and if feasible, not later than 2 weeks prior to the 1st drug administration. 
25 Whole blood, plasma (T-ALL/T-LBL): samples will be collected as per the schedule and time window indicated in Section 8.5.3. 
26 
 EOT: within 14 days after the last administration of CB-103. All participating patients must complete this visit even if they have had to prematurely discontinue treatment with 
CB-103. 
27 Safety Follow-up: within 28 days after the last dose of CB-103 after which the End-of-Study is reached. All patients must have this visit, even if they have prematurely 
discontinued CB-103 treatment. 
28 Continuation after cycle 12: patients on treatment at that time may be eligible to continue treatment with CB-103. The Sponsor reserves the unilateral right, at its sole discretion, 
to determine whether to supply CB-103, and by what mechanism, after the end of study is reached or termination of the trial and before it is commercially available.  
 
 
 
 


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EudraCT No. 2017-001491-35 
 
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Appendix 3 
Overview of Selected Cancer Indications for the Study 
Table 1 
Solid Tumour Indications  
INDICATION (SOLID 
TUMOURS) 
NOTCH-EXPRESSION (MODE OF 
ACTIVATION) 
Breast Cancer (TNBC) 
• 9% chromosomal translocations (NOTCH1/2)1 
• 13% GOF mutations (NOTCH1-3)2,3 
• 46% JAG1/NOTCH1,3 up-regulation 
(resistant/refractory TNBC) 4 
Breast Cancer (ER+, HER2-) 
• 38% NOTCH4 upregulated5 
• 14% NUMB deficient/reduced6 
Breast Cancer (HER2+, ER-)  
• 70% of Trastuzumab resistance leading to 
NOTCH up-regulation7 
Colorectal Cancer (CRC) 
• 70% NOTCH up-regulation8 
Hepatocellular Carcinoma (HCC) 
 
• 5% JAG1 / NOTCH2 overexpression9 
Osteosarcoma  
• 11% NOTCH3 amplification10 
Adenoid Cystic Carcinoma 
• 18% NOTCH1 GOF mutations11,12 
• 40% NOTCH pathway alterations12,13 
Malignant Glomus Tumour14 
• 52% with NOTCH2 gene rearrangements 
• 9% with NOTCH3 gene rearrangements 
T-cell lymphoblastic leukaemia/ 
lymphoma (T-ALL/T-LBL) 
• 55% NOTCH1 GOF mutations15 
• ~30% FBXW7 LOF mutations16 
 
 
 


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 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
References:   
1. Alexander Stoeck et al., (2014). Discovery of Biomarkers Predictive of GSI 
Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma. 
Cancer Discovery. DOI: 10.1158/2159-8290.CD-13-0830. 
2. Kai Wang et al., (2015). PEST Domain Mutations in Notch Receptors Comprise 
an Oncogenic Driver Segment in Triple-Negative Breast Cancer Sensitive to a 
g-Secretase Inhibitor. Clin Cancer Res 21(6):1487-1496.  
3. Masahito Kawazu et al., (2017). Integrative analysis of genomic alterations in 
triple-negative breast cancer in association with homologous recombination 
deficiency. PLOS. https://doi.org/10.1371/journal.pgen.1006853. 
4. Michael Reedijk et al., (2005). High-level coexpression of JAG1 and NOTCH1 
is observed in human Breast Cancer and is associated with poor Overall 
Survival. Cancer Res 65(18): 8530-8537. 
5. Bruno M. Simões et al., (2015). Anti-estrogen resistance in human Breast 
tumors is driven by JAG1-NOTCH4-dependent cancer stem cell activity. 12: 
Supplement 1. 
6. Karin Rennstam et al., (2010). Numb protein expression correlates with a 
basal-like phenotype and cancer stem cell markers in primary breast cancer. 
Breast Cancer Res Treat. 122:315–324. 
7. Thuy Vu and Francois X. Claret (2012). Trastuzumab: updated mechanisms of 
action and resistance in breast cancer. 
8. Raymond Meng et al., (2009). Gamma-Secretase Inhibitors Abrogate 
Oxaliplatin-Induced Activation of the Notch-1 Signaling Pathway in Colon 
Cancer Cells Resulting in Enhanced Chemosensitivity. Cancer Res. 69(2): 
573–582. 
9. Chris Siebel (2017). Oral presentation at the NOTCH Meeting X, October 5th 
2017, Athens – Greece. 
10. Leanne Sayles et al., (2019). Genome-Informed Targeted Therapy for 
Osteosarcoma. Cancer Discov. Jan;9(1):46-63. 
11. Renata Ferrarotto et al., (2016). Activating NOTCH1 Mutations Define a 
Distinct Subgroup of Patients with Adenoid Cystic Carcinoma who have poor 
prognosis, propensity to bone and liver metastasis, and potential 
responsiveness to Notch1 Inhibitors. J Clin Oncol 34: 1-11. 
12. Sajed et al., (2017). Diffuse staining for activated NOTCH1 correlates with 
NOTCH1 Mutation Status and is Associated with worse outcome in Adenoid 
Cystic Carcinoma. AJSP 
13. Ferrarotto & Heymach (2017). Taking it up a NOTCH: A novel subgroup of ACC 
is identified. Oncotarget. 
14. Juan-Miguel Mosquera et al., (2013). Novel MIR143-NOTCH Fusions in Benign 
and Malignant Glomus Tumors. Genes, Chromosomes & Cancer. 


Clinical Study Protocol 
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CONFIDENTIAL 
 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
15. Aster J.C. et al., (2017). The varied Roles of Notch in Cancer. Annu. Rev. 
Pathol. Mech. Dis. 12:245-75. 
16. Yet et al. (2016). Oncogenic mutations in the FBXW7 gene of adult T-cell 
leukemia patients. PNAS 113(24) 6731-6736. 
 


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Appendix 4 
QT Prolonging Drugs with Risk of Torsades de Pointes. 
Table 1 List of prohibited QT prolonging drugs with a known risk to induce Torsades 
de Pointes 
Drug 
QT risk (*) 
Comment 
Aclarubicin 
Known risk for TdP 
Not available in US 
Amiodarone 
Known risk for TdP 
Females >Males, TdP risk regarded as 
low 
Anagrelide 
Known risk for TdP 
 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole  
Known risk for TdP 
Removed from US market 
Azithromycin 
Known risk for TdP  
Females>Males 
Bepridil 
Known risk for TdP 
Removed from US market; 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Cilostazol 
Known risk for TdP 
 
Ciprofloxacin 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Removed from US market; 
Females>Males 
Citalopram 
Known risk for TdP 
 
Clarithromycin 
Known risk for TdP 
 
Cocaine 
Known risk for TdP 
 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the US 
Donepezil 
Known risk for TdP 
 
Dronedarone 
Known risk for TdP 
 
Droperidol 
Known risk for TdP 
 
Erythromycin 
Known risk for TdP 
 
Escitalopram 
Known risk for TdP 
 
Flecainide 
Known risk for TdP 
 
Fluconazole 
Known risk for TdP 
 
Gatifloxacin 
Known risk for TdP 
Removed from US market 
Grepafloxacin 
Known risk for TdP 
Removed from US market 
Halofantrine 
Known risk for TdP 
Not available in US; Females>Males 
Haloperidol 
Known risk for TdP 
When given i.v. or at higher than 
recommended doses, risk of sudden 
death, QT prolongation and torsades 
increased 
Hydroquinidine 
Known risk for TdP 
Not available in US 
Hydroxychloroqui
ne 
Known risk for TdP 
 
Ibogaine 
Known risk for TdP 
Not available in US 
Ibutilide 
Known risk for TdP 
Females>Males 
Levofloxacin 
Known risk for TdP 
 
Levomepromazin
e 
Known risk for TdP 
Not available in the US 
Levomethadyl 
acetate 
Known risk for TdP 
Removed from US market 
Levosulpiride 
Known risk for TdP 
Not available in US 
Mesoridazine 
Known risk for TdP 
Removed from US market 


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Drug 
QT risk (*) 
Comment 
Methadone 
Known risk for TdP 
Females>Males 
Moxifloxacin 
Known risk for TdP 
 
Nifekalant 
Known risk for TdP 
Not available in US 
Ondansetron 
Known risk for TdP 
 
Oxaliplatin 
Known risk for TdP 
 
Papaverine HCl 
Known risk for TdP 
Intracoronary 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
Removed from US market 
Procainamide 
Known risk for TdP 
 
Propofol 
Known risk for TdP 
 
Quinidine 
Known risk for TdP 
Females>Males 
Roxithromycin 
Known risk for TdP 
Not available in US 
Sevoflurane 
Known risk for TdP 
 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
Removed from US market 
Sulpiride 
Known risk for TdP 
Not available in US 
Sultopride 
Known risk for TdP 
Not available in US 
Terfenadine 
Known risk for TdP 
Removed from US market 
Terlipressin 
Known risk for TdP 
Not available in US 
Terodiline 
Known risk for TdP 
Not available in US 
Thioridazine 
Known risk for TdP 
 
Vandetanib 
Known risk for TdP 
 
Source: 
(*) Classification according to the Qtdrugs org advisory board of the Arizona CET. Updated 
versions of medications which may prolong the QTc interval may be found at the following 
website: https://crediblemeds.org/index.php/?cID=328    
 


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Table 2 List of QT prolonging drugs with a conditional risk to induce Torsades de 
Pointes 
Drug 
QT risk (*) 
Abiraterone 
Conditional risk for TdP 
Amantadine  
Conditional risk for TdP 
Amisulpride (not available in the US) 
Conditional risk for TdP 
Amitriptyline 
Conditional risk for TdP 
Amphotericin B 
Conditional risk for TdP 
Amsacrine (not available in the US) 
Conditional risk for TdP 
Atazanavir 
Conditional risk for TdP 
Bendroflumethiazide or bendrofluazide 
Conditional risk for TdP 
Chloral hydrate 
Conditional risk for TdP 
Cimetidine 
Conditional risk for TdP 
Diphenhydramine 
Conditional risk for TdP 
Doxepin 
Conditional risk for TdP 
Eperisone (not available in the US) 
Conditional risk for TdP 
Esomeprazole 
Conditional risk for TdP 
Famotidine 
Conditional risk for TdP 
Fluoxetine 
Conditional risk for TdP 
Fluvoxamine 
Conditional risk for TdP 
Furosemide (frusemide) 
Conditional risk for TdP 
Galantamine 
Conditional risk for TdP 
Garenoxacin (not available in the US) 
Conditional risk for TdP 
Hydrochlorothiazide 
Conditional risk for TdP 
Hydroxyzine 
Conditional risk for TdP 
Indapamide 
Conditional risk for TdP 
Itraconazole 
Conditional risk for TdP 
Ivabradine 
Conditional risk for TdP 
Ketoconazole 
Conditional risk for TdP 
Lansoprazole 
Conditional risk for TdP 
Loperamide 
Conditional risk for TdP 
Metoclopramide 
Conditional risk for TdP 
Metolazone 
Conditional risk for TdP 
Metronidazole 
Conditional risk for TdP 
Nelfinavir 
Conditional risk for TdP 
Olanzapine 
Conditional risk for TdP 
Omeprazole 
Conditional risk for TdP 
Pantoprazole 
Conditional risk for TdP 
Paroxetine 
Conditional risk for TdP 
Piperacillin/Tazobactam 
Conditional risk for TdP 
Posaconazole 
Conditional risk for TdP 
Propafenone 
Conditional risk for TdP 
Quetiapine 
Conditional risk for TdP 
Quinine sulfate 
Conditional risk for TdP 
Ranolazine 
Conditional risk for TdP 
Risperidone 
Conditional risk for TdP 
Sertraline 
Conditional risk for TdP 
Solifenacin 
Conditional risk for TdP 
Telaprevir 
Conditional risk for TdP 
Torsemide (Torasemide) 
Conditional risk for TdP 
Trazodone 
Conditional risk for TdP 


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Drug 
QT risk (*) 
Voriconazole 
Conditional risk for TdP 
Ziprasidone 
Conditional risk for TdP  
Source: 
(*) Classification according to the Qtdrugs org advisory board of the Arizona CET. 
Updated versions of medications which may prolong the QTc interval may be found 
at the following website: https://crediblemeds.org/index.php/?cID=328   
 
Table 3 List of QT prolonging drugs with a possible risk to induce Torsades de 
Pointes 
Drug 
QT risk (*) 
Abarelix (not available in the US) 
Possible risk for TdP 
Alfuzosin 
Possible risk for TdP  
Alimemazine (not available in the US) 
Possible risk for TdP 
Apalutamide 
Possible risk for TdP 
Apomorphine 
Possible risk for TdP 
Aripiprazole 
Possible risk for TdP 
Artemether/Lumefantrine 
Possible risk for TdP 
Artenimol+piperaquine (not available in the 
US) 
Possible risk for TdP 
Asenapine 
Possible risk for TdP 
Atomoxetine 
Possible risk for TdP 
Bedaquiline 
Possible risk for TdP 
Bendamustine 
Possible risk for TdP 
Benperidol (not available in the US) 
Possible risk for TdP 
Betrixaban 
Possible risk for TdP 
Bortezomib 
Possible risk for TdP 
Bosutinib 
Possible risk for TdP 
Buprenorphine 
Possible risk for TdP 
Cabozantinib 
Possible risk for TdP 
Capecitabine 
Possible risk for TdP 
Ceritinib 
Possible risk for TdP 
Clofazimine (not available in the US) 
Possible risk for TdP 
Clomipramine 
Possible risk for TdP 
Clotiapine (not available in US) 
Possible risk for TdP 
Clozapine 
Possible risk for TdP 
Cobimetinib 
Possible risk for TdP 
Crizotinib 
Possible risk for TdP 
Cyamemazine (not available in the US) 
Possible risk for TdP 
Dabrafenib 
Possible risk for TdP 
Dasatinib 
Possible risk for TdP 
Degarelix 
Possible risk for TdP 
Delamanid (not available in the US) 
Possible risk for TdP 
Desipramine 
Possible risk for TdP 
Deutetrabenazine 
Possible risk for TdP 
Dexmedetomidine 
Possible risk for TdP 
Dextromethorphan/Quinidine 
Possible risk for TdP 
Dolasetron 
Possible risk for TdP 
Efavirenz 
Possible risk for TdP 
Eliglustat 
Possible risk for TdP 
Encorafenib 
Possible risk for TdP 


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CONFIDENTIAL 
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Drug 
QT risk (*) 
Entrectinib 
Possible risk for TdP 
Epirubicin 
Possible risk for TdP 
Eribulin mesylate 
Possible risk for TdP 
Ezogabine (Retigabine) 
Possible risk for TdP 
Felbamate 
Possible risk for TdP 
Fingolimod 
Possible risk for TdP 
Fluorouracil (5-FU) 
Possible risk for TdP 
Flupentixol (not available in the US) 
Possible risk for TdP  
Gemifloxacin 
Possible risk for TdP 
Gilteritinib 
Possible risk for TdP 
Glasdegib 
Possible risk for TdP 
Granisetron 
Possible risk for TdP 
Hydrocodone - ER 
Possible risk for TdP 
Iloperidone 
Possible risk for TdP 
Imipramine (melipramine) 
Possible risk for TdP 
Inotuzumab ozogamicin 
Possible risk for TdP 
Isradipine 
Possible risk for TdP  
Ivosidenib 
Possible risk for TdP 
Ketanserin (not available in the US) 
Possible risk for TdP 
Lacidipine (not available in the US) 
Possible risk for TdP 
Lapatinib 
Possible risk for TdP 
Lefamulin 
Possible risk for TdP 
Lenvatinib 
Possible risk for TdP 
Leuprolide 
Possible risk for TdP 
Levomethadone (not available in the US) 
Possible risk for TdP 
Lithium 
Possible risk for TdP  
Lofexidine 
Possible risk for TdP 
Lopinavir/Ritonavir 
Possible risk for TdP 
Maprotiline 
Possible risk for TdP 
Melperone (not available in the US) 
Possible risk for TdP 
Memantine 
Possible risk for TdP 
Mianserin (not available in the US) 
Possible risk for TdP 
Midostaurin 
Possible risk for TdP 
Mifepristone 
Possible risk for TdP 
Mirabegron 
Possible risk for TdP 
Mirtazapine 
Possible risk for TdP 
Moexipril/HCTZ 
Possible risk for TdP  
Necitumumab 
Possible risk for TdP 
Nicardipine 
Possible risk for TdP 
Nilotinib 
Possible risk for TdP 
Norfloxacin  
Possible risk for TdP 
Nortriptyline 
Possible risk for TdP 
Nusinersen 
Possible risk for TdP 
Ofloxacin 
Possible risk for TdP  
Osimertinib 
Possible risk for TdP 
Oxytocin 
Possible risk for TdP  
Paliperidone 
Possible risk for TdP 
Palonosetron 
Possible risk for TdP 
Panobinostat 
Possible risk for TdP 
Pasireotide 
Possible risk for TdP 
Pazopanib 
Possible risk for TdP 


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Drug 
QT risk (*) 
Perflutren lipid microspheres  
Possible risk for TdP 
Perphenazine 
Possible risk for TdP 
Pilsicainide (not available in the US) 
Possible risk for TdP 
Pimavanserin 
Possible risk for TdP 
Pipamperone (not available in the US) 
Possible risk for TdP 
Pitolisant 
Possible risk for TdP 
Pretomanid 
Possible risk for TdP 
Primaquine phosphate 
Possible risk for TdP 
Promethazine 
Possible risk for TdP 
Prothipendyl (not available in the US) 
Possible risk for TdP 
Ribociclib 
Possible risk for TdP 
Rilpivirine 
Possible risk for TdP 
Romidepsin 
Possible risk for TdP 
Saquinavir 
Possible risk for TdP 
Sertindole (not available in the US) 
Possible risk for TdP  
Siponimod 
Possible risk for TdP 
Sorafenib 
Possible risk for TdP 
Sunitinib 
Possible risk for TdP 
Tacrolismus 
Possible risk for TdP 
Tamoxifen 
Possible risk for TdP 
Telavancin 
Possible risk for TdP 
Telithromycin 
Possible risk for TdP 
Tetrabenazine 
Possible risk for TdP 
Tiapride (not available in the US) 
Possible risk for TdP 
Tipiracil and Trifluridine 
Possible risk for TdP 
Tizanidine 
Possible risk for TdP 
Tolterodine 
Possible risk for TdP 
Toremifene 
Possible risk for TdP 
Tramadol 
Possible risk for TdP 
Trimipramine 
Possible risk for TdP 
Tropisetron (not available in the US) 
Possible risk for TdP 
Valbenazine 
Possible risk for TdP 
Vardenafil 
Possible risk for TdP 
Vemurafenib 
Possible risk for TdP 
Venlafaxine 
Possible risk for TdP  
Vorinostat 
Possible risk for TdP 
Zotepine (not available in the US) 
Possible risk for TdP 
Zuclopenthixol, Zuclopentixol (not available in 
the US) 
Possible risk for TdP 
Source: 
(*) Classification according to the Qtdrugs org advisory board of the Arizona CET. Updated 
versions of medications which may prolong the QTc interval may be found at the following 
website: https://crediblemeds.org/index.php/?cID=328  
 
 
 
 


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Appendix 5 
Classification of Cytochrome Substrates 
Table 1 Examples (1) of sensitive in vivo CYP substrates and CYP substrates with 
narrow therapeutic range 
CYP Enzymes Sensitive substrates(2) 
Substrates with  
narrow therapeutic 
range(3) 
CYP1A2 
Alosetron, caffeine, 
duloxetine, melatonin, ramelteon, 
tacrine, tizanidine 
Theophylline, tizanidine 
CYP2B6 (4) 
Bupropion, efavirenz 
 
CYP2C8 
Repaglinide(5) 
Paclitaxel 
CYP2C9 
Celecoxib 
Warfarin, phenytoin 
CYP2C19 
Lansoprazole, omeprazole, S-
mephenytoin 
S-mephenytoin 
CYP3A(6) 
Alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, 
maraviroc, midazolam, nisoldipine, 
quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, 
tipranavir, triazolam, vardenafil 
Alfentanil, astemizole,(7) 
cisapride,(7) cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus,  
terfenadine(7) 
CYP2D6 
Atomoxetine, desipramine,  
dextromethorphan, metoprolol, 
nebivolol, perphenazine, tolterodine, 
venlafaxine 
Thioridazine 
(1) Source: www.fda.gov; list from 7/28/2011. Note that this is not an exhaustive list. For an 
updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInterac
tionsLabeling/ucm080499.htm   
(2) Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to 
increase 5-fold or higher when co-administered with a known CYP inhibitor. 
(3) CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of 
CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
(4) The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 
inhibitor, but they represent the most sensitive substrates studied with available inhibitors 
evaluated to date. 
(5) Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 
substrate if the inhibition of OATP1B1 by the investigational drug has been ruled out.   
(6) Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates 
of P-gp, the observed increase in exposure could be due to inhibition of both CYP3A and P-
gp. 
(7) Withdrawn from the United States market because of safety reasons. 
 


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Appendix 6 
List of CYP3A Inhibitors and Inducers 
Table 1 
List of drugs inhibiting or inducing CYP3A enzymes 
Strong 
CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
amprenavir 
carbamazepine* felbamate * 
conivaptan 
aprepitant 
phenobarbital * 
topiramate 
*(> 200 mg/day) 
indinavir 
atazanavir 
Phenytoin* 
oxcarbazepin * 
itraconazole 
cimetidine 
fosphenytoin * 
eslicarbazepin * 
ketoconazole 
ciproflaxin 
primidone * 
rufinamide * 
lopinavir 
darunavir 
avasimibe 
bosentan 
mibefradil 
diltiazem 
Rifabutin 
efavirenz 
nefazodone 
elvitegravir 
Rifampin 
etravirine 
nelfinavir 
erythromycin 
St.John’s Wort 
modafenil 
posaconazole 
fluconazole 
 
nafcillin 
ritonavir 
grapefruit juice 
 
ritonavir 
saquinavir 
schisandra 
sphenanthera 
 
talviraline 
telithromycin 
tipranavir 
 
tipranavir 
troleandomycin tofisopam 
 
 
voriconazole 
verapamil 
 
 
*These drugs are Enzyme-Inducing Anti-Epileptic drugs. 
This database of CYP inhibitors and inducers was compiled from the University of 
Washington’s Drug Interaction Database based on in vitro studies and from the FDA’s 
“Guidance for Industry, Drug Interaction Studies” from the Indiana University of School of 
Medicine’s “Clinically Relevant” Table 
 
 
 


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Appendix 7 
Tumour Response Assessment Based on RECIST v1.1 Criteria 
for Solid Tumours 
The following sections are applicable to this protocol and contain some relevant 
explanations. For details please refer to the original publication. 
Evaluation of tumour response according RECIST v1.1 for solid tumour 
indications with protocol specific modifications 
Tumour response will be evaluated according to RECIST v1.1 (Eisenhauer et al., 
2009). 
The RECIST version 1.1 may be accessed at the following link: 
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
Additional information regarding using RECIST is available at the following link: 
http://www.recist.com/  
Measurability of tumour lesions at baseline  
At baseline, tumour lesions/lymph nodes will be categorised as measurable or non-
measurable as follows: 
Measurable 
Tumour lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; refer to the 
Imaging Manual) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
Malignant lymph nodes: to be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 mm). 
At baseline and in follow-up, only the short axis will be measured and followed 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions.  
Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, and abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 


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Special considerations regarding the measurability of the lesions 
Types of lesions 
• Bone lesions, cystic lesions and lesions previously treated with local therapy: 
‒ 
Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, 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 above.  
‒ 
Blastic bone-lesions are non-measurable. 
‒ 
If a patient enrolled in this study has known bone metastases, these should 
be followed by CT or MRI in case they are measurable. 
‒ 
If they are not measurable, a baseline bone scan should be performed and 
repeated only if the patient has suspected progression of bone metastases 
or if a CR of other lesions has been documented. 
• Cystic lesions 
‒ 
Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patients, these are preferred for selection as target lesions. 
• Previously irradiated lesions and lesions with prior local treatment 
Tumour lesions situated in a previously irradiated area or lesions that have been 
subject to other loco-regional therapy are usually not considered measurable unless 
there has been a demonstrated progression of the lesion.  
Specification of methods of measurement 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start. 
Method of assessment  
The same method of assessment and the same technique should be used to 
characterise each identified and reported lesion at baseline and during follow-up. 
Imaging–based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
• Clinical lesions: Clinical lesions will be only considered measurable when they 
are superficial and ≥ 10 mm diameter as assessed using calipers (e.g. skin 
nodules). Skin lesions will be documentation by colour photography including a 
ruler to estimate the size of the lesions. As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be 


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undertaken since it is more objective and may also be reviewed at the end of the 
study. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slide thickness. MRI is also acceptable in 
certain situations (e.g. for body scans). More details concerning the use of both 
CT and MRI for assessment of objective tumour response evaluation including 
use of i.v. contrast are provided in Appendix II of the RECIST publication 
(Eisenhauer et al., 2009). 
• Ultrasound: Ultrasound should not be used as a method of measurement. If new 
lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. 
• Endoscopy, laparoscopy: The use of these techniques for objective tumour 
evaluation is not advised. However, they can be useful to confirm a complete 
pathological response when biopsies are obtained. 
• Cytology, histology: In case a new effusion will appear or worsen during study 
treatment and the measurable tumour has met criteria for response or SD a 
cytological confirmation of the neoplastic origin of the effusion can be considered 
in order to differentiate between response/SD and progressive disease. 
• Biopsy of skin lesions: Biopsy and histological examination may be used to 
confirm or define responses of skin lesions (e.g. after regression of melanoma 
skin lesions to differentiate between residual pigmented areas and residual 
malignant lesions). A biopsy of residual pigmented areas or other residual 
masses suspected to no longer contain tumour can be obtained from a lesion at 
any time-point to confirm a partial or complete response. 
Assessment of overall tumour burden and measurable disease 
Overall tumour burden should be estimated at baseline and used as comparator for 
subsequent measurements. 
Baseline documentation of target and non-target lesions 
For patients enrolled in this protocol lesions will be considered measurable (refer to 
criteria for measurability). When more than one measurable lesion is present at 
baseline, all lesions up to a total of 5 lesions and a maximum of 2 lesions per organ 
will be recorded under target lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. 


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Lymph nodes must meet the criterion of a short axis of ≥ 15 mm in order to be 
evaluated as target lesions. Only the short axis of these nodes will contribute to the 
baseline sum. 
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scans this is almost always the axial plane, for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. 
Baseline sum of diameters 
A sum of 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 to be included in the sum, then only the short axis is added to the sum as 
noted above. 
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 lesions or sites of disease not recorded as target lesions should be recorded as 
non-target lesions at baseline. There is no limit to the number of non-target lesions 
that can be recorded at baseline.  
• 
Measurable non-target lesions: measurements are required and will be 
recorded in the eCRF (longest diameter for non-nodal lesions and short axis 
diameter for nodal lesions). Lesions should be nevertheless followed up 
qualitatively as “present”, “absent”, or “unequivocal progression”. 
• 
All other non-target lesions: measurements are not required, these lesions 
should be followed as “present”, “absent”, or “unequivocal progression”. In 
addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. “multiple enlarged pelvic 
lymph nodes” or “multiple liver metastases”). 
Response criteria 
Evaluation of target lesions 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have a reduction in short axis 
to < 10 mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions; the baseline sum diameters serve as reference. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm 
(Note: the appearance of one or more new lesions is also considered 
progression).  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 


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Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measurement in the same anatomical plane as the 
baseline examination) even if the nodes regress to below 10 mm on study. 
In the CRF, the target nodal lesions will be recorded in a separate section, where, 
in order to qualify for CR, each node must achieve a short axis of < 10 mm. For 
PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions. 
Target lesions that become “too small to measure” 
If in the opinion of the radiologist the lesion has likely disappeared, the measurement 
should be recorded as 0 mm in the CRF. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned. 
However, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
Lesions that split or coalesce at treatment 
When non-nodal lesions “fragment”, the longest diameter of the fragmented portions 
should be added together to calculate the target lesion sum.  
As lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions 
have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the “coalesced 
lesion”. 
Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
• 
Complete Response (CR): Disappearance of all non-target lesions and 
normalisation of tumour marker (CEA, CYFRA 21) levels. All lymph nodes must 
be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) or/and 
maintenance of tumour markers (CEA, CYFRA 21) above the normal limits. 
• 
Progressive Disease (PD): Unequivocal progression of existing non-target 
lesions. The appearance of one or more new lesions is also considered 
progression. To achieve ‘unequivocal progression’, there must be an overall 
level of substantial worsening in non-target disease that is of a magnitude that, 
even in the presence of SD or PR in target disease, the treating physician 
seriously considers changing therapy. 
New lesions 
The finding of a new lesion should be unequivocal: i.e., not attributable to differences 
in scanning technique, change in imaging modality or findings thought to represent 
something other than tumour. This is particularly important when the patient’s baseline 
lesions show partial or complete response. 


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A lesion identified on a follow up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression.  
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitively a new lesion, then progression should be declared using 
the date of the initial scan.  
For more details, refer to the Imaging Manual and the RECIST publication (Eisenhauer 
et al., 2009). 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of study 
treatment until the EOT taking into account any requirement for confirmation. A 
response occurring after the end of study treatment but prior to the start of a new 
cancer treatment will also be considered for the assessment of best overall response. 
This assessment should be performed as per clinical standard practice. When a 
response assessment according to RECIST 1.1 is available, the result should be 
recorded in the eCRF. If no results of response assessment according to RECIST are 
available, then the result of other tumour evaluation should be recorded in the eCRF 
including the method used. 
Table 1 
Overall Response assessment for patients with target and non-target 
lesions at a given timepoint 
Target lesions  
Non-target 
lesions  
New 
lesions  
Overall 
response 
CR  
CR  
No  
CR  
CR  
Non-CR/Non-PD  
No  
PR  
CR  
Not evaluated  
No  
PR  
PR  
Non-PD or not all 
evaluated  
No  
PR  
SD  
Non-PD or not all 
evaluated  
No  
SD 
Not all evaluated  Non-PD  
No  
NE  
PD  
Any  
Yes or No  PD  
Any  
PD  
Yes or No  PD  
Any  
Any  
Yes  
PD  
CR = complete response; NE = not evaluable; PD = progressive 
disease; PR = partial response; SD = stable disease 
Missing assessments and not evaluable designation 
When no imaging/measurement is done at a particular time point, the patient is not 
evaluable (NE) for this time point. If only a subset of lesion measurements is made at 
an assessment, usually a convincing argument can be made that the contribution of 
individual missing lesion(s) would not change response at the assigned time point. 
This would be most likely to happen in the case of PD. For example, if a patient had a 
baseline sum of 50 mm with 3 measured lesions and at follow–up, only two lesions 


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were assessed, but those had a sum of 80 mm, the patient would have achieved PD 
status, regardless of the contribution of the missing lesion. 
Confirmation of responses 
Any complete or partial response should be confirmed by the next routinely scheduled 
scan or at least 4 weeks after the 1st occurrence of the respective response.  
Table 2 
Best overall response 
Overall response 
first time point 
Overall response 
second time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR A 
CR 
SD 
SD provided minimum criteria for SD duration B 
are met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration B 
are met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration B 
are met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
 SD provided minimum criteria for SD duration B 
are met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration B 
are met, otherwise NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease 
A If a CR is truly met at the first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline makes the disease PD at that time point (since 
disease must have reappeared after CR). Best Response would depend on whether minimum 
duration for SD was met. However, sometimes “CR” may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had a PR, not CR at the first 
time point. Under these circumstances, the original CR should be changes to PR and the best 
response is PR. 
B  The minimum requirement for SD duration according to this protocol is that the follow-up scan has 
been performed at least 8 weeks (patients with HNSCC or ACC) or 12 weeks (patients with cMEL 
or cSCC) after the baseline assessment (i.e., the day of first vaccination). 
Symptomatic deterioration 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy. The objective response status of such patients is to be determined by 
evaluation of target and non-target disease. 
 


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References:  
1. Eisenhauer, E.A., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, 
R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009). New 
response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 45, 228-247. 
 
 
 


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Appendix 8 
Response Assessment in Acute Lymphoblastic Leukaemia/ 
Lymphoblastic Lymphoma  
Response criteria for Blood and Bone Marrow: 
• 
CR 
o No circulating lymphoblasts or extramedullary disease 
o No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular 
mass/CNS involvement 
o Trilineage haematopoiesis (TLH) and <5% blasts 
o Absolute neutrophil count (ANC) >1000/microL 
o Platelets >100,000/microL 
o No recurrence for 4 weeks 
• 
CR with incomplete blood count recovery (CRi) 
o Meets all criteria for CR except platelet count or ANC 
• 
Overall response rate (ORR = CR + CRi) 
• 
NOTE: MRD assessment is not included in morphologic assessment and 
should be obtained 
• 
Refractory disease 
o Failure to achieve CR at the end of induction 
• 
Progressive disease (PD) 
o Increase of at least 25% in the absolute number of circulating or bone 
marrow blasts or development of extramedullary disease 
• 
Relapsed disease 
o Reappearance of blasts in the blood or bone marrow (>5%) or in any 
extramedullary site after a CR 
Response Criteria for CNS Disease: 
• 
CNS remission: Achievement of CNS-1 status in a patient with CNS-2 or CNS-
3 status at diagnosis. 
• 
CNS relapse: New development of CNS-3 status or clinical signs of CNS 
leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic 
syndrome without another explanation. 
Response Criteria for Lymphomatous Extramedullary Disease: 
• 
CT of neck/chest/abdomen/pelvis with IV contrast and PET/CT should be 
performed to assess response for extramedullary disease. 
• 
CR: Complete resolution of lymphomatous enlargement by CT. For patients 
with a previous positive PET scan, a post-treatment residual mass of any size 
is considered a CR as long as it is PET negative. 
• 
PR: >50% decrease in the sum of the product of the greatest perpendicular 
diameters (SPD) of the mediastinal enlargement. For patients with a previous 
PET scan, post-treatment PET must be positive in at least one previously-
involved site. 
• 
PD: >25% increase in the SPD of the mediastinal enlargement. For patients 
with a previous positive PET scan, post-treatment PET must be positive in at 
least one previously-involved site. 
• 
No Response (NR): Failure to qualify for PR or PD. 


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• 
Relapse: Recurrence of mediastinal enlargement after achieving CR. For 
patients with a previous positive PET scan, post-treatment PET must be 
positive in at least one previously-involved site. 
Reference: National Comprehensive Cancer Network (NCCN) Clinical Practice 
Guidelines in Oncology: Acute Lymphoblastic Leukemia, Version 1.2020, January 15, 
2020. Accessible at: www.NCCN.org  
 


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Appendix 9 
[18F] FDG-PET 
FDG ([18F]-Fluoro-Deoxy-Glucose) PET imaging will be performed in this study for 
patients with certain cancers at baseline and - if positive at baseline - at cycle 2 day 
15. 
To assure reproducibility of the examination, please refer to the PET-CT site procedure 
manual from BMS/ERT to see details on imaging acquisition and patient preparation. 
All PET scans should start between 60-70 minutes after 18F-FDG injection and patients 
should be always imaged on the same PET/CT scanner. It is particularly important that 
the time interval between injection and start of the scan is the same at follow-up 
compared to baseline. 
Blood glucose level will be checked on the day of the FDG PET scan and results 
assessed prior to the administration of FDG.  
Regular diet can be resumed after the scan. 
Of note FDG-PET must be performed before biopsy to avoid potential false 
positive findings whenever possible. However, during the screening period, 
baseline FDG-PET assessment should be performed at the closest date as possible 
from start of study treatment, at least one week after tumour biopsy and once the 
eligibility based on mutation status is known. All patients should be encouraged to 
increase fluid intake for a few hours after the scan to promote excretion of the FDG.  
A diuretic (furosemide, typically 20-40 mg IV) may be administered at the discretion of 
the investigator before or during the FDG-PET scan in order to accelerate elimination 
of the [18F]-FDG from the renal collecting system. 
Diazepam may be used to promote muscle relaxation and reduce muscular uptake if 
tumour deposits are in the neck or shoulder girdle area. Diazepam administration and 
diuretic administration must be recorded in the Concomitant Medications eCRF page. 
 
 


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Appendix 10 Statistical Appendix including Model Performance and Data 
Scenarios 
 
Part A (escalation): 
The model was assessed by two different metrics: hypothetical on-study data 
scenarios and long-run operating characteristics.  
Hypothetical data scenarios 
Hypothetical data scenarios are shown in Table 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model and the 
100% escalation limit. For each scenario, the probability of overdose for the current 
dose, as well as the next potential dose and related probabilities of under-dosing, 
target dose and over-dosing are shown.  
For example, scenario 1 represents the case that no DLT is observed in three patients 
at the starting dose of 15 mg. In this case, the next dose permitted by the model and 
by the 100% escalation rule is 30 mg. Similarly, scenario 2 represents the case that 
one DLT is observed in the first cohort of three patients at 15 mg, the model would 
than not allow to escalate to 30 mg and would require more patients enrolled on the 
dose level of 15 mg.  Scenario 6 represents the case that two DLTs are observed in 
the second cohort in three patients at 30 mg. The model then allows a de-escalation 
to 15 mg. Despite the fact that no DLTs were seen in the previous cohort (6 patients 
in total), the model reacts immediately to the data observed at 30 mg and requires a 
de-escalation to 15 mg. This case illustrates the adaptive behaviour of the model even 
in extreme situations. 
Table 1 
Hypothetical data scenarios  
Scenario 
Dose 
#DLT 
#Pat 
Current 
Dose  
-P(OD) 
Next 
Dose 
Next 
Dose  
- P(UD) 
Next 
Dose  
- P(TD) 
Next 
Dose - 
P(OD) 
1 
15 
0 
3 
0.011 
30 
0.89 
0.079 
0.031 
2 
15 
1 
3 
0.239 
15 
0.467 
0.294 
0.239 
3 
15 
2 
3 
0.685 
4 
15 
0 
3 
 
30 
0 
3 
0.007 
60 
0.871 
0.094 
0.035 
5 
15 
0 
3 
30 
1 
3 
0.121 
30 
0.602 
0.277 
0.121 
6 
15 
0 
3 
30 
2 
3 
0.4 
15 
0.439 
0.356 
0.206 
7 
15 
0 
3 
30 
1 
6 
0.034 
60 
0.53 
0.308 
0.162 
8 
15 
0 
3 
30 
0 
3 
60 
1 
3 
0.102 
60 
0.61 
0.289 
0.102 
 


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Operating characteristics 
Operating characteristics are a way to assess the long-run behaviour of a model. 
Under an assumed true dose-toxicity curve, metrics such as the probability of 
recommending a dose with true DLT rate in the target interval can be approximated 
via simulation. Table 2 describes 3 assumed true dose-toxicity scenarios which were 
used to assess the operating characteristics of the model. These scenarios reflect a 
wide range of possible cases as follows: 
• Scenario 1 (P): 
aligned with prior means 
• Scenario 2 (H): 
high-toxicity scenario 
• Scenario 3 (LH): low-toxicity followed by high-toxicity 
Table 2 
Assumed true dose-toxicity scenarios 
Scenario 
 
Dose 
 
 
10 
mg 
15 
mg 
30 
mg 
60 
mg 
120 
mg 
180 
mg 
240 
mg 
320 
mg 
400 
mg 
1 (P) 
P (DLT) 
0.08 
0.09 
0.12 
0.17 
0.25 
0.35 
0.42 
0.48 
0.52 
2 (H) 
0.12 
0.17 
0.25 
0.42 
0.55 
0.63 
0.7 
0.8 
0.9 
3 (LH) 
0.05 
0.08 
0.12 
0.16 
0.2 
0.4 
0.5 
0.65 
0.9 
Bold numbers indicate true DLT rates in the target interval [0.16-0.33). 
For each of these scenarios, 500 trials were simulated. It was then assessed how often 
a dose was declared as MTD with true DLT rate in the under-, targeted or over-dose 
range. Furthermore, the average, minimum and maximum number of patients per trial 
and the average number of DLTs per trial are reported. Results are shown in Table 3. 
Table 3 
Simulated operating characteristics 
Scenario 
% of trials declaring an MTD with true DLT 
rate in 
# Patients 
# DLT 
 
Underdose 
Target 
dose 
Overdose 
Stopped 
Mean 
(Min-Max) 
Mean 
(Min- Max) 
1 (P) 
23.6 
61.6 
9.4 
5.4 
19.13 (3-51) 
3.09 (1-11) 
2 (H) 
1.8 
61.2 
16.2 
20.8 
15.30 (3-39) 
3.68 (1-11) 
3 (LH) 
22.6 
67.4 
9.1 
3.6 
19.89 (3-52) 
3.25 (1-12) 
 
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior 
means, 61.6% of the simulated trials declared a dose as MTD with true DLT rate in the 
targeted dose range. Since this reflects a low toxicity prior assumptions the highest 
currently planned dose of 150 mg was identified quite often as MTD, namely in 61.4% 
of the simulated cases.  


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In Scenario 2 (high-toxicity scenario), the starting dose has already > 17% probability 
of observing at least 2 DLTs in the first cohort. This contributes to the high percentage 
(20.8%) of all simulated trials for which the trial is stopped since none of the doses is 
considered tolerable anymore. This is an expected situation for a high-toxicity scenario. 
In Scenario 3, more than 67.4% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range. 
The mean patient numbers range from 15.30 patients (high-toxicity scenario) to 19.89 
patients (low-high) and the maximum number of patients was 52. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity 
scenario.  
In summary, the considered data scenarios show a reasonable behaviour of the model 
and the operating characteristics demonstrate a good precision of MTD determination.  
 
Part B (Expansion): 
The following indications for patients with NOTCH activated pathway are considered 
and grouped into the expansion arms for Part B of this study: 
1. Adenoid cystic carcinoma (ACC) 
2. Triple Negative Breast Cancer (TNBC) 
3. Breast Cancer (ER+/-, HER2+/-) 
4. Osteosarcoma, malignant glomus tumour 
5. GI cancers (resistant to oxaliplatin or irinotecan-based therapy colorectal 
cancer, hepatocellular carcinoma) 
6. r/r T-ALL/T-LBL  
7. Any other cancer (haematologic or solid) with confirmed Notch pathway 
activation (basket arm) 
Table 4 
Hypothetical data scenarios for selected potential indications 
 
Dose 
 
1.ACC 
2.TNBC 
3.Breast 
Cancer 
4. Osterosarcoma,  
Malignant glomus 
tumour 
5.GI 
 
n/N 
Median; (CI) 
n/N 
Median; (CI) 
n/N 
Median; (CI) 
n/N 
Median; (CI) 
n/N 
Median; (CI) 
Interim 1: 
1.  Low 
response 
0/5  
10%  
(0%-32%) 
1/10 
12%  
(2%-32%) 
1/7 
13%  
(2%-38%) 
0/5  
10 % 
(0%-32%) 
3/5 
29%  
(8%-74%)  
2. High 
response 
3/5 
48%  
(26%-75%) 
2/5 
45%  
(21%-69%) 
4/10 
44% 
(23%-65%) 
4/7 
48% 
(27%-73%) 
2/5 
45%  
(21%-69%) 
3. Strong 
hetero-
geneity 
4/5 
65%  
(28%-94%) 
3/5 
51% 
(18%- 85%) 
6/10 
54% 
(27%- 81%) 
0/7 
10%  
(0%- 43%) 
0/5 
12% 
(0%- 48%) 


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Final analysis: 
1.  Low 
response 
5/20 
19%  
(9%- 36%) 
0/10 
13% 
(1%- 27%) 
5/20 
19% 
(9%-37%) 
1/10 
15% 
(4%-30%) 
3/20 
16% 
(6%-29%) 
2. High 
response 
7/20 
29%  
(17%- 46%) 
2/10 
26% 
(11% -42%) 
5/20 
26% 
(14%-41%) 
4/10 
29% 
(16%- 51%) 
4/20 
25% 
(12%-39%) 
3. Strong 
hetero-
geneity 
4/20 
20%  
(8%- 38%) 
1/10 
15% 
(2%-37%) 
6/20 
28% 
(13%- 47%) 
0/10 
10% 
(1%- 31%) 
11/20 
47% 
(26%-69%) 
 
Table 5 
Assumed true response scenarios and simulated operating 
characteristics 
 
Indication 
1.ACC 
N=10 
2.TNBC  
N=20 
3.Breast Cancer 
N=10 
4. 
Osteosarcoma, 
Malignant 
glomus tumour 
N=10 
5.GI 
N=10 
 
Success criteria 
>25% 
True Response 
Rate 
Success criteria 
>25% 
True Response 
Rate 
Success criteria 
>25% 
True Response 
Rate 
Success criteria 
>25% 
True Response 
Rate 
Success criteria 
>25% 
True Response 
Rate 
 
Low  
response 
success  
failure 
20% 
 
17% 
83% 
20% 
 
16% 
84% 
20% 
 
16% 
84% 
20% 
 
18% 
82% 
20% 
 
18% 
82% 
 
High  
response 
success 
failure 
30% 
 
73% 
27% 
30% 
 
72% 
28% 
30% 
 
72% 
28% 
30% 
 
71% 
29% 
30% 
 
71% 
29% 
 
Strong 
hetero-
geneity 
success 
failure 
10% 
 
2% 
98% 
10% 
 
1% 
99% 
10% 
 
2% 
98% 
30% 
 
29% 
71% 
 
30% 
 
26% 
74% 
 
 
 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
Page 218/222 
Final Version 
Version 4.3, 28 May 2021 
 
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 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Appendix 11 PK SUB-STUDY 1 
Background and rationale  
The majority of the novel orally administered, molecularly targeted anti-cancer drugs 
are weak bases that exhibit pH-dependent solubility and suppression of gastric acidity 
with acid-reducing agents (ARAs) could impair their absorption1. In this context it is 
noted that a majority of cancer patients frequently take ARAs to alleviate symptoms of 
gastroesophageal reflux disease, thereby raising the potential for a common but 
underappreciated drug-drug interaction (DDI) that could decrease the exposure of anti-
cancer medication and result in subsequent failure of therapy. A large survey using 
data from almost 3 million cancer patients has shown that the total prevalence 
proportion of ARA use was between 20% and 33% in this population2. Proton pump 
inhibitors were the most commonly prescribed agents, comprising 65% to 79% of all 
cancer patients receiving a prescription for an ARA. Clinically significant decreases in 
the exposure of dasatinib, gefitinib, erlotinib and nilotinib are thought to be the results 
of elevated gastric pH caused by concomitant use of ARAs. 
CB-103 is a weak base and exhibits pH-dependent solubility. It is therefore possible 
that CB-103 absorption is dependent on the gastric pH and that ARAs change the 
absorption characteristics of the molecule. The study protocol per se currently forbids 
the concomitant use of ARAs. 
Ranitidine is chosen as representative H2RA, as it is one of the strongest compounds 
in its class and the planned pH DDI evaluation is not expected to be confounded by 
additional cytochrome or transporter interactions of this compound, which were 
observed for example for cimetidine and famotidine3. The dose of ranitidine follows the 
prescription information for the compound. Ranitidine is commonly given as either 150 
mg twice daily (evening and morning administration) or as 300 mg once daily (evening 
administration). For ranitidine the most reported AEs are: 
- 
Uncommon AEs (≥1/1000, ≤1/100): Abdominal pain, constipation, nausea 
(these symptoms mostly improved during continued treatment) 
- 
Rare AEs ( ≥1/10,000, ≤1/1000): Hypersensitivity reactions (urticaria, 
angioneurotic oedema, fever, bronchospasm, hypotension and chest pain), 
transient and reversible changes in liver function tests, skin rash, elevation of 
plasma creatinine (usually slight; normalised during continued treatment). 
The administration of two doses of 150 mg ranitidine in the context of this sub-study is 
expected to be well tolerated; upon careful assessment it was determined that the 
benefit-risk ratio remains favourable and that this PK sub-study does not compromise 
the patient safety or represent a burden that could interfere with their willingness to 
complete their participation in the CB103-C-101 study, but to the contrary, will support 
to better define the safety profile of CB-103. 
 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
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Final Version 
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 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Objective PK sub-study 1 
PK-sub-studies are part of the main study CB103-C-101 as described in Section 8.4.2 
and schedule of assessments of the approved study protocol.  
The objective of this first per-protocol PK sub-study is to investigate the effect of gastric 
pH on absorption of CB-103 when co-administered with standard dose of ranitidine 
(150 mg), a histamine H2-receptor antagonist (H2RA) that is a potent acid-reducing 
agent frequently prescribed to cancer patients. 
 
Study conduct 
Outline of Study Procedures 
The patients will have to be instructed to: 
 
o Take one single dose/tablet of ranitidine 150 mg in the evening of cycle 2 day 
1 before bed time and to remain fasted overnight (water intake is allowed). 
o Attend fasted to the clinic in the morning of cycle 2 day 2 (C2D2, study visit for 
the PK sub-study only) without taking ranitidine and/or CB-103, but bringing the 
dose of CB-103 to the clinic. If the patient is not able to adhere to the long 
fasting conditions, they can be allowed a small breakfast/snack up to 2 hours 
before arrival in the clinic on C2D2. If this happens, it should be documented 
in the patient’s record. 
The patient will have to confirm the intake of ranitidine on C2D1 (as indicated 
in the above bullet) and the study team will document it in the patient’s 
record/chart together with the exact time of ranitidine intake on C2D2.  
o Take one single dose/tablet of ranitidine 150mg while at the clinic on C2D2 in 
the presence of the available study team and remain fasted up to 3 hours post 
CB-103 intake (water intake is allowed). 
o Take CB-103 with a glass of 200 mL water, exactly 2 hours after the intake of 
the ranitidine, and in the presence of the available study team. 
Overall, the co-administration of ranitidine is limited to two intakes (post-CB-103 dose 
on cycle 2 day 1 and pre-CB-103 dose on day 2) in order to test the on-off effect. 
 
On C2D2 the PK sampling (7 in total) will have to be taken at the following time points 
(for the patients in the twice daily regimen of CB-103 the timepoints are relative to the 
first intake): 
 
• Pre-dose (after ranitidine intake and within 30 mins before CB-103 
administration) 
• 0.5 hours post CB-103 dose (± 5 mins) 
• 1 hour post CB-103 dose (± 5 mins) 
• 2 hours post CB-103 dose (± 5 mins) 
• 4 hours post CB-103 dose (± 5 mins) 
• 6 hours post CB-103 dose (± 5 mins) 
• 8 hours post CB-103 dose (± 5 mins) 
 
The PK sampling scheme is the same as on C2D1 and allows the comparison of CB-
103 PK in the absence (C2D1) and presence (C2D2) of ranitidine. 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
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Final Version 
Version 4.3, 28 May 2021 
 
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 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
 
All other PK samples and assessments specified in the study protocol (pre and post 
C2D2) will remain the same and are to be performed. 
 
Ranitidine provision 
The clinical site(s) can choose the brand of ranitidine locally available, amongst the 
readily available marketed brands, and take it from the hospital pharmacy or as per 
the site’s procurement procedures. The same brand of ranitidine should be used 
across the patients enrolled at the clinical site to reduce potential variability.  
The clinical site staff will then dispense ranitidine to the patients and instruct them how 
to use the ARA. 
 
eCRF recording 
The concerned e-CRF form for the PK sub-study (i.e., Visit 8a – Cycle 2 Day 2) is to 
be properly completed by indicating the type of sub-study the patient is taking part in 
(in this case Sub-Study PK1), as well as, the exact time of ranitidine and CB-103 intake, 
and the date/time of the PK samples collection. In case, on C2D2 the patient vomits 
within 2 hours after drug administration either ranitidine or CB-103 this needs to be 
captured as well in the comment field of e-CRF. 
  
References 
1. 
Budha NR et al. Drug absorption interactions between oral targeted anticancer 
agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? 
Clin Pharmacol Ther 2012; 92 (2):203-13. 
2. 
Smelick GS et al. Prevalence of acid-reducing agents (ARA) in cancer 
populations and ARA drug-drug interaction potential for molecular targeted 
agents in clinical development. Mol Pharm 2013; 10 (11): 4055-62. 
3. 
Zhang L, Wu F, Lee SC, Zhao H, Zhang L. ph-dependent drug-drug interactions 
for weak base drugs: potential implications for new drug development. Clin 
Pharmacol Ther 2014; 96 (2): 266-77. 
 
 
 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
Page 221/222 
Final Version 
Version 4.3, 28 May 2021 
 
CONFIDENTIAL 
 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
Appendix 12 PK SUB-STUDY 2 
Background and rationale  
Administration of a drug product with food may change the bioavailability (BA) by 
various means, including:  
• 
Delay gastric emptying  
• 
Stimulate bile flow  
• 
Change gastrointestinal (GI) pH  
• 
Increase splanchnic blood flow  
• 
Change luminal metabolism of a drug substance  
• 
Physically or chemically interact with a dosage form or a drug substance  
 
Food effects on BA are generally greatest when the drug product is administered 
shortly after a meal is ingested. The nutrient and caloric contents of the meal, the meal 
volume, and the meal temperature can cause physiological changes in the GI tract in 
a way that affects drug product transit time, luminal dissolution, drug permeability, and 
systemic availability.  
For immediate-release drug products of compounds with low solubility or low 
permeability, food effects are most likely to result from a complex combination of 
factors that influence the in vivo dissolution of the drug product and/or the absorption 
of the drug substance. In these cases, the relative direction and magnitude of food 
effects on BA are difficult, if not impossible, to predict without investigating it. 
 
Objective PK sub-study 2 
PK-sub-studies are part of the main study CB103-C-101 as described in Section 8.4.2 
and schedule of assessments of the approved study protocol.  
The objective of the second per-protocol PK sub-study is to evaluate the effect of a 
standard breakfast (moderate fat: composed of approximately 21g fat and 533 Kcal in 
total, with ca. 189 Kcal from fat, ca. 268 Kcal from carbohydrates and ca. 76 Kcal from 
protein). 
 
Study conduct 
Outline of Study Procedures 
The patients will have to be instructed to: 
 
o come to the clinic in the morning of cycle 2 day 2 (C2D2, extra study visit for 
the PK sub-study only) without taking CB-103, and bring the dose of CB-103 
to the clinic. 
 
o consume a standard breakfast supplied by the site based on the above 
indicated Kcal (e.g., four slices of bread, one slice of ham, one slice of cheese, 
butter, jelly and two cups of decaffeinated coffee or tea with milk and/or sugar, 
if desired) in its entirety within 30 minutes. The study team will document the 
type of meal given to the patient in the patient’s record/chart together with the 
time of food intake. 


Clinical Study Protocol 
Protocol No.  CB103-C-101 
EudraCT No. 2017-001491-35 
 
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Final Version 
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 May not be used, divulged, published, or otherwise disclosed without the consent of Cellestia Biotech AG 
 
o take CB-103 with a glass of 200mL water 30 minutes after the start of breakfast 
and in the presence of the available study team  
 
o remain fasted, after the breakfast, for at least 4 hours post-dose (water intake 
is allowed) 
 
On C2D2 the PK sampling (7 in total) will have to be taken at the following time points 
(for the patients in the twice daily regimen of CB-103 the timepoints are relative to the 
first intake): 
 
• Pre-dose (within 30 mins before CB-103 administration) 
• 0.5 hours post CB-103 dose (± 5 mins) 
• 1 hour post CB-103 dose (± 5 mins) 
• 2 hours post CB-103 dose (± 5 mins) 
• 4 hours post CB-103 dose (± 5 mins) 
• 6 hours post CB-103 dose (± 5 mins) 
• 8 hours post CB-103 dose (± 5 mins) 
 
The PK sampling scheme is the same as on C2D1 and allows the comparison of CB-
103 PK in the absence (C2D1) and presence (C2D2) of food. 
 
All other PK samples and assessments specified in the study protocol (pre and post 
C2D2) will remain the same and are to be performed. 
 
eCRF recording 
The concerned e-CRF form for the PK sub-study (i.e., Visit 8a – Cycle 2 Day 2) is to 
be properly completed by indicating the type of sub-study the patient is taking part in 
(in this case Sub-Study PK2), as well as, the exact time of food and CB-103 intake, 
and the date/time of the PK samples collection. In case the patient vomits within 2 
hours after drug administration on C2D2, this needs to be captured it as well in the 
comment field of e-CRF.