Clinical trial NCT04393298
Conditions: Advanced Solid Tumors
Keywords: Advanced solid tumors UCB6114 Phase 1/2
Sponsor: UCB Biopharma SRL
Start date: 2020-07-09; Completion date: 2024-04-11
Enrollment: 93 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of the study is to characterize the safety and pharmacokinetic (PK) profile of UCB6114 administered as monotherapy or in combination with selected standard of care (SOC) regimens.

Detailed description:

Arms: arm 1: Study participants assigned this arm will receive UCB6114 as monotherapy in escalating cohorts at pre-specified dose levels. arm 2: Study participants will receive predefined doses of UCB6114 as monotherapy administered intravenously at pre-specified time points. arm 3: Study participants assigned to this arm will receive UCB6114 in escalating cohorts at pre-specified dose levels in combination with trifluridine/tipiracil (TFD/TPI). arm 4: Study participants assigned to this arm will receive UCB6114 in escalating cohorts at pre-specified dose levels in combination with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) regimen.
Interventions: intervention 1: ginisortamab intervention 2: trifluridine/tipiracil intervention 3: mFOLFOX6
Intervention descriptions: intervention 1: Study participants will receive predefined doses of ginisortamab (UCB6114) administered intravenously at pre-specified time points. intervention 2: Study participants will receive predefined doses of trifluridine/tipiracil (TFD/TPI) administered as film-coated tablets at pre-specified time points. intervention 3: Study participants will receive predefined doses of oxaliplatin, Leucovorin and 5-fluorouracil as part of the mFOLFOX6 chemotherapy regimen administered as intravenous (iv) infusion at prespecified time points.

Protocol documents:
Prot_000.pdf: 
UCB 
26 Jun 2023 
Clinical Study Protocol Amendment 6 
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ONC001 
Confidential 
Page 1 of 195 
A PHASE 1/2 OPEN-LABEL, MULTICENTER STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND 
ANTITUMOR ACTIVITY OF UCB6114 ADMINISTERED 
INTRAVENOUSLY TO PARTICIPANTS WITH ADVANCED 
SOLID TUMORS 
PROTOCOL ONC001 – AMENDMENT 6 
PHASE 1/2 
SHORT TITLE: 
An open-label, multicenter, first in human study in participants with advanced solid tumors 
treated with UCB6114 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
Eudra CT Number: 
2019-002598-78 
IND Number 
151751 
NCT Number 
NCT04393298 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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ONC001 
 
 
 
Confidential 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Type of amendment 
Protocol Amendment 6 
26 Jun 2023 
Substantial  
Protocol Amendment 5 
14 Jan 2022 
Substantial  
Protocol Amendment 4 
17 Jun 2021 
Substantial  
Protocol Amendment 3.2 (UK) 
07 Apr 2021 
Substantial 
Protocol Amendment 3.1 (US) 
24 Mar 2021 
Not applicable 
Protocol Amendment 3 
07 Jan 2021 
Substantial 
Protocol Amendment 2 
12 Oct 2020 
Substantial 
Protocol Amendment 1 
11 Jun 2020 
Substantial 
Original Protocol 
14 Oct 2019 
Not applicable 
Amendment 6 (26 Jun 2023) 
Overall Rationale for the Amendment 
The overall rationale for Amendment 6 is to provide clarity for the suspension of the study and to 
reflect the ability to stop either the entire study or individual study part.  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
6.7 Criteria for study hold or dosing 
stoppage 
11.6 Appendix 6: Rapid Alert 
Procedures 
Clarification that either the entire study or 
an individual Study Part can be suspended. 
Clarification of the process for 
study/individual Study Part hold/potential 
restart when criteria for study/individual 
Study Part suspension are met.  
To clarify the 
study/Study Part 
hold procedures 
1.3 Schedule of Activities 
9.8 Pharmacodynamics 
Footnotes j and n of Table 1-6 (Part A1, 
Cohort 3) have been updated to clarify 
when  blood sample for PK and cGremlin 
should be collected with regards to biopsy. 
Footnotes o and p of Table 1-7 (Part B) and 
Table 1.8 (Part C) has been updated to 
clarify when blood samples for ADA, 
circulating gremlin-1 and ctDNA analysis 
are to be collected. In line with this change, 
a footnote has been added for Table 9-9 and 
Table 9-21. 
Clarification 
Global 
Correction of typographical errors. 
Correction 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
PSRapidalert@ucb.com 
Phone 
UCB Study Physician: 
 
UCB Celltech, 208 Bath Rd, Slough, Berkshire, SL1 3WE, UK 
24h Rapid Response Helpline: +448081640230 
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ONC001 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................................... 2 
1 
PROTOCOL SUMMARY ............................................................................................... 12 
1.1 
Synopsis ....................................................................................................................... 12 
1.2 
Schema ......................................................................................................................... 18 
1.3 
Schedule of Activities .................................................................................................. 24 
2 
INTRODUCTION ........................................................................................................... 42 
2.1 
Study rationale ............................................................................................................. 42 
2.2 
Background .................................................................................................................. 42 
2.3 
Benefit/risk assessment ................................................................................................ 43 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 45 
4 
STUDY DESIGN ............................................................................................................. 47 
4.1 
Overall design .............................................................................................................. 47 
4.1.1 
Study oversight .................................................................................................... 51 
Safety monitoring committee ......................................................................................... 51 
Study steering committee ............................................................................................... 51 
4.1.2 
Part A – Monotherapy dose escalation ................................................................ 51 
4.1.2.1 
SMC ........................................................................................................... 52 
4.1.2.2 
Dose escalation criteria ............................................................................. 52 
4.1.2.3 
Dose de-escalation following initial dose level ......................................... 54 
4.1.2.4 
Dose-limiting toxicity determination and maximum tolerated dose 
definition ................................................................................................... 54 
4.1.2.5 
Defining the recommended Phase 2 dose for monotherapy ...................... 55 
4.1.3 
Part A1 – Dose optimization (alternative dosing schedules) ............................... 55 
4.1.4 
Part B – Dose escalation with TFD/TPI .............................................................. 56 
4.1.4.1 
Study oversight .......................................................................................... 57 
4.1.4.2 
Dose-limiting toxicity and maximum tolerated dose definition and 
determination ............................................................................................. 57 
4.1.4.3 
Definition of recommended Phase 2 dose in combination with TFD/TPI 59 
4.1.5 
Part C – Dose escalation with mFOLFOX6 ........................................................ 59 
4.1.5.1 
Study oversight .......................................................................................... 60 
4.1.5.2 
Dose-limiting toxicity determination and maximum tolerated dose 
definition ................................................................................................... 61 
4.1.5.3 
Defining the recommended Phase 2 dose in combination with 
mFOLFOX6 .............................................................................................. 62 
4.1.6 
Part D – Monotherapy 1 expansion ..................................................................... 62 
4.1.7 
Part E – Monotherapy 2 expansion ...................................................................... 63 
4.1.8 
Part F – Combination 1 expansion ....................................................................... 63 
4.1.9 
Part G – Combination 2 expansion ...................................................................... 63 
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4.1.10 
Tumor type selection for modules post-Part A .................................................... 63 
4.2 
Scientific rationale for study design ............................................................................ 63 
4.2.1 
Rationale for Part A ............................................................................................. 63 
4.2.2 
Rationale for Part A1 ........................................................................................... 64 
4.2.3 
Rationale for Part B and Part C ........................................................................... 64 
4.2.4 
Dosing strategy .................................................................................................... 64 
4.3 
Justification for dose .................................................................................................... 65 
4.3.1 
Starting dose in Part A ......................................................................................... 65 
4.3.2 
Doses in Part A1 .................................................................................................. 65 
4.3.3 
Starting doses for UCB6114 and standard of care regimens in Part B and Part C66 
4.3.3.1 
UCB6114 dosing ....................................................................................... 66 
4.3.3.2 
Standard of Care regimen dosing .............................................................. 67 
4.4 
End of study definition................................................................................................. 68 
5 
STUDY POPULATION .................................................................................................. 68 
5.1 
Inclusion criteria .......................................................................................................... 69 
5.1.1 
Part A ................................................................................................................... 69 
5.1.2 
Part A1 ................................................................................................................. 70 
5.1.3 
Part B ................................................................................................................... 71 
5.1.4 
Part C ................................................................................................................... 73 
5.2 
Exclusion criteria ......................................................................................................... 74 
5.2.1 
Part A ................................................................................................................... 74 
5.2.2 
Part A1 ................................................................................................................. 76 
5.2.3 
Part B ................................................................................................................... 78 
5.2.4 
Part C ................................................................................................................... 80 
5.3 
Lifestyle restrictions..................................................................................................... 82 
5.4 
Screen failures .............................................................................................................. 82 
6 
STUDY TREATMENTS ................................................................................................. 83 
6.1 
Treatments administered .............................................................................................. 83 
6.1.1 
Part A ................................................................................................................... 83 
6.1.2 
Part A1 ................................................................................................................. 83 
6.1.3 
Part B ................................................................................................................... 84 
6.1.4 
Part C ................................................................................................................... 86 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 89 
6.2.1 
UCB6114 ............................................................................................................. 89 
6.2.2 
TFD/TPI ............................................................................................................... 89 
6.2.3 
mFOLFOX6 ......................................................................................................... 89 
6.2.4 
Drug accountability ............................................................................................. 89 
6.3 
Measures to minimize bias: Randomization and blinding ........................................... 90 
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6.4 
Treatment compliance .................................................................................................. 90 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 90 
6.5.1 
Permitted concomitant treatments (medications and therapies) during Part A ... 90 
6.5.2 
Permitted concomitant treatments (medications and therapies) during Part A1 . 91 
6.5.3 
Permitted concomitant treatments (medications and therapies) during Part B .... 91 
6.5.4 
Permitted concomitant treatments (medications and therapies) during Part C .... 92 
6.5.5 
Prohibited concomitant treatments (medications and therapies) during Part A .. 92 
6.5.6 
Prohibited concomitant treatments (medications and therapies) during Part A1 93 
6.5.7 
Prohibited concomitant treatments (medications and therapies) during Part B... 93 
6.5.8 
Prohibited concomitant treatments (medications and therapies) during Part C... 94 
6.5.9 
Vaccines ............................................................................................................... 94 
6.5.10 
Rescue medication ............................................................................................... 95 
6.6 
Dose modification ........................................................................................................ 95 
6.6.1 
Part A and Part A1 ............................................................................................... 95 
6.6.1.1 
Dose escalation scheme ............................................................................. 95 
6.6.1.2 
Within participant dose modification in Part A ......................................... 97 
6.6.1.3 
Within participant dose modification in Part A1 ....................................... 97 
6.6.2 
Part B ................................................................................................................... 98 
6.6.2.1 
Dose escalation scheme ............................................................................. 98 
6.6.2.2 
UCB6114 dose modifications ................................................................... 98 
6.6.2.3 
TFD/TPI dose modifications ..................................................................... 99 
6.6.3 
Part C ................................................................................................................. 101 
6.6.3.1 
Dose escalation scheme ........................................................................... 101 
6.6.3.2 
UCB6114 dose modifications ................................................................. 101 
6.6.3.3 
mFOLFOX6 dosing ................................................................................. 102 
6.6.3.4 
mFOLFOX6 dose modifications ............................................................. 102 
6.7 
Criteria for study hold or dosing stoppage ................................................................. 106 
6.8 
Treatment after the end of the study .......................................................................... 106 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................... 106 
7.1 
Discontinuation of study medication ......................................................................... 106 
7.1.1 
Liver Chemistry Stopping Criteria .................................................................... 107 
7.1.2 
QTc Stopping Criteria ........................................................................................ 107 
7.1.3 
Other criteria for discontinuation of study medication ...................................... 108 
7.1.4 
Temporary discontinuation of study medication ............................................... 109 
7.2 
Participant discontinuation/withdrawal from the study ............................................. 109 
7.3 
Lost to follow up ........................................................................................................ 110 
7.4 
COVID-19 Pandemic ................................................................................................. 110 
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8 
STUDY AND SITE DISCONTINUATION ................................................................. 111 
9 
STUDY ASSESSMENTS AND PROCEDURES ......................................................... 111 
9.1 
Safety assessments ..................................................................................................... 114 
9.1.1 
Physical examination ......................................................................................... 114 
9.1.2 
Vital signs .......................................................................................................... 115 
9.1.3 
Electrocardiograms ............................................................................................ 115 
9.1.4 
Echocardiograms ............................................................................................... 115 
9.1.5 
Clinical safety laboratory assessments .............................................................. 115 
9.1.6 
Pregnancy testing ............................................................................................... 116 
9.2 
Adverse events and serious adverse events ............................................................... 116 
9.2.1 
Time period and frequency for collecting AE and SAE information ................ 117 
9.2.2 
Method of detecting AEs and SAEs .................................................................. 117 
9.2.3 
Follow-up of AEs and SAEs .............................................................................. 117 
9.2.4 
Regulatory reporting requirements for SAEs .................................................... 118 
9.2.5 
Pregnancy .......................................................................................................... 118 
9.2.6 
Adverse events of special interest ...................................................................... 118 
9.2.7 
Adverse events of special monitoring ................................................................ 119 
9.2.8 
Anticipated serious adverse events .................................................................... 119 
9.2.9 
Infusion-related reactions (hypersensitivity reactions) ...................................... 119 
9.3 
Safety signal detection ............................................................................................... 120 
9.4 
Treatment of overdose ............................................................................................... 120 
9.5 
Pharmacokinetics ....................................................................................................... 121 
9.6 
Efficacy assessments .................................................................................................. 124 
9.6.1 
Tumor assessments ............................................................................................ 124 
9.6.2 
ECOG Performance Status ................................................................................ 125 
9.7 
Genetics...................................................................................................................... 125 
9.8 
Pharmacodynamics .................................................................................................... 125 
9.8.1 
Blood samples for circulating gremlin-1 ........................................................... 126 
9.8.2 
Blood samples for serum protein analysis and blood transcriptomics .............. 128 
9.8.3 
Blood samples for circulating tumor DNA analysis .......................................... 129 
9.8.4 
Blood samples for serum bone turnover markers .............................................. 130 
9.8.5 
Urine samples for urinary bone turnover markers ............................................. 131 
9.8.6 
Blood samples for genetic analysis .................................................................... 132 
9.8.7 
Tumor biopsy for PD assessments and predictive biomarker assessments ....... 132 
Biopsy procedure in Part A1 ........................................................................................ 133 
9.8.8 
Historical tumor samples ................................................................................... 134 
9.9 
Biomarkers ................................................................................................................. 134 
9.10 
Immunogenicity ......................................................................................................... 134 
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10 STATISTICAL CONSIDERATIONS ........................................................................... 136 
10.1 
Definition of analysis sets .......................................................................................... 136 
10.2 
General statistical considerations ............................................................................... 137 
10.3 
Planned safety and other analyses.............................................................................. 137 
10.3.1 
Safety analyses ................................................................................................... 137 
10.3.2 
Analysis of Baseline and Demographic Variables ............................................ 140 
10.3.3 
Other analyses .................................................................................................... 140 
10.3.3.1 
Analysis of PK endpoints ........................................................................ 140 
10.3.3.2 
Analysis of genetic endpoints .................................................................. 141 
10.3.3.3 
Analysis of PD endpoints ........................................................................ 142 
10.3.3.4 
Analysis of biomarker endpoints ............................................................. 142 
10.3.3.5 
Analysis of immunologic endpoints ........................................................ 142 
10.4 
Planned efficacy/outcome analyses ........................................................................... 142 
10.4.1 
Analysis of antitumor activity/outcome endpoint .............................................. 142 
10.4.1.1 
Antitumor activity endpoint definitions .................................................. 142 
10.4.1.2 
Analysis of the antitumor activity endpoints ........................................... 143 
10.5 
Handling of protocol deviations................................................................................. 144 
10.6 
Handling of dropouts or missing data ........................................................................ 144 
10.7 
Planned interim analysis and data monitoring ........................................................... 144 
10.8 
Determination of sample size ..................................................................................... 145 
10.8.1 
Dose escalation modules .................................................................................... 145 
10.8.2 
Expansion modules ............................................................................................ 145 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS. 146 
11.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ....................... 146 
11.1.1 
Regulatory and ethical considerations ............................................................... 146 
11.1.2 
Financial disclosure ........................................................................................... 147 
11.1.3 
Informed consent process .................................................................................. 147 
11.1.4 
Data protection ................................................................................................... 147 
11.1.5 
Committees structure ......................................................................................... 148 
11.1.6 
Data quality assurance ....................................................................................... 148 
11.1.6.1 
Electronic Case Report Form completion ............................................... 148 
11.1.7 
Source documents .............................................................................................. 149 
11.1.8 
Study and site closure ........................................................................................ 149 
11.1.9 
Publication policy .............................................................................................. 150 
11.2 
Appendix 2: Clinical laboratory tests ........................................................................ 151 
11.3 
Appendix 3: Adverse events – Definitions and procedures for recording, evaluating, 
follow-up, and reporting ............................................................................................ 154 
11.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 159 
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11.5 
Appendix 5: Genetics ................................................................................................. 163 
11.6 
Appendix 6: Rapid Alert Procedures ......................................................................... 164 
11.7 
Appendix 7: Country-specific Requirements............................................................. 166 
11.8 
Appendix 8: ECOG Performance Status Scale .......................................................... 166 
11.9 
Appendix 9: RECIST v1.1 guidelines ....................................................................... 166 
11.9.1 
Measurability of tumor at Baseline .................................................................... 166 
11.9.2 
Objective response status at each evaluation ..................................................... 168 
11.10 Appendix 10: Abbreviations and Trademarks ........................................................... 172 
11.11 Appendix 11: Protocol amendment history ............................................................... 175 
Amendment 5 (14 Jan 2022) .............................................................................................. 175 
Amendment 4 (17 June 2021) ............................................................................................ 176 
Amendment 3 (07 Jan 2021) .............................................................................................. 182 
Amendment 2 (12 Oct 2020) ............................................................................................. 183 
Amendment 1 (11 Jun 2020) ............................................................................................. 186 
12 REFERENCES .............................................................................................................. 192 
SPONSOR DECLARATION ................................................................................................ 195 
 
LIST OF TABLES 
Table 1-1: 
Objectives and endpoints for the dose escalation module (Part A) and the 
dose optimization module (Part A1) ................................................................ 13 
Table 1-2: 
Objectives and endpoints for the dose escalation modules in Part B and 
Part C ............................................................................................................... 14 
Table 1-3: 
Objectives and endpoints for the expansion modules in Parts D, E, F, and 
G ....................................................................................................................... 15 
Table 1-4: 
Schedule of Activities for Part A (monotherapy dose escalation) ................... 24 
Table 1-5: 
Schedule of Activities for Part A1 – Cohorts 1, 2, 4 ....................................... 29 
Table 1-6: 
Schedule of Activities for Part A1 – Cohort 3 ................................................. 32 
Table 1-7: 
Schedule of Activities for Part B ..................................................................... 35 
Table 1-8: 
Schedule of Activities for Part C ..................................................................... 39 
Table 3-1: 
Objectives and endpoints for the dose escalation module (Part A) and the 
dose optimization module (Part A1) ................................................................ 45 
Table 3-2: 
Objectives and endpoints for the dose escalation modules in Part B and 
Part C ............................................................................................................... 46 
Table 3-3: 
Objectives and endpoints for the expansion modules in Parts D, E, F, and 
G ....................................................................................................................... 47 
Table 4-1: 
Study modules for dose escalation and expansion ........................................... 48 
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Table 4-2: 
Part B dose escalation/de-escalation schema for mTPI designa ...................... 59 
Table 4-3: 
Part C dose escalation/de-escalation schema for mTPI designa ...................... 62 
Table 4-4: 
TFD/TPI dosage calculation ............................................................................ 67 
Table 4-5: 
mFOLFOX6 dosing ......................................................................................... 68 
Table 5-1: 
Study population .............................................................................................. 68 
Table 6-1: 
Treatments administered in Part A .................................................................. 83 
Table 6-2: 
Treatments administered in Part A1 ................................................................ 84 
Table 6-3: 
Study treatments in Part B ............................................................................... 84 
Table 6-4: 
Treatments administered in Part C ................................................................... 87 
Table 6-5: 
Dose escalation steps and justification (Part A) .............................................. 95 
Table 6-6: 
Planned dose optimization scheme for Part A1 ............................................... 97 
Table 6-7: 
Dose escalation steps and justification (Part B) ............................................... 98 
Table 6-8: 
TFD/TPI dose interruption and resumption criteria for hematological 
toxicities ........................................................................................................... 99 
Table 6-9: 
TFD/TPI dose modifications in case of hematological and non-
hematological toxicities ................................................................................... 99 
Table 6-10: 
TFD/TPI dose reductions according to body surface area ............................. 100 
Table 6-11: 
Dose escalation steps and justification (Part C) ............................................. 101 
Table 6-12: 
mFOLFOX6 dosing ....................................................................................... 102 
Table 6-13: 
Dose modification for oxaliplatin-related neurological toxicity .................... 103 
Table 6-14: 
Dose modification for hematological toxicity ............................................... 103 
Table 6-15: 
Dose modification for non-hematological, non-neurological toxicity ........... 104 
Table 7-1: 
Bundle Branch Block discontinuation criteria ............................................... 108 
Table 9-1: 
Total blood volume collected during Cycle 1 of Part A ................................ 112 
Table 9-2: 
Total blood volume collected during Cycle 1 of Part A1 .............................. 113 
Table 9-3: 
Total blood volume collected during Cycle 1 of Parts B and C .................... 114 
Table 9-4: 
Blood collection time points for PK analysis for Part A ............................... 122 
Table 9-5: 
Blood collection time points for PK analysis for Part A1 ............................. 123 
Table 9-6: 
Blood collection time points for PK analysis for Part B and Part C .............. 124 
Table 9-7: 
Sample time points for serum gremlin-1 analysis in Part A .......................... 127 
Table 9-8: 
Sample time points for serum gremlin-1 analysis in Part A1 ........................ 127 
Table 9-9: 
Sample time points for serum gremlin-1 analysis in Part B and Part C ........ 128 
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Table 9-10: 
Sample time points for serum protein analysis and blood transcriptomics 
in Part A ......................................................................................................... 128 
Table 9-11: 
Sample time points for serum protein analysis and blood transcriptomics 
in Part A1 ....................................................................................................... 129 
Table 9-12: 
Sample time points for ctDNA analysis in Part A ......................................... 129 
Table 9-13: 
Sample time points for ctDNA analysis in Part A1 ....................................... 130 
Table 9-14: 
Sample time points for ctDNA analysis in Part B and Part C ....................... 130 
Table 9-15: 
Blood samples for serum bone turnover markers in Part A ........................... 131 
Table 9-16: 
Blood samples for serum bone turnover markers in Parts B and C ............... 131 
Table 9-17: 
Urine samples for urinary bone turnover markers in Part A .......................... 132 
Table 9-18: 
Urine samples for urinary bone turnover markers in Parts B and C .............. 132 
Table 9-19: 
Blood sample time points for ADA analysis in Part A .................................. 135 
Table 9-20: 
Blood sample time points for ADA analysis in Part A1 ................................ 135 
Table 9-21: 
Blood sample time points for ADA analysis in Part B and Part C ................ 136 
Table 10-1: 
Pharmacokinetic parameters .......................................................................... 141 
 
LIST OF FIGURES 
Figure 1-1: 
ONC001 study design ...................................................................................... 19 
Figure 1-2: 
ONC001 Part A cohorts ................................................................................... 20 
Figure 1-3: 
ONC001 Part A1 .............................................................................................. 21 
Figure 1-4: 
ONC001 Part B ................................................................................................ 22 
Figure 1-5: 
ONC001 Part C ................................................................................................ 23 
Figure 4-1: 
Dose escalation decision making: no DLT observed in sentinel participant ... 53 
Figure 4-2: 
Dose escalation decision making: DLT observed in sentinel participant ........ 54 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: A Phase 1/2 open-label, multicenter study to assess the safety, pharmacokinetics 
(PK), and antitumor activity of UCB6114 administered intravenously (iv) to participants with 
advanced solid tumors. 
Short Title: An open-label, multicenter, first in human (FIH) study in participants with 
advanced solid tumors treated with UCB6114. 
Rationale: Gremlin-1, secreted by the tumor stroma, binds to bone morphogenetic proteins 
(BMPs) and antagonizes signaling, thereby allowing tumor cell expansion, renewal, and a more 
mesenchymal phenotype. By blocking this gremlin-1 BMP antagonism, UCB6114 is expected to 
restore BMP signaling, limit tumor cell expansion, and favor a more epithelial phenotype. 
Gremlin-1 messenger ribonucleic acid (mRNA) has been shown to be expressed in >60% of 
colorectal, pancreatic, and esophageal cancer cases and approximately 50% of bladder, breast, 
and lung cancer cases (Sneddon et al, 2006). It has also been shown to be a key driver in 
hereditary mixed polyposis syndrome (HMPS) (Jaeger et al, 2012), a rare and severe 
premalignant condition characterized by the development of mixed morphology colorectal 
tumors. Despite advances in the treatment regimens in the last decade, there is still a large unmet 
need in the therapy of cancer types mentioned above. For example, in colorectal cancer (CRC), 
nearly 25% will present with metastatic disease and 40% to 50% of those initially diagnosed 
with early-stage disease will eventually develop metastatic disease (Moriarity et al, 2016). 
UCB6114 is a fully human immunoglobulin G4 (IgG4) monoclonal antibody (mAb), optimized 
for neutralizing activity against the human gremlin-1 protein, for the treatment of advanced solid 
tumors. Based on the mechanism of action of UCB6114 and previously generated nonclinical 
data, it is believed that UCB6114 could potentially represent an advance in the treatment of 
advanced solid tumors. This supports the testing of the objectives of this FIH study, which are to 
evaluate the safety, PK, and antitumor activity of iv UCB6114 and identify the recommended 
Phase 2 dose (RP2D) for UCB6114 when administered as monotherapy or in combination with 
standard of care (SOC) in participants with advanced solid tumors. 
Objectives and endpoints 
Study objectives and endpoints for the dose escalation and expansion modules are presented in 
Table 1-1 (Part A and Part A1), Table 1-2 (Part B and Part C), and Table 1-3 (Parts D, E, F, and 
G), respectively. The overarching objective of this study is to determine the RP2D for 
monotherapy (RP2D-M) and for combination therapy. This will be determined using the totality 
of data generated based on the objectives in Table 1-1 (Part A and Part A1), Table 1-2 (Part B 
and Part C), and Table 1-3 (Parts D, E, F, and G). 
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Table 1-1: 
Objectives and endpoints for the dose escalation module (Part A) 
and the dose optimization module (Part A1) 
Objectives 
Endpoints 
Primary 
To characterize the safety profile of UCB6114 as 
monotherapy  
Incidence of TEAEs 
Severity of TEAEs 
Incidence of DLTs 
Secondary 
To characterize the PK of UCB6114 administered 
as monotherapy  
UCB6114 concentration by scheduled assessment 
and cohort 
Tertiary/exploratory 
To document any antitumor activity observed with 
UCB6114 according to relevant RECIST criteria 
Antitumor activity as indicated by:  
• 
ORR 
• 
DCR 
• 
DOR 
• 
PFS 
• 
OS 
To explore PD biomarkers of UCB6114 
• 
Change in transcriptional and protein marker 
levels in blood and tumor tissue by scheduled 
assessment and cohort 
• 
Change in ctDNA levels in blood by scheduled 
assessment and cohort 
To evaluate the incidence, emergence, and impact 
of ADA 
ADA (anti-UCB6114 antibody) titer and sample 
status by scheduled assessment 
ADA=antidrug antibody; ctDNA= circulating tumor DNA; DCR=disease control rate; DOR=duration of antitumor 
response; DLT=dose-limiting toxicity; ORR=objective response rate; OS=overall survival; 
PD=pharmacodynamic(s); PFS=progression-free survival; PK=pharmacokinetic(s); RECIST=Response 
Evaluation Criteria in Solid Tumors; TEAE=treatment-emergent adverse event 
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Table 1-2: 
Objectives and endpoints for the dose escalation modules in Part B 
and Part C 
Objectives 
Endpoints 
Primary 
To characterize the safety profile of UCB6114 
administered in combination with selected SOC 
regimens  
Incidence of TEAEs 
Severity of TEAEs 
Incidence of DLTs 
Secondary 
To characterize the PK of UCB6114 administered 
in combination with selected SOC regimens 
UCB6114 concentration by scheduled assessment 
and dose level 
Tertiary/exploratory 
To document any antitumor activity observed with 
UCB6114 administered in combination with 
selected SOC regimens according to relevant 
RECIST criteria  
Antitumor activity as indicated by: 
• 
ORR 
• 
DCR 
• 
DOR 
• 
PFS 
• 
OS 
To explore PD biomarkers of UCB6114 
administered in combination with selected SOC 
regimens 
• 
Change in protein marker levels in blood by 
scheduled assessment and dose level 
• 
Change in ctDNA levels in blood by scheduled 
assessment and dose level 
To evaluate the immunogenicity of UCB6114 
administered in combination with selected SOC 
regimens 
ADA (anti-UCB6114 antibody) titer and sample 
status by scheduled assessment 
ADA=antidrug antibody; ctDNA= circulating tumor DNA; DCR=disease control rate; DLT=dose-limiting toxicity; 
DOR=duration of antitumor response; ORR=objective response rate; OS=overall survival; 
PD=pharmacodynamic(s); PFS=progression-free survival; PK=pharmacokinetic(s); RECIST=Response Evaluation 
Criteria in Solid Tumors; SOC=standard of care; TEAE=treatment-emergent adverse event 
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Table 1-3: 
Objectives and endpoints for the expansion modules in Parts D, E, F, 
and G 
Objectives 
Endpoints 
Primary 
To assess preliminary antitumor activity of 
UCB6114 when administered as monotherapy 
(Part D and Part E) or in combination with selected 
SOC regimens (Part F and Part G) according to 
relevant RECIST criteria 
Antitumor activity as indicated by ORR 
Secondary 
To characterize the safety profile of UCB6114 as 
monotherapy or in combination with selected SOC 
regimens 
• Incidence of TEAEs 
• 
Severity of TEAEs 
To document any antitumor activity observed with 
UCB6114 when administered as monotherapy or in 
combination with selected SOC regimens 
Antitumor activity as indicated by: 
• 
DCR 
• 
DOR 
• 
PFS 
• 
OS 
Tertiary/exploratory 
To explore PD biomarkers of UCB6114 
administered as monotherapy or in combination 
with selected SOC regimens 
Change in transcriptional and protein marker levels 
in blood and tumor tissue by scheduled assessment 
To characterize the PK of UCB6114 administered 
as monotherapy or in combination with selected 
SOC regimens 
UCB6114 concentration by scheduled assessment 
and dose level 
To evaluate the immunogenicity of UCB6114 
administered as monotherapy or in combination 
with selected SOC regimens 
ADA (anti-UCB6114 antibody) titer and sample 
status by scheduled assessment 
ADA=antidrug antibody; DCR=disease control rate; DOR=duration of antitumor response; ORR=objective response 
rate; OS=overall survival; PD=pharmacodynamic(s); PFS=progression-free survival; PK=pharmacokinetic(s); 
RECIST=Response Evaluation Criteria in Solid Tumors; SOC=standard of care; TEAE=treatment-emergent 
adverse event 
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Overall design 
ONC001 is a multicenter, nonrandomized, open-label, Phase 1/2 study evaluating the safety, PK, 
efficacy (as assessed by antitumor activity), pharmacodynamics (PD), biomarkers, and 
immunogenicity (as assessed by antidrug antibody[ADA] participant classification) of iv 
UCB6114 as monotherapy (Parts A, A1, D, and E) or in combination with selected SOC 
regimens (Parts B, C, F, and G) in participants with advanced solid tumors. The RP2D-M or 
RP2D of iv UCB6114 for each combination therapy under evaluation will also be determined. 
The study has a modular design including up to 3 dose escalation modules (Parts A, B, and C), 
1 dose optimization module (Part A1), and up to 4 expansion modules (Parts D, E, F, and G) 
(see Table 4-1). Depending on emerging data, not all modules may open. 
After completion of Part A, specific characteristics of modules subsequent to Part A will be 
described in planned protocol amendments. The updated characteristics will include, but not be 
limited to, tumor type selection, participant inclusion/exclusion criteria, route and frequency of 
study medication administration, and selection of the SOC treatment regimen. 
Part A consists of a Screening Period, Treatment Period (consisting of 28-day cycles), a Safety 
Follow-Up (SFU) Visit, and a Final Visit, as shown in Table 1-4 and Figure 1-2. During the 
Treatment Period, UCB6114 is administered by iv infusion on Days 1 and 15 of each cycle, until 
the occurrence of progressive disease, unacceptable toxicity, or withdrawal of consent. The full 
Schedule of Activities is provided in Table 1-4. 
Part A1 may commence after the fifth cohort in Part A (2000mg, every 2 weeks [Q2W]) has 
been determined to be 
 (ie, DLT incidence <33%, see Section 4.1.2.4). Based on emerging 
data from Part A, this module will evaluate different frequencies of dosing (eg, every 3 weeks 
[Q3W], every 4 weeks [Q4W]) and different durations of infusion (Figure 1-3). Four different 
dosing schedules (cohorts) have been defined:  
• Cohort 1: 2000mg Q2W (60-minute infusion), 28-day treatment cycle 
• Cohort 2: 2000mg Q2W (30-minute infusion), 28-day treatment cycle 
• Cohort 3: 3000mg Q3W (90-minute infusion), 21-day treatment cycle 
• Cohort 4: 4000mg Q4W (120-minute infusion), 28-day treatment cycle 
In Part A1, as all cohorts will receive a new dose formulation, Cohort 1 will repeat the dosing 
schedule of Part A Cohort 5.  
Part A1 consists of a Screening Period, Treatment Period (consisting of 28-day cycles for 
Cohorts 1, 2, and 4, and of 21-day cycles for Cohort 3), a SFU Visit and a Final Visit. During the 
Treatment Period, UCB6114 is administered as iv infusion as per defined dosing schedules until 
the occurrence of progressive disease, unacceptable toxicity, or withdrawal from the study. The 
full Schedule of Activities is provided in Table 1-5 and Table 1-6. 
Part B consists of a Screening Period, Treatment Period (consisting of 28-day cycles), a SFU 
Visit, and a Final Visit, as shown in Table 1-7 and Figure 1-4 During the Treatment Period, 
UCB6114 will be administered in combination with trifluridine/tipiracil (TFD/TPI; TAS-102; 
Lonsurf®). UCB6114 will be administered as an iv infusion every 2 weeks (Q2W), while 
TFD/TPI will be administered orally twice daily (bid) within 1 hour of completion of morning 
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and evening meals on Days 1 to 5 and Days 8 to 12 (28-day cycle). For the convenience of the 
participants, TFD/TPI can be administered at home to allow for the 12-hour interval between 
TFD/TPI doses associated with meals. For administration at home on Cycle 1 Day 1, eligibility 
must be confirmed within 3 days prior to Day 1 dosing as per the Schedule of Assessments. 
Trifluridine/tipiracil will be administered at the recommended standard of care dose. The starting 
dose of UCB6114 in Part B will depend on the dose level evaluated in Cohort 3 of Part A 
(anticipated to be 500mg Q2W iv) and the emerging safety profile of UCB6114 monotherapy, 
including any overlapping toxicity with TFD/TPI. The full Schedule of Activities is provided in 
Table 1-7. 
Part C consists of a Screening Period, Treatment Period (consisting of 28-day cycles), a SFU 
Visit, and a Final Visit, as shown in Table 1-8 and Figure 1-5. During the Treatment Period, 
UCB6114 will be administered as an iv infusion Q2W followed by iv oxaliplatin, leucovorin, 
and 5-fluorouracil (FOLFOX) Q2W on a 28-day cycle. Modified FOLFOX 6 (mFOLFOX6) will 
be administered at the recommended standard of care dose: oxaliplatin 85mg/m2 iv infusion on 
Day 1, leucovorin 400mg/m2 iv infusion on Day 1, 5-fluorouracil 400mg/m2 iv bolus on Day 1, 
followed by 5-fluorouracil 1200mg/m2/day continuous infusion on Days 1 and 2 (2400mg/m2 
over 46 hours). The starting dose of UCB6114 in Part C will depend on the dose level evaluated 
in Cohort 3 of Part A (anticipated to be 500mg Q2W iv), and the emerging safety profile of 
UCB6114 monotherapy, including any overlapping toxicity with the mFOLFOX6 regimen. The 
full Schedule of Activities is provided in Table 1-8. 
If any participant withdraws early, the site will attempt to contact the participant and facilitate 
completion of the SFU Visit and the Final Visit. 
The end of the study is defined as the date of the Final Visit/last contact of the last participant in 
the study. 
Number of participants 
Overall, approximately 150 to 250 participants will be assigned to study treatment. Enrollment is 
anticipated to last 3 years. 
The planned number of study participants for each study part is provided below. 
Part A – Dose escalation (monotherapy) 
Up to 42 eligible participants will be assigned to study treatment. 
Part A1 – Dose optimization (monotherapy) 
Up to 32 eligible participants will be assigned to study treatment. 
Part B – Dose escalation (combination therapy) 
Up to 27 eligible participants will be assigned to each combination therapy regimen to be 
explored. 
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Part C – Dose escalation (combination therapy) 
Up to 27 eligible participants will be assigned to each combination therapy regimen to be 
explored. 
Part D and Part E – Monotherapy expansion 
Up to 15 eligible participants each will be assigned to study treatment in Part D and Part E. 
Up to 15 additional participants each may be enrolled in Part D and Part E (ie, a total sample size 
of up to 30 participants in each expansion cohort, depending on emerging data). 
Part F and Part G – Combination therapy expansion 
Up to 15 eligible participants each will be assigned to study treatment in Part F and Part G. 
Up to 15 additional participants each may be enrolled in Part F and Part G (ie, a total sample size 
of up to 30 participants in each expansion cohort, depending on emerging data). 
Treatment groups and duration 
Participants will continue treatment with study medication until disease progression, 
unmanageable toxicity, criteria for discontinuation are met, or withdrawal of consent. 
Where possible, participants will attend an SFU Visit approximately 30 days after 
discontinuation of study treatment and a Final Visit approximately 3 months after 
discontinuation of study treatment. The Final Visit may be undertaken by phone, where 
applicable. 
1.2 
Schema 
A schematic of the study design is shown in Figure 1-1 and a detailed description of Part A is 
shown in Figure 1-2. A detailed schematic of Part A1 is shown in Figure 1-3. A detailed 
schematic of Part B is shown in Figure 1-4. A detailed schematic of Part C is shown in 
Figure 1-5. 
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Figure 1-1: ONC001 study design 
 
FIH=first in human; FOLFOX=oxaliplatin, leucovorin, and 5-fluorouracil regimen; PAC3=Part A Cohort 3; PD=pharmacodynamics; PK=pharmacokinetics; 
RP2D-F=Recommended phase 2 dose in combination with FOLFOX; RP2D-M=Recommended phase 2 dose for monotherapy based on acceptable safety and 
tolerability profile and PK, may also include available PD data; RP2D-T=Recommended phase 2 dose in combination with TFD/TPI; TBD=to be determined; 
TFD/TPI=trifluridine/tipiracil 
Dose optimization
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Figure 1-2: ONC001 Part A cohorts 
 
d=days; iv=intravenous; PK=pharmacokinetic(s); Q2W=every 2 weeks; SMC=Safety Monitoring Committee 
Note: The SMC may add up to 2 additional cohorts based on emerging data, not to exceed 2000mg iv Q2W. 
 
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Figure 1-3: ONC001 Part A1 
 
D=day; iv=intravenous; Q2W=every 2 weeks; Q3W=every 3 weeks; Q4W=every 4 weeks 
Pre-treatment 
period
Cycle 1 *
Subsequent Cycles * 
Safety 
Follow-up
Up to 28 days
Baseline
Assessments
Cohort 1: n=1+7
UCB6114 iv 2000mg, 60-minute infusion
D1 +  D15
Up to 30 days
Cohort 3: n=1+7
UCB6114 iv 3000mg, 90-minute infusion
D1 
Sentinel 
assessment 
period
48 hours
Cohort 4: n=1+7
UCB6114 iv 4000mg, , 120-minute infusion
D1 
Sentinel 
assessment 
period 
48 hours
Cohort 2: n=1+7
UCB6114 iv 2000mg 30-minute infusion
D1 + D15 
Cohort 1:
UCB6114 iv 2000mg 
Q2W in 28 Day Cycles
Cohort 2:
UCB6114 iv 2000mg 
Q2W in 28 Day Cycles
Cohort 3:
UCB6114 iv 3000mg
Q3W in 21 Day Cycles
Cohort 4:
UCB6114 iv 4000mg
Q4W in 28 Day Cycles
* Cohorts 1, 2, and 4: 28-day treatment cycles; Cohort 3: 21-day treatment cycles 
Sentinel 
assessment 
period 
48 hours
Treatment Period
Sentinel 
assessment 
period 
48 hours
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Figure 1-4: ONC001 Part B 
 
bid=twice daily; D=Day; DLT=dose-limiting toxicity; iv=intravenous; mTPI= modified toxicity probability interval; po=oral; TFD/TPI=trifluridine/tipiracil 
*Dose must not exceed 80mg/dose 
Notes: Dose levels may have more than 1 cohort. 
Escalation to the next dose level or de-escalation to the previous dose level will be guided by the mTPI algorithm. 
 
Dose level 1
Dose level 2
Dose level 3
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Figure 1-5: ONC001 Part C 
 
D=Day; DLT=dose-limiting toxicity; mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 and Day 2, 
and oxaliplatin 85mg/m2 on Day 1; iv=intravenous; Q2W=every 2 weeks; mTPI= modified toxicity probability interval 
Notes: Dose levels may have more than 1 cohort. 
Escalation to the next dose level or de-escalation to the previous dose level will be guided by the mTPI algorithm. 
 
Dose level 1
Dose level 2
Dose level 3
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1.3 
Schedule of Activities 
The Schedule of Activities for Part A (monotherapy dose escalation) is provided in Table 1-4.  
Table 1-4: 
Schedule of Activities for Part A (monotherapy dose escalation) 
Assessments 
Screeninga 
Treatmenta 
SFU Visita 
Final 
Visita 
 
-28 
to -
1 
-14 
to -1 
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 onwardsc 
(28 days) 
Within 
30 days 
after last 
dosef 
3 months 
after last 
dosef 
Cycle day 
1d 
2/3 
8 
15d/16 
22 
1d 
8 
15d 
22e 
1d 
15d 
22 
Informed consent g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
Xee 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data and 
height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/cancer 
history/ 
concomitant disease 
and current medical 
status. 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG
h 
 
X 
X 
 
X 
Xz 
X 
X 
 
X 
 
X 
X 
 
X 
 
Pregnancy test, if 
applicablei 
 
X 
X 
 
 
Xz 
 
X 
 
X 
 
X 
X 
 
X 
X 
Study medication 
(UCB6114) 
administrationj 
 
 
X 
 
 
Xz 
 
X 
 
X 
 
X 
X 
 
 
 
Physical examination 
and weightgg 
 
X
k 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Vital signs (BP, HR, 
RR, and temperature) l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
ECOG performance 
status 
 
X 
X 
 
X 
Xz 
X 
X 
 
X 
 
X 
X 
 
X 
 
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Table 1-4: 
Schedule of Activities for Part A (monotherapy dose escalation) 
Assessments 
Screeninga 
Treatmenta 
SFU Visita 
Final 
Visita 
 
-28 
to -
1 
-14 
to -1 
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 onwardsc 
(28 days) 
Within 
30 days 
after last 
dosef 
3 months 
after last 
dosef 
Cycle day 
1d 
2/3 
8 
15d/16 
22 
1d 
8 
15d 
22e 
1d 
15d 
22 
Urinalysism 
 
X
k 
X
k 
 
 
Xz 
 
X 
 
X 
 
X 
X 
 
X 
 
Urinalysis for urinary 
markers of bone 
turnovern 
 
 
X 
 
 
Xz 
  
X 
 
 
 
X 
 
 
X 
 
Hematology 
 
X
k 
X
k 
 
X 
Xz 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Blood chemistry 
 
X
k 
X
k 
 
X 
Xz 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Coagulation 
 
X
k 
X
k 
 
 
Xz 
 
X 
 
 
 
X 
 
 
X 
 
Blood collection for 
serum markers of bone 
turnover n 
 
 
X 
  
 
Xz 
 
X 
 
 
 
X 
 
 
X 
 
Blood collection for 
immunogenicity 
(ADA)p,q,r 
 
 
Xr 
 
 
Xz 
X 
X 
 
 
 
X 
 
 
X 
 
Blood collection for 
circulating gremlin-1 
analysisn, r,dd 
 
 
X 
X
s 
 
Xz 
 
X 
 
 
 
X 
 
 
X 
 
Blood collection for 
serum 
protein/proteomic 
analysisn 
 
 
X 
 
 
Xz 
 
X 
 
 
 
X 
 
 
X 
 
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Table 1-4: 
Schedule of Activities for Part A (monotherapy dose escalation) 
Assessments 
Screeninga 
Treatmenta 
SFU Visita 
Final 
Visita 
 
-28 
to -
1 
-14 
to -1 
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 onwardsc 
(28 days) 
Within 
30 days 
after last 
dosef 
3 months 
after last 
dosef 
Cycle day 
1d 
2/3 
8 
15d/16 
22 
1d 
8 
15d 
22e 
1d 
15d 
22 
Blood collection for 
transcriptomic analysisn 
 
 
X 
 
 
Xz 
 
X 
 
 
 
X 
 
 
X 
 
Blood collection for 
genetic analysis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for 
ctDNA analysis 
 
 
X 
 
 
Xz 
 
X 
 
 
 
Xaa 
 
 
X 
 
Echocardiogram 
 
X 
 
 
 
 
 
X 
 
 
 
Xbb 
 
 
X 
 
Tumor assessmentscc 
X
t 
 
 
 
 
 
 
 
 
 
X
u 
 
 
X
v 
Xcc 
 
Tumor biopsy for PD 
analysisw 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Historical tumor sample 
(from prior to entry into 
study) if availablex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
Recorded throughout 
X 
 
Adverse events 
(including DLT in 
Cycle 1) 
X 
X 
Recorded throughout 
X
y 
 
Survival censusff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine transaminase; ANC=absolute neutrophil count; AST=aspartate transaminase; 
COVID-19=SARS-CoV2 (COVID-19) pandemic; CR=complete response; CT=computed tomography; ctDNA=circulating tumor DNA; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; h=hours; hCG=human chorionic gonadotropin; iv=intravenous; 
LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PD=pharmacodynamic(s); PK=pharmacokinetic(s); PR=partial response; PSA=prostate 
specific antigen; RBC=red blood cell; SFU=Safety Follow-Up; SMC=Safety Monitoring Committee; WBC=white blood cell 
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a Allowed visit window: ± 2 days (unless specified otherwise). Note: Day 2 of Cycle 1 must occur on the scheduled day relative to Day 1, due to the 
PK sampling. See PK schedule for allowed sample windows for PK. If needed in context of the COVID-19 pandemic, assessments currently scheduled for 
Day -28 to Day-1 and assessments scheduled for Screening Days -14 to -1 may be combined into 1 visit conducted within 14 days of first dose.  
b Deleted. 
c From Cycle 3 and Cycle 4 onwards, visits on Day 22 may be omitted at the discretion of the investigator and based on toxicity seen at Cycle 1 and 2, unless 
these visits were required for tumor assessments, or participant assessment. 
d The following safety assessments will be performed predose: physical examination, vital signs, hematology, blood chemistry, coagulation, urinalysis, 
pregnancy testing, ECOG performance status, echocardiograms, and ECG. All other safety assessments will be performed postdose.  
e The visit on Day 22 may take place at any point from Day 21 to Day 28 of Cycle 2; tumor assessments should take place within this window at the 
investigator’s discretion. 
f When participants are unable to attend the SFU or Final Visit, it will not be considered a protocol deviation. 
g Informed consent must be given before any study-specific Screening procedures are performed. 
h ECGs are to be performed in triplicate with the participant in a supine position after a minimum of 5 min rest. When ECG coincides with PK (and PD), the 
ECG should be performed first. On Days 1 and 15 of Cycle 1, triplicate ECGs should be performed 3 times: the first predose; the second at the end of the 
infusion; and the third 8 hours after the end of the infusion. For all other cycles, triplicate ECGs should be performed predose. 
I Pregnancy tests measure serum or urine ß-hCG. Serum tests should be performed at Screening and visit immediately before the investigational product 
administration on Day 1 Cycle 1. Serum or urine pregnancy tests must be performed prior to dosing on dosing days. Additional pregnancy tests should also be 
performed during the study if indicated. 
j UCB6114 is administered as an iv infusion on Days 1 and 15 of each cycle, until the occurrence of progressive disease, unacceptable toxicity, or withdrawal of 
consent. 
k Physical examination, weight, and laboratory tests (hematology, blood chemistry, coagulation, and urinalysis), may be repeated within 72h prior to Cycle 1 Day 
1 for any borderline assessments identified at Days -14 to -3. Laboratory tests (hematology, blood chemistry, coagulation, and urinalysis) do not have to be 
repeated on Day 1 predose if performed within 72h of starting dosing. Laboratory tests (hematology, blood chemistry, coagulation, and urinalysis) may be 
obtained 24h prior to the scheduled visit and may be obtained at local laboratories. 
l Vital signs on treatment days will be assessed at multiple time points in a semi-supine position after 5 minutes of rest: predose, 10min (±5min) and 30min 
(±10min) after the start of the infusion, at the end of the infusion (+15min); and at 1h (+15min) after the end of the infusion. In addition, on Cycle 1 Day 1 vital 
signs will also be assessed at 2 hours (+1h) and 8 hours (+2h) after the end of the infusion, to correspond with PK time points; vital signs will be assessed prior 
to collection of PK samples. 
m Urinalysis parameters include specific gravity, pH, glucose, protein, ketones, blood, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick. If there are 
abnormalities in urine dipstick blood or protein results, microscopic analysis should be performed (including crystals). 
n Samples will only be collected up to and including Cycle 4. 
q At visits where UCB6114 is administered, ADA samples will be collected predose as described in Section 9.10. 
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r The Cycle 1 predose samples may be used for data integrity and assay verification purposes. 
s The sample will be collected on Day 2 only. 
t Screening tumor assessments including contrast–enhanced spiral CT or MRI scan of the chest, abdomen, pelvis, and any other areas of known or suspected 
disease, must be obtained within 42 days prior to starting study medication. If there is a contraindication to iodinated iv contrast, chest CT should be performed 
without iv contrast and MRI scans (with gadolinium chelate contrasts) of the abdomen and pelvis may be used instead of CT scans of the abdomen and pelvis. 
A CT or MRI scan that is dated prior to consent (up to 42 days prior to starting study medication) for this study may be used as the Screening assessment, 
where this has been performed as per standard care or at the end of a prior research study. The same method of assessment is to be used per participant for the 
duration of study participation. 
u Further tumor assessments are to be performed between Days 21 and 28 of every even cycle (±2 days). 
v Tumor assessments are to be completed on even cycles. 
w If there are accessible tumor lesions, optional biopsies may be performed at Screening and at Cycle 1 Day 22. The allowed time-window for collection of the 
Cycle 1 Day 22 sample is from Cycle 1 Day 22 up to Cycle 2 Day 22. 
x If an historical tumor biopsy specimen obtained prior to the participant’s entry into the study (eg, at the time of diagnosis) is available, samples of this tissue 
will be requested for PD analysis. 
y Follow-up of AEs: AEs will be recorded up to 30 days after the last dose of study medication. After that time, any unresolved drug-related AEs should be 
followed until resolution or stabilization of the AE to obtain the date of resolution/stabilization (this follow-up can be via routine clinic visits or correspondence 
with a treating physician or other healthcare professional). 
z Assessed on Day 15 only of Cycle 1. 
aa Only at Day 1 of Cycle 3. 
bb Echocardiograms are to be completed on even cycles from Cycle 3 onwards. 
cc Tumor assessment at SFU is not required if the participant has withdrawn due to progressive disease or if the previous tumor assessment was within 42 days of 
SFU visit. 
dd At visits where UCB6114 is administered, circulating gremlin-1 samples will be collected predose as described in Section 8.8.1. 
ee Cycle 1 Day 1, the eligibility assessment will be performed predose. 
ff Survival census will be performed at SFU and participants will also be contacted to ascertain their survival status 3 months after last dose. 
gg A complete physical examination is to be performed at Screening and on Cycle 1 Day 1 predose. Physical examinations will be symptom-directed and 
performed prior to administration of UCB6114 on all other visits.  
 
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The Schedule of Activities for Part A1 (monotherapy dose optimization) is provided in Table 1-5 (Cohorts 1, 2 and 4) and Table 1-6 
(Cohort 3).  
Table 1-5: 
Schedule of Activities for Part A1 – Cohorts 1, 2, 4 
Assessments 
Screening 
Treatment 
SFU Visit 
Final Visit 
 
-28 
to -1 
-14 
to -1 
Cycle 1 
(28 days) 
Cycle 2  
(28 days) 
Cycle 3 
onwards 
(28 days) 
Within 
30 days after 
last dose 
3 months 
after last 
dose 
Cycle day 
1 
15 
1 
15 
1 
15 
 
 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessmentb 
X 
X 
X 
 
 
 
 
 
 
 
Demographic data and height 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/cancer history/ 
concomitant disease and current medical status. 
X 
 
X 
 
 
 
 
 
 
 
ECG
c 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy test, if applicabled 
X 
 
X 
 
X 
 
X 
 
X 
X 
UCB6114 - Cohort 1 (Q2W) 
 
 
X 
X 
X 
X 
X 
X 
 
 
UCB6114 – Cohort 2 (Q2W) 
 
 
X 
X 
X 
X 
X 
X 
 
 
UCB6114 – Cohort 4 (Q4W) 
 
 
X 
 
X 
 
X 
 
 
 
Physical examination and weighte 
X 
 
X 
X 
X 
X 
X 
X f 
X 
 
Vital signs (BP, HR, RR, and temperature)g 
X 
 
X 
X 
X 
X  
X 
X f 
X 
 
ECOG performance status 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysish 
X 
 
X 
X 
X 
X 
X 
X f 
X 
 
Hematologyi 
X 
 
X 
X  
X 
X  
X 
X f 
X 
 
Chemistryi 
X 
 
X 
X 
X 
X 
X 
X f 
X 
 
Coagulationi 
X 
 
X 
 
X 
 
X 
 
X 
 
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Table 1-5: 
Schedule of Activities for Part A1 – Cohorts 1, 2, 4 
Assessments 
Screening 
Treatment 
SFU Visit 
Final Visit 
 
-28 
to -1 
-14 
to -1 
Cycle 1 
(28 days) 
Cycle 2  
(28 days) 
Cycle 3 
onwards 
(28 days) 
Within 
30 days after 
last dose 
3 months 
after last 
dose 
Cycle day 
1 
15 
1 
15 
1 
15 
 
 
Echocardiogramj 
X 
 
 
 
 
 
X 
 
X 
 
Immunogenicity (ADA)l 
 
 
X 
 
X 
 
X 
 
X 
 
Tumor assessmentm 
X 
 
Every 8 weeks from Day 1 
X 
 
Concomitant medication  
X 
 
Recorded throughout 
X 
 
Adverse Events (including DLT in Cycle 1)n 
X 
 
Recorded throughout 
X 
 
Survival census 
 
 
 
 
 
 
 
 
X 
X 
Biomarker analyses 
 
 
 
 
 
 
 
 
 
 
Blood collection for circulating gremlin-1 
analysiso 
 
 
X 
X 
X 
 
X 
 
X 
 
Blood collection for serum protein/proteomic 
analysisp 
 
X 
 
X 
X 
 
X 
 
X 
 
Blood collection for transcriptomic analysisp 
 
X 
 
X 
X 
 
X 
 
X 
 
Blood collection for genetic analysis 
 
X 
 
 
 
 
 
 
 
 
Blood collection for ctDNA analysis 
 
X 
 
X 
X 
 
X 
 
X 
 
Tumor biopsy for PD analysisq 
X 
 
 
X 
 
 
 
 
 
 
Historical tumor sample (from prior to entry 
into study) if availabler 
X 
 
 
 
 
 
 
 
 
 
ADA=anti-drug antibodies; AE=adverse event; BP= blood pressure; CT=computed tomography; ctDNA=circulating tumor DNA; h=hours; DLT=Dose limiting 
toxicity; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; HR=heart rate; min=minutes; MRI=magnetic resonance imaging; 
PD=pharmacodynamic(s); PK=pharmacokinetic(s); Q2W=every 2 weeks; Q4W=every 4 weeks; RR= respiratory rate; SFU=Safety Follow Up;  
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Note: The allowed visit window is ± 2 days (unless specified otherwise). All assessments are to be performed prior to dosing with UCB6114 (unless specified 
otherwise) 
a Informed consent must be given before any study-specific Screening procedures are performed. 
b Eligibility must be confirmed prior to proceeding to tumor biopsy and on Cycle 1 Day 1 prior to dosing with UCB6114. 
c ECGs are to be performed at screening; during Cycle 1 prior to dosing, at the end of the infusion, and 2h after the end of infusion; during each subsequent cycle 
prior to dosing with UCB6114 on Day 1. Electrocardiograms are to be performed in triplicate with the participant in a supine position after a minimum of 5min 
rest. When ECG coincides with PK (and PD), the ECG should be performed first. 
d Serum pregnancy test must be performed at screening. Serum or urine pregnancy test must be performed prior to dosing on Day 1 of each cycle. Additional 
pregnancy tests should also be performed during the study if indicated. 
e A complete physical examination is to be performed at Screening and on Cycle 1 Day 1 prior to dosing with UCB6114. Physical examination will be symptom-
directed and performed prior to administration of UCB6114 on all other visits.  
f Assessments to be performed on dosing day only. Not applicable for Cohort 4. 
g On treatment days, vital signs will be assessed at multiple time points in a semi-supine position after 5min of rest: prior to dosing, 10min (±5min) and 30min 
(±10min) after the start of the infusion, at the end of the infusion (+15min) and 2h after the end of the infusion (+15min). In addition, on Cycle 1 Day 1, vital 
signs will also be assessed at 5h (+2h) after the end of the infusion. Vital signs will be assessed prior to collection of PK samples. 
h If there are abnormalities in urine dipstick, a microscopic analysis should be performed (including crystals). Urinalysis does not have to be repeated on Cycle 1 
Day 1 predose if performed within 72h of starting dosing. 
i Laboratory tests (hematology, blood chemistry, and coagulation) do not have to be repeated on Day 1 predose if performed within 72h of starting dosing. They 
may be obtained 24h prior to the scheduled visit and may be obtained at local laboratories. 
j During the treatment period, echocardiograms are to be completed at the beginning of Cycle 3 (± 7 days), as clinically indicated afterwards, and at the SFU 
Visit.  
l Immunogenicity (ADA) samples will be collected on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of every third cycle thereafter (i.e. cycle 6, 9 
etc.) and at the SFU Visit. 
m Tumor assessments including spiral CT or MRI scan of the chest, abdomen, and any other area of known or suspected disease, must be obtained at Screening. 
A CT or MRI scan that is dated prior to consent (up to 42 days prior to starting IMP) for this study may be used as the Screening assessment, where this has 
been performed as per standard of care or at the end of a prior study. The same method of assessment is to be used per participant for the duration of study 
participation. Tumor assessments are to be performed every 8 weeks from Day 1 (± 7 days). Tumor assessment at SFU is not required if the participant has 
withdrawn due to progressive disease or if the previous tumor assessment was within 42 days of SFU visit. 
n Follow-up of AEs: AEs will be recorded up to 30 days after the last dose of study medication. After that time, any unresolved drug-related AEs should be 
followed until resolution or stabilization of the AE to obtain the date of resolution/stabilization (this follow-up can be via routine clinic visits or correspondence 
with a treating physician or other healthcare professional). 
o Blood samples for circulating gremlin-1 analysis will be collected at Cycle 1 Day 1, pre-dose (within 30 min prior to dosing), end of infusion (+15min), and 4h 
(+1h) post-infusion as well as at Day 15 at predose (within 30min prior to dosing) or on day of visit if a non-dosing day. At all subsequent cycles, blood 
samples will be collected at Day 1 predose (within 30min prior to dosing) and at the SFU Visit; for Cycle 3 only, an additional 4h (+1h) postdose sample 
should be taken on Day 1. An additional sample should also be collected on the day of on-treatment biopsy (only if taking place on a day where no PK samples 
are scheduled). 
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p To be confirmed based on Part A Cohorts 1 to 3 analysis. 
q Baseline biopsy should be collected between Day -28 and Day -1. Whenever possible, on-treatment biopsy should be performed within 2 weeks post Cycle 1 
Day 15 (ie, between Cycle 1 Day 15 and Cycle 2 Day 1). If on-treatment biopsy occurs a non-dosing day, an additional PK and an additional cGremlin-1 
samples should be collected on the day of biopsy. 
r If an historical tumor biopsy specimen obtained prior to the participant’s entry into the study (eg, at the time of diagnosis) is available, samples of this tissue 
will be requested for PD analysis at the time of consent. 
 
Table 1-6: 
Schedule of Activities for Part A1 – Cohort 3 
Assessments 
Screening 
Treatment 
SFU Visit 
Final Visit 
 
-28 
to -1 
-14 
to -1 
Cycle 1 
(21 days) 
Cycle 2  
(21 days) 
Cycle 3 
onward 
(21 days) 
Within 30 
days after last 
dose 
 
Cycle day 
1 
15 
1 
15 
1 
15 
 
 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessmentb 
X 
X 
X 
 
 
 
 
 
 
 
Demographic data and height 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/cancer history/ 
concomitant disease and current medical status. 
X 
 
X 
 
 
 
 
 
 
 
ECG
c 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy test, if applicabled 
X 
 
X 
 
X 
 
X 
 
X 
X 
UCB6114 - Schedule 3 (Q3W) 
 
 
X 
 
X 
 
X 
 
 
 
Physical examination and weighte 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital signs (BP, HR, RR, and temperature)f 
X 
 
X 
 
X 
 
X 
 
X 
 
ECOG performance status 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysisg 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematologyh 
X 
 
X 
 
X 
 
X 
 
X 
 
Chemistryh 
X 
 
X 
 
X 
 
X 
 
X 
 
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Table 1-6: 
Schedule of Activities for Part A1 – Cohort 3 
Assessments 
Screening 
Treatment 
SFU Visit 
Final Visit 
 
-28 
to -1 
-14 
to -1 
Cycle 1 
(21 days) 
Cycle 2  
(21 days) 
Cycle 3 
onward 
(21 days) 
Within 30 
days after last 
dose 
 
Cycle day 
1 
15 
1 
15 
1 
15 
 
 
Coagulationh 
X 
 
X 
 
X 
 
X 
 
X 
 
Echocardiogrami 
X 
 
 
 
 
 
X 
 
X 
 
Immunogenicity (ADA) 
 
 
X 
 
X 
 
Xk 
 
X 
 
Tumor assessmentl 
X 
 
Every 8 weeks from Day 1 
X 
 
Concomitant medication  
X 
 
Recorded throughout 
X 
 
Adverse Events (including DLT in Cycle 1)m 
X 
 
Recorded throughout 
X 
 
Survival census 
 
 
 
 
 
 
 
 
X 
X 
Biomarker studies 
 
 
 
 
 
 
 
 
 
 
Blood, collection for circulating gremlin-1 
analysisn 
 
 
X 
X 
X 
 
X 
 
X 
 
Blood collection for serum protein/proteomic 
analysiso 
 
X 
 
 
X 
 
X 
 
X 
 
Blood collection for transcriptomic analysiso 
 
X 
 
 
X 
 
X 
 
X 
 
Blood collection for genetic analysis 
 
X 
 
 
 
 
 
 
 
 
Blood collection for ctDNA analysis 
 
X 
 
 
X 
 
X 
 
X 
 
Tumor biopsy for PD analysisp 
X 
 
 
 
X 
 
 
 
 
 
Historical tumor sample (from prior to entry 
into study) if availableq 
X 
 
 
 
 
 
 
 
 
 
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ADA=anti-drug antibodies; AE=adverse event; BP= blood pressure; CT=computed tomography; ctDNA=circulating tumor DNA; h=hours; DLT=Dose limiting 
toxicity; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; HR=heart rate; min=minutes; MRI=magnetic resonance imaging; 
PD=pharmacodynamic(s); PK=pharmacokinetic(s); Q3W=every 3 weeks; RR= respiratory rate; SFU=Safety Follow Up;  
Note: The allowed visit window is ± 2 days (unless specified otherwise). All assessments are to be performed prior to dosing with UCB6114 (unless specified 
otherwise) 
a Informed consent must be given before any study-specific Screening procedures are performed. 
b Eligibility must be confirmed prior to proceeding to tumor biopsy and on Cycle 1 Day 1 prior to dosing with UCB6114. 
c ECGs are to be performed at screening; during Cycle 1 prior to dosing, at the end of the infusion, and 2h after the end of infusion; during each subsequent cycle 
prior to dosing with UCB6114 on Day 1. Electrocardiograms are to be performed in triplicate with the participant in a supine position after a minimum of 5min 
rest. When ECG coincides with PK (and PD), the ECG should be performed first. 
d Serum pregnancy test must be performed at screening. Serum or urine pregnancy test must be performed prior to dosing on Day 1 of each cycle. Additional 
pregnancy tests should also be performed during the study if indicated. 
e A complete physical examination is to be performed at Screening and on Cycle 1 Day 1 prior to dosing with UCB6114. Physical examination will be symptom-
directed and performed prior to administration of UCB6114 on all other visits.  
f On treatment days, vital signs will be assessed at multiple time points in a semi-supine position after 5min of rest: prior to dosing, 10min (±5min) and 30min 
(±10min) after the start of the infusion, at the end of the infusion (+15min) and 2h after the end of the infusion (+15min). In addition, on Cycle 1 Day 1, vital 
signs will also be assessed at 5h (+2h) after the end of the infusion. Vital signs will be assessed prior to collection of PK samples.  
g If there are abnormalities in urine dipstick, a microscopic analysis should be performed (including crystals). Urinalysis does not have to be repeated on Cycle 1 
Day 1 predose if performed within 72h of starting dosing. 
h Laboratory tests (hematology, blood chemistry, and coagulation) do not have to be repeated on Day 1 predose if performed within 72h of starting dosing. They 
may be obtained 24h prior to the scheduled visit and may be obtained at local laboratories.  
i During the treatment period, echocardiograms are to be completed at the beginning of Cycle 3 (± 7 days), as clinically indicated afterwards, and a the SFU 
Visit. 
k Immunogenicity (ADA) samples will be collected on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of every third cycle thereafter (i.e. cycle 6, 9 
etc.) as well as at the SFU Visit. 
l Tumor assessments including spiral CT or MRI scan of the chest, abdomen, and any other area of known or suspected disease, must be obtained at Screening. 
A CT or MRI scan that is dated prior to consent (up to 42 days prior to starting IMP) for this study may be used as the Screening assessment, where this has 
been performed as per standard of care or at the end of a prior study. The same method of assessment is to be used per participant for the duration of study 
participation. Tumor assessments are to be performed every 8 weeks from Day 1 (± 7 days). Tumor assessment at SFU is not required if the participant has 
withdrawn due to progressive disease or if the previous tumor assessment was within 42 days of SFU Visit. 
m Follow-up of AEs: AEs will be recorded up to 30 days after the last dose of study medication. After that time, any unresolved drug-related AEs should be 
followed until resolution or stabilization of the AE to obtain the date of resolution/stabilization (this follow-up can be via routine clinic visits or correspondence 
with a treating physician or other healthcare professional). 
n Blood samples for circulating gremlin-1 analysis will be collected at Cycle 1 Day 1 at predose (within 30min prior to dosing), end of infusion (+15min), and 4h 
(+1h) post-infusion. An additional sample should be collected on Day 15 post-infusion on day of visit.. In all subsequent cycles blood samples will be collected 
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at Day 1 predose (within 30min prior to dosing) and at the SFU Visit; for Cycle 3 only an additional 4h (+1h) sample should be taken on Day 1. An additional 
sample should also be collected on the day of the on-treatment biopsy (only if taking place on a day where no PK samples are scheduled). 
o To be confirmed based on Part A Cohort 1 to 3 analysis. 
p Baseline biopsy should be collected between Day -28 and Day -1. Whenever possible, on-treatment biopsy should be performed within 2 weeks post Cycle 2 
Day 1 (ie, between Cycle 2 Day 1 and Cycle 2 Day 15). If on-treatment biopsy occurs a non-dosing day, an additional PK and an additional cGremlin-1 
samples should be collected on the day of biopsy. 
q If an historical tumor biopsy specimen obtained prior to the participant’s entry into the study (eg, at the time of diagnosis) is available, samples of this tissue 
will be requested for PD analysis at the time of consent. 
 
The Schedule of Activities for Part B is provided in Table 1-7. 
Table 1-7: 
Schedule of Activities for Part B 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-3 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessmentb 
X 
X 
Xg 
 
 
 
 
 
 
 
Demographic data and height 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/cancer history/concomitant 
disease and current medical status 
X 
 
Xg 
 
 
 
 
 
 
 
ECG
c  
X 
X 
X 
 
X 
 
X 
 
X 
 
Pregnancy test, if applicabled 
X 
X 
X 
 
 
 
X 
 
X 
X 
TFD/TPI dispensinge 
 
X 
X 
 
 
 
 
 
 
 
TFD/TPI administration 
 
 
TFD/TPI is administered orally twice daily 
on Days 1 to 5 and Days 8 to 12 of each cycle 
 
 
UCB6114 administration 
 
 
UCB6114 is administered as an iv infusion 
on Days 1 and 15 of each cycle 
 
 
Physical examination and weightf 
X 
X 
X 
Xg 
X 
Xg 
X 
X 
X 
 
Vital signs (BP, HR, RR, and temperature)h 
X 
X 
X 
Xg 
X 
Xg 
X 
X 
X 
 
ECOG performance statush 
X 
X 
X 
Xg 
X 
Xg 
X 
X 
X 
 
Urinalysisi 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Urinalysis for urinary markers of bone turnover 
 
 
X 
 
X 
 
X 
 
X 
 
Hematologyk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistryl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulationm 
X 
X 
X 
 
Xg 
 
X 
 
X 
 
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Table 1-7: 
Schedule of Activities for Part B 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-3 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
Blood collection for serum markers of bone 
turnover  
 
 
X 
 
X 
 
X 
 
X 
 
Blood collection for immunogenicity (ADA)  
 
 
X 
 
 
 
Xp 
 
X 
 
Blood collection for circulating gremlin-1 
analysis  
X 
Xo 
Xo,q 
 
Xq 
 
Xp,q 
 
X 
 
Blood collection for genetic analysis 
X 
Xo 
 
 
 
 
 
 
 
 
Blood collection for ctDNA analysis 
X 
Xo 
Xo 
 
X 
 
X 
 
X 
 
Echocardiogram 
X 
 
 
 
 
 
Xu 
 
X 
 
Tumor assessmentsr 
X 
 
Every 8 weeks from Day 1 
X 
 
Historical tumor sample if availables 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
Recorded throughout 
X 
 
Adverse eventst 
X 
 
Recorded throughout 
X 
 
Survival census 
 
 
 
 
 
 
 
 
X 
X 
ADA=antidrug antibody; AE=adverse event; ALP=alkaline phosphatase; BP=blood pressure; CT=computed tomography; ctDNA=circulating tumor DNA; 
DLT=dose-limiting toxicity; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; h=hour(s); HR=heart rate; iv=intravenous; 
min=minute(s); MRI=magnetic resonance imaging; PD=pharmacodynamic(s); PK=pharmacokinetic(s); RR=respiratory rate; TFD/TPI= trifluridine/tipiracil; 
SFU=Safety Follow-Up 
Note: The allowed visit window is ±2 days (unless specified otherwise). All assessments are to be performed prior to dosing with IMP (unless specified 
otherwise). 
a Informed consent must be given before any study-specific Screening procedures are performed. 
b Eligibility must be confirmed within 3 days prior to starting any IMP. Confirmation does not have to be repeated on Day 1 predose if it was performed 
within 3 days prior to starting any IMP. 
c ECGs are to be performed prior to dosing with IMP in triplicate with the participant in a supine position after a minimum of 5 minutes of rest. ECGs are to 
be performed in Screening and do not have to be repeated on Day 1 predose if performed within 3 days prior to starting any IMP. On Days 1 and 15 of Cycle 
1 only, ECGs will also be performed at multiple timepoints in relation to dosing with UCB6114 (pre-infusion, end of infusion, and at 2 hours post infusion). 
When ECG coincides with blood collection for PK (and PD), the ECG should be performed first.  
d Serum pregnancy test must be performed in Screening and does not have to be repeated on Day 1 predose if performed within 3 days prior to starting any 
IMP. If a serum pregnancy test was performed at Screening more than 3 days prior to starting any IMP, a urinary pregnancy test can be performed on Day 1 
prior to dosing with any IMP. A serum or urinary test can be performed on all other visits. 
e TFD/TPI can be dispensed once eligibility is confirmed (see footnote b). 
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Table 1-7: 
Schedule of Activities for Part B 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-3 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
f A complete physical examination is to be performed in Screening and does not have to be repeated on Day 1 predose if performed within 3 days prior to 
starting any IMP. Physical examinations will be symptom-directed and performed prior to administration of IMP on all other visits.  
g Not to be done in Cycle 2. 
h Vital signs and ECOG performance status are to be performed in Screening and do not have to be repeated on Day 1 predose if performed within 3 days 
prior to starting any IMP. Vital signs on treatment days with UCB6114 will be assessed at multiple time points in a semi-supine position after 5min of rest: 
predose, 10min (±5min) and 30min (±10min) after the start of the infusion, at the end of the infusion (+15min); and at 1h (+15min) after the end of the 
infusion. In addition, on Cycle 1 Day 1 vital signs will be assessed at 2h (+1h) and 5h (+1h) after the end of the infusion. 
i Urinalysis is to be performed in Screening and does not have to be repeated on Day 1 predose if performed within 3 days prior to starting any IMP. If there 
are abnormalities in urine dipstick, a microscopic analysis should be performed (including crystals).  
j Deleted 
k Hematology is to be performed in Screening and does not have to be repeated on Day 1 predose if performed within 3 days prior to starting any IMP. At all 
other visits, the hematology sample may be obtained 24h prior to the scheduled visit. 
l Blood chemistry is to be performed in Screening and does not have to be repeated on Day 1 if performed within 3 days prior to dosing with any IMP. At all 
other visits blood, the chemistry sample may be obtained 24h prior to the scheduled visit. In the case of liver function abnormalities considered potential 
Hy’s law cases, the liver-specific ALP must be separated from the total in participants with bone metastases and used to assess the liver function instead of 
the total ALP. 
m Coagulation is to be performed in Screening and does not have to be repeated on Day 1 pre-dose if performed within 3 days prior to starting any IMP. At all 
o No sample required if done previously.  
p To be completed in Cycle 3 and thereafter in even cycles only (i.e., Cycle 4, 6) 
q Sample for circulating gremlin-1 will be collected at the same time as PK samples (ie, 30 minutes prior to dosing with UCB6114). 
r Tumor assessments including spiral CT or MRI scan of the chest, abdomen, pelvis, and any other areas of known or suspected disease, must be obtained at 
Screening. A CT or MRI scan that is dated prior to consent (up to 42 days prior to starting IMP) for this study may be used as the Screening assessment, 
where this has been performed as per standard care or at the end of a prior research study. The same method of assessment is to be used per participant for 
the duration of study participation. Tumor assessments are to be performed every 8 weeks from Day 1 (±7 days). Tumor assessment at SFU is not required if 
the participant has withdrawn due to progressive disease or if the previous tumor assessment was within 42 days of SFU visit. 
s If an historical tumor biopsy specimen obtained prior to the participant’s entry into the study (eg, at the time of diagnosis) is available, samples of this tissue 
will be requested for PD analysis. 
t Including DLT in Cycle 1. Follow-up of AEs: AEs will be recorded up to 30 days after the final dose of IMP. After that time, any unresolved drug-related 
AEs should be followed until resolution or stabilization of the AE to obtain the date of resolution/stabilization (this follow-up can be via routine clinic visits 
or correspondence with a treating physician or other healthcare professional). 
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Table 1-7: 
Schedule of Activities for Part B 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-3 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
u During the treatment period, echocardiograms are to be completed at the beginning of Cycle 3 (±7 days), as clinically indicated afterwards, and at the SFU 
Visit. 
 
 
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The Schedule of Activities for Part C is provided in Table 1-8. The Schedule of Activities for modules subsequent to Parts A, B, and C 
will be defined in a planned protocol amendment. 
Table 1-8: 
Schedule of Activities for Part C 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-14 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 
onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessmentb 
X 
X 
Xg 
 
 
 
 
 
 
 
Demographic data and height 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/cancer history/concomitant 
disease and current medical status 
X 
 
Xg 
 
 
 
 
 
 
 
ECG
c  
 
X 
X 
 
X 
 
X 
X 
X 
 
Pregnancy test, if applicable  
 
Xd 
X 
 
 
 
X 
 
X 
X 
UCB6114 administration 
 
 
UCB6114 is administered as an iv infusion on Days 1 
and 15 of each cycle 
 
 
mFOLFOX6 administration 
 
 
mFOLFOX6 is administered iv starting on Days 1 and 
15 of each cyclee 
 
 
Physical examination and weightf 
 
X 
X 
Xg 
X 
Xg 
X 
X 
X 
 
Vital signs (BP, HR, RR, and temperature)h 
 
X 
X 
Xg 
X 
Xg 
X 
X 
X 
 
ECOG performance status 
 
X 
X 
Xg 
X 
Xg 
X 
X 
X 
 
Urinalysisi 
 
X 
X 
 
X 
X 
X 
 
X 
 
Urinalysis for urinary markers of bone turnover 
 
 
X 
 
X 
 
X 
 
X 
 
Blood collection for serum markers of bone 
turnover 
 
 
X 
 
X 
 
X 
 
X 
 
Hematologyk 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistryl 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulationm 
 
X 
X 
 
Xg 
 
X 
 
X 
 
Blood collection for immunogenicity (ADA)  
 
 
X 
 
 
 
Xp 
 
X 
 
Blood collection for circulating gremlin-1 
analysis 
X 
Xo 
Xo, q 
 
Xq 
 
Xp,q 
 
X 
 
Blood collection for genetic analysis 
X 
Xo 
 
 
 
 
 
 
 
 
Blood collection for ctDNA analysis 
X 
Xo 
Xo 
 
X 
 
X 
 
X 
 
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Table 1-8: 
Schedule of Activities for Part C 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-14 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 
onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
Echocardiogram 
X 
 
 
 
 
 
Xu 
 
X 
 
Tumor assessmentsr 
X 
 
Every 8 weeks from Day 1 
X 
 
Historical tumor sample if availables 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
Recorded throughout 
X 
 
Adverse events t 
X 
X 
Recorded throughout 
X 
 
Survival census 
 
 
 
 
 
 
 
 
X 
X 
ADA=antidrug antibody; AE=adverse event; BP=blood pressure; CT=computed tomography; ctDNA=circulating tumor DNA; DLT=dose-limiting toxicity; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; HR=heart rate; iv=intravenous; mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-
fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 and Day 2, and oxaliplatin 85mg/m2 on Day 1; MRI=magnetic resonance imaging; 
PD=pharmacodynamic(s); PK=pharmacokinetic(s); RR=respiratory rate; SFU=Safety Follow-Up 
Note: The allowed visit window is ±2 days (unless specified otherwise). All assessments are to be performed prior to dosing with UCB6114 (unless specified 
otherwise). 
a Informed consent must be given before any study-specific Screening procedures are performed. 
b Eligibility must be confirmed on Cycle 1 Day 1 prior to dosing with any IMP. 
c ECGs are to be performed prior to dosing with UCB6114 in triplicate with the participant in a supine position after a minimum of 5 minutes of rest. On 
Days 1 and 15 of Cycle 1 only, ECGs will also be performed at the end of infusion and at 2 hours after the infusion of UCB6114. When ECG coincides with 
blood collection for PK (and PD), the ECG should be performed first.  
d Serum pregnancy tests must be performed at Screening. Serum or urine pregnancy test must be performed on dosing days prior to dosing with any IMP. 
Tests should also be performed during the study if indicated. 
e The infusions will begin on Day 1 and Day 15 and continue over 46 hours, thus ending on Days 3 and 17, respectively. 
f A complete physical examination is to be performed at Screening and on Cycle 1 Day 1 prior to dosing with UCB6114. Physical examinations will be 
symptom-directed and performed prior to administration of UCB6114 on all other visits. 
g Not to be done in Cycle 2. 
h Vital signs on treatment days will be assessed at multiple time points in a semi-supine position after 5 minutes of rest: prior to dosing with UCB6114, 10min 
(±5min) and 30min (±10min) after the start of the infusion, at the end of the infusion (+15min), and at 1h (+15min) after the end of the infusion of 
UCB6114. In addition, on Cycle 1 Day 1 vital signs will be assessed at 2 hours (+1h) and 5 hours (+1h) after the end of the infusion of UCB6114. 
i If there are abnormalities in urine dipstick, a microscopic analysis should be performed (including crystals). Urinalysis does not have to be repeated on 
Cycle 1 Day 1 predose if performed within 72h of starting dosing. At all other visits, the urinalysis sample may be obtained 24h prior to the scheduled visit. 
j Deleted 
k Hematology does not have to be repeated on Day 1 predose if performed within 72h of starting dosing. At all other visits, the hematology sample may be 
obtained 24h prior to the scheduled visit. 
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Table 1-8: 
Schedule of Activities for Part C 
Procedure 
Screening 
Treatment 
SFU Visit 
Final Visit 
-28 
to -1 
-14 
to -1 
Cycle 1 & Cycle 2 
(28 days) 
Cycle 3 
onwards 
(28 days) 
Within 
30 days after 
final dose 
3 months 
after final 
dose 
Cycle day 
1 
8 
15 
22 
1 
15 
l Blood chemistry does not have to be repeated on Day 1 predose if performed within 72h of starting dosing. At all other visits, the blood chemistry sample 
may be obtained 24h prior to the scheduled visit. In the case of liver function abnormalities considered potential Hy’s law cases, the liver-specific ALP must 
be separated from the total in participants with bone metastases and used to assess the liver function instead of the total ALP. 
m Coagulation does not have to be repeated on Day 1 predose if performed within 72h of starting dosing. At all other visits, the coagulation sample may be 
obtained 24h prior to the scheduled visit. 
o No sample required if done previously.  
p To be completed in Cycle 3 and thereafter in even cycles only (i.e., Cycle 4, 6) 
q Sample for circulating gremlin-1 will be collected at the same time as PK samples (ie, 30 minutes prior to dosing with UCB6114). 
r Tumor assessments including spiral CT or MRI scan of the chest, abdomen, pelvis, and any other areas of known or suspected disease, must be obtained at 
Screening. A CT or MRI scan that is dated prior to consent (up to 42 days prior to starting IMP) for this study may be used as the Screening assessment, 
where this has been performed as per standard care or at the end of a prior research study. The same method of assessment is to be used per participant for 
the duration of study participation. Tumor assessments are to be performed every 8 weeks from Day 1 (±7 days). Tumor assessment at SFU is not required if 
the participant has withdrawn due to progressive disease or if the previous tumor assessment was within 42 days of the SFU visit. 
s If an historical tumor biopsy specimen obtained prior to the participant’s entry into the study (eg, at the time of diagnosis) is available, samples of this tissue 
will be requested for PD analysis. 
t Including DLT in Cycle 1. Follow-up of AEs: AEs will be recorded up to 30 days after the final dose of IMP. After that time, any unresolved drug-related 
AEs should be followed until resolution or stabilization of the AE to obtain the date of resolution/stabilization (this follow-up can be via routine clinic visits 
or correspondence with a treating physician or other healthcare professional). 
u During the treatment period, echocardiograms are to be completed at the beginning of Cycle 3 (±7 days), as clinically indicated afterwards, and at the SFU 
Visit. 
 
 
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2 
INTRODUCTION 
2.1 
Study rationale 
UCB6114 is a fully human IgG4P mAb optimized for neutralizing activity against the human 
gremlin-1 protein and is currently under development for advanced solid tumors. Gremlin-1, 
secreted by the tumor stroma, binds to BMP and antagonizes signaling, thereby allowing tumor 
cell expansion, renewal, and a more mesenchymal phenotype. By blocking this gremlin-1 BMP 
antagonism, UCB6114 is expected to restore BMP signaling, limit tumor cell expansion, and 
favor a more epithelial phenotype. Gremlin-1 has been shown to be expressed in multiple solid 
tumor types, with mRNA expression being observed in >60% of colorectal, pancreatic, and 
esophageal cases. Despite advances in the treatment regimens in the last decade, there is still a 
large unmet need in the therapy of cancer types mentioned above. Expression data in human 
tumor models, together with nonclinical evidence, suggests a therapeutic potential of UCB6114 
and supports its proposed initial clinical investigation in participants with advanced solid tumors.  
The primary objectives of this study are to characterize the safety profile (dose escalation 
modules of this study), to assess preliminary antitumor activity (expansion modules of this 
study), and to determine the RP2D of iv UCB6114 as monotherapy and in combination with 
selected SOC regimens. In addition, the PK, PD, PD biomarker profiles, and ADA of iv 
UCB6114 will be assessed.  
The scientific rationale for the study design is presented in Section 4.2. 
2.2 
Background 
Gremlin-1 has an essential role in skeletal development and homeostasis, and in kidney 
development (Khokha et al, 2003). The protein is highly conserved between species. Gremlin-1 
has several cellular signaling mechanisms (Brazil et al, 2015). The most well-described role for 
gremlin-1 is as a high affinity antagonist regulating the activity of BMPs 2, 4, and 7, members of 
the transforming growth factor-β superfamily (Mulloy and Rider, 2015). Gremlin-1 has also been 
reported to bind to the vascular endothelial growth factor receptor 2, however the functional 
relevance is currently unclear. Further described roles for gremlin-1 include binding to slit 
guidance ligand 1 and 2 (Slit1 and Slit2) and facilitating their binding to the roundabout receptor 
which leads to inhibition of monocyte chemotaxis, as well as associating to fibrillin microfibers 
and activating Slug expression, leading to epithelial–mesenchymal transition and mesothelioma 
cell survival (Mulloy et al, 2015). 
Gremlin-1 mRNA has been shown to be expressed in >60% of colorectal, pancreatic, and 
esophageal cancer cases and in approximately 50% of bladder, breast, and lung cancer cases 
(Sneddon et al, 2006). It has also been shown to be a key driver in HMPS (Jaeger et al, 2012), a 
rare and severe premalignant condition characterized by the development of mixed morphology 
colorectal tumors. It was demonstrated in this condition that there is a 4000-fold increase in 
gremlin-1 mRNA caused by a 40kb duplication in the gremlin-1 promotor region. 
In mouse models of HMPS and CRC, the murinized version of UCB6114, Ab7326 mIgG1, has 
demonstrated the ability to inhibit disease pathology and profoundly extends the lifespan of 
mice. Long-term treatment of the ApcMin mouse model of CRC with Ab7326 mIgG1 initiated 
at 6 or 16 weeks of age had a consistent effect on polyp development, allowing prolonged 
survival of animals through reduced tumor burden. In a highly aggressive model of CRC with 
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established disease, the combination of Ab7326 mIgG1 antibody together with cytotoxic 
chemotherapy was efficacious, whereas either individual agent alone was not. 
The nonclinical safety program for UCB6114 comprised two 13-week Good Laboratory Practice 
(GLP) compliant repeated iv dose toxicity studies at dose levels of 30mg/kg and 150mg/kg, one 
in cynomolgus monkeys and the other in rats. No adverse effects, related to the mechanism of 
action (MoA) of UCB6114, were observed in any of the toxicology, safety pharmacology, and 
immunotoxicology parameters examined in cynomolgus monkeys or in male rats. In female rats, 
histopathological changes were noted in the ovaries, mammary gland, adrenal gland, and 
pituitary. No histopathological changes were noted in the cynomolgus monkey (females and 
males) and male rats. The endocrine changes in the female rats are considered related to the 
MoA of UCB6114 through BMPs effects in ovarian function and this pattern of changes occurs 
commonly in rats, particularly in aging Sprague Dawley rats. The potential effects on ovarian 
function in the rat led to an anovulatory state (lack of corpora lutea and cystic follicles) with a 
series of downstream rat-specific effects in the uterus, vagina, and mammary gland. Rodents are 
known to be specifically sensitive to hormonal changes and related impact on the 
hypothalamic-pituitary-adrenal (HPA)-mammary axis. The findings noted at the end of the main 
phase were either not observed or noted at comparable incidence to the control group at the end 
of the recovery period (Day 183). 
For more detailed information regarding the nonclinical program, see the current Investigator’s 
Brochure (IB). 
2.3 
Benefit/risk assessment 
This is the first study of UCB6114 in humans. Nonclinical studies demonstrate that UCB6114 
binds to gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in 
vivo mouse cancer models. Gremlin-1 is also known to be expressed in a range of human tumors 
and high expression has been associated with a poor prognosis in multiple tumor types. Taken 
together these data indicate that UCB6114 could play a role in treating a range of solid tumors. 
No adverse effects, related to the MoA of UCB6114, were observed in any of the toxicology, 
safety pharmacology, and immunotoxicology parameters examined in cynomolgus monkeys or 
in male rats. In female rats, histopathological changes were noted in the ovaries, mammary 
gland, adrenal gland, and pituitary. No histopathological changes were noted in the cynomolgus 
monkey (females and males) and male rats. The endocrine changes in the female rats were 
considered related to the MoA of UCB6114 through BMPs effects in ovarian function and this 
pattern of changes occurs commonly in rats, particularly in aging Sprague Dawley rats. The 
potential effects on ovarian function in the rat led to an anovulatory state (lack of corpora lutea 
and cystic follicles) with a series of downstream rat-specific effects in the uterus, vagina, and 
mammary gland. Rodents are known to be specifically sensitive to hormonal changes and related 
impact on the HPA-mammary axis. The findings noted at the end of the main phase were either 
not observed or noted at comparable incidence to the control group at the end of the recovery 
period (Day 183). These drug-related changes are considered pharmacologically-related and 
shown to be reversible, and do not preclude further development of this molecule in the oncology 
indication. 
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The FIH start dose (Part A, UCB6114 monotherapy) is anticipated to have a >100-fold safety 
margin based on the outcome of the 13-week GLP toxicity study in rats (the most sensitive 
species). 
In Part A, a number of safeguards are in place to minimize risk to study participants which 
reflect the state of knowledge of the study medication. There are detailed selection criteria and 
the study is designed using a sequential dose-escalation strategy (modified rolling-6), with at 
least 16 days elapsing between the first and subsequent participants enrolled in each cohort. 
In Part A1, alternative dosing schedules have been determined based upon the currently available 
data, including the safety profile, pharmacokinetic (PK) data, pharmacodynamic (PD) biomarker 
data, and available anti-tumor activity. A number of safety measures are in place to minimize the 
risk to study participants. Each of the 4 cohorts incorporates a sentinel participant. The 
enrollment of a sentinel participant has been included as an additional risk mitigation measure to 
monitor potential infusion reactions and other potential acute adverse events as UCB6114 will be 
administered with a new dose formulation (all cohorts), with a shorter infusion time (Cohort 2), 
or higher initial dose (Cohorts 3 and 4) than previously administered in Part A of the study. Each 
sentinel participant will be assessed for at least 48 hours following the first treatment 
administration before further participants within the same cohort can be enrolled. 
Parts B and C will use the modified toxicity probability interval (mTPI) design to guide dose 
escalation. The mTPI design replaces the algorithmic rules that are based on events (ie, 0 of 3, 
1 of 3, 2 of 3, and 3 of 5) with a model-based inference on the toxicity probability intervals. The 
number of observed dose-limiting toxicities (DLTs) within a dose level will be used to calculate 
the probability that the current dose level under consideration is within the underdosing, 
equivalent dosing, or overdosing range relative to the prespecified target toxicity considered 
acceptable for the disease setting. 
The target toxicity specified within this protocol (25%) results in a more conservative set of 
escalation rules as compared with an algorithmic approach in that a single DLT observed in the 
first cohort of 3 will result in a recommendation to treat the next cohort of participants at the 
same dose level rather than a recommendation to dose escalate. Consequently, the mTPI will 
treat fewer participants at doses above the maximum tolerated dose (MTD) and generally yields 
higher probabilities in identifying the true MTD. 
Dose escalation between cohorts in Part A, Part B, and Part C will follow clearly defined criteria 
including a review by a Safety Monitoring Committee (SMC), with a dose de-escalation, if 
appropriate. In consultation with the SMC, a Study Steering Committee (SSC) will recommend 
to the Sponsor the dose and dosing regimen to be taken forward for the combination therapy dose 
escalation modules (Part B and C). The dosing schedules in Part A1 have been designed to 
achieve similar exposures at steady-state to those deemed sufficiently safe by the SMC in Part A. 
There are also clearly defined criteria for stopping dosing and participant withdrawal.  
Targeted therapies have progressed current treatment of advanced solid tumors, increasing 
survival rates in combination with cytotoxic chemotherapy. Despite the advances in therapy, the 
paucity of approved agents for progressive disease constitutes an important medical need that 
needs to be addressed. 
There is the potential for UCB6114 to be a beneficial treatment for patients with advanced solid 
tumors both in the context of this study and the wider clinical development program. Therefore, 
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taking into account the above considerations, the benefit/risk is considered favorable for the 
clinical study ONC001. 
More detailed information about the preclinical pharmacology activity, potential benefits, and 
potential adverse events (AEs) of UCB6114 may be found in the current IB. 
3 
OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints for the dose escalation and expansion modules are presented in 
Table 3-1 (Part A and Part A1), Table 3-2 (Part B and Part C), and Table 3-3 (Parts D, E, F, and 
G), respectively. The overarching objective of this study is to determine the RP2D for 
monotherapy (RP2D-M) and for combination therapy. This will be determined using the totality 
of data generated based on the objectives in and Table 3-1 (Part A and Part A1), Table 3-2 (Part 
B and Part C), and Table 3-3 (Parts D, E, F, and G). 
Table 3-1: 
Objectives and endpoints for the dose escalation module (Part A) 
and the dose optimization module (Part A1) 
Objectives 
Endpoints 
Primary 
To characterize the safety profile of UCB6114 as 
monotherapy  
Incidence of TEAEs 
Severity of TEAEs 
Incidence of DLTs 
Secondary 
To characterize the PK of UCB6114 administered 
as monotherapy  
UCB6114 concentration by scheduled assessment 
and cohort 
Tertiary/exploratory 
To document any antitumor activity observed with 
UCB6114 according to relevant RECIST criteria 
Antitumor activity as indicated by:  
• 
ORR 
• 
DCR 
• 
DOR 
• 
PFS 
• 
OS 
To explore PD biomarkers of UCB6114 
• 
Change in transcriptional and protein marker 
levels in blood and tumor tissue by scheduled 
assessment and cohort 
• 
Change in ctDNA levels in blood by scheduled 
assessment and cohort 
To evaluate the incidence, emergence, and impact 
of ADA 
ADA (anti-UCB6114 antibody) titer and sample 
status by scheduled assessment 
ADA=antidrug antibody; ctDNA= circulating tumor DNA; DCR=disease control rate; DOR=duration of antitumor 
response; DLT=dose-limiting toxicity; ORR=objective response rate; OS=overall survival; 
PD=pharmacodynamic(s); PFS=progression-free survival; PK=pharmacokinetic(s); RECIST=Response 
Evaluation Criteria in Solid Tumors; TEAE=treatment-emergent adverse event 
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Table 3-2: 
Objectives and endpoints for the dose escalation modules in Part B 
and Part C 
Objectives 
Endpoints 
Primary 
To characterize the safety profile of UCB6114 
administered in combination with selected SOC 
regimens  
Incidence of TEAEs 
Severity of TEAEs 
Incidence of DLTs 
Secondary 
To characterize the PK of UCB6114 administered 
in combination with selected SOC regimens 
UCB6114 concentration by scheduled assessment 
and dose level 
Tertiary/exploratory 
To document any antitumor activity observed with 
UCB6114 administered in combination with 
selected SOC regimens according to relevant 
RECIST criteria  
Antitumor activity as indicated by: 
• 
ORR 
• 
DCR 
• 
DOR 
• 
PFS 
• 
OS 
To explore PD biomarkers of UCB6114 
administered in combination with selected SOC 
regimens 
• 
Change in protein marker levels in blood by 
scheduled assessment and dose level 
• 
Change in ctDNA levels in blood by scheduled 
assessment and dose level 
To evaluate the immunogenicity of UCB6114 
administered in combination with selected SOC 
regimens 
ADA (anti-UCB6114 antibody) titer and sample 
status by scheduled assessment 
ADA=antidrug antibody; ctDNA= circulating tumor DNA; DCR=disease control rate; DLT=dose-limiting toxicity; 
DOR=duration of antitumor response; ORR=objective response rate; OS=overall survival; 
PD=pharmacodynamic(s); PFS=progression-free survival; PK=pharmacokinetic(s); RECIST=Response Evaluation 
Criteria in Solid Tumors; SOC=standard of care; TEAE=treatment-emergent adverse event 
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Table 3-3: 
Objectives and endpoints for the expansion modules in Parts D, E, F, 
and G 
Objectives 
Endpoints 
Primary 
To assess preliminary antitumor activity of 
UCB6114 when administered as monotherapy 
(Part D and Part E) or in combination with selected 
SOC regimens (Part F and Part G) according to 
relevant RECIST criteria 
Antitumor activity as indicated by ORR 
Secondary 
To characterize the safety profile of UCB6114 as 
monotherapy or in combination with selected SOC 
regimens 
• Incidence of TEAEs 
• 
Severity of TEAEs 
To document any antitumor activity observed with 
UCB6114 when administered as monotherapy or in 
combination with selected SOC regimens 
Antitumor activity as indicated by: 
• 
DCR 
• 
DOR 
• 
PFS 
• 
OS 
Tertiary/exploratory 
To explore PD biomarkers of UCB6114 
administered as monotherapy or in combination 
with selected SOC regimens 
Change in transcriptional and protein marker levels 
in blood and tumor tissue by scheduled assessment 
To characterize the PK of UCB6114 administered 
as monotherapy or in combination with selected 
SOC regimens 
UCB6114 concentration by scheduled assessment 
and dose level 
To evaluate the immunogenicity of UCB6114 
administered as monotherapy or in combination 
with selected SOC regimens 
ADA (anti-UCB6114 antibody) titer and sample 
status by scheduled assessment 
ADA=antidrug antibody; DCR=disease control rate; DOR=duration of antitumor response; ORR=objective response 
rate; OS=overall survival; PD=pharmacodynamic(s); PFS=progression-free survival; PK=pharmacokinetic(s); 
RECIST=Response Evaluation Criteria in Solid Tumors; SOC=standard of care; TEAE=treatment-emergent 
adverse event 
4 
STUDY DESIGN 
4.1 
Overall design 
ONC001 is a multicenter, nonrandomized, open-label, Phase 1/2 study evaluating the safety, PK, 
and antitumor activity of iv UCB6114 in participants with advanced solid tumors. 
The study has a modular design including up to 3 dose escalation modules (Parts A, B, and C), 
1 dose optimization module (Part A1), and up to 4 expansion modules (Parts D, E, F, and G) (see 
Section 1.2). Depending on emerging data, not all modules may open. 
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After completion of Part A, Part A1, Part B, and Part C, specific characteristics of modules 
subsequent to Part A, Part A1, Part B, and Part C will be described in planned protocol 
amendments. The updated characteristics will include, but not be limited to, tumor type 
selection, participant’s inclusion/exclusion criteria, route and frequency of study medication 
administration, and selection of the SOC treatment regimen. 
There are 8 different study modules for dose escalation and expansion, which are shown in 
Table 4-1. 
Table 4-1: 
Study modules for dose escalation and expansion 
Module Module description 
Part A 
Dose-escalation to identify the RP2D-M, based on emerging safety, PK, PD, and antitumor 
effect data. Participants will receive UCB6114 Q2W via iv infusion. The starting dose will 
be escalated (or de-escalated) stepwise in successive cohorts of 3 to 6 evaluable participants 
(modified rolling-6 design) (see Section 4.1.2), until the RP2D-M is determined. Up to 
42 participants may be enrolled. 
Part A1 
Dose-optimization to evaluate alternative dosing schedules for UCB6114 administered as 
monotherapy in participant with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, adenocarcinoma of the gastroesophageal junction, 
or pancreatic cancer. Based on emerging data from Part A, this module will evaluate a new 
dose formulation, different frequencies of dosing (eg, Q3W, QW4), and different time of 
infusion. Up to 32 participants may be enrolled. 
Part B 
Dose-escalation with TFD/TPI in participants with unresectable locally advanced or 
metastatic colorectal adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the 
gastroesophageal junction to identify the RP2D-T. 
The starting dose of UCB6114 in Part B will depend on the dose level evaluated in Cohort 3 
of Part A (anticipated to be 500mg Q2W iv) and the emerging safety profile of UCB6114 
monotherapy, including any overlapping toxicity with TFD/TPI. It is expected that 2 or 3 
dose levels of UCB6114 will be explored. The starting dose will be escalated stepwise in 
successive cohorts of 2 to 4 evaluable participants (mTPI design), until the RP2D-T is 
determined. Up to 27 participants may be enrolled. 
Part C 
Dose-escalation with mFOLFOX6 in participants with unresectable locally advanced or 
metastatic colorectal adenocarcinoma, gastric adenocarcinoma, and adenocarcinoma of the 
gastroesophageal junction to identify the RP2D-F. 
The starting dose of UCB6114 in Part C will depend on the dose level evaluated in Cohort 3 
of Part A (anticipated to be 500mg Q2W iv), and the emerging safety profile of UCB6114 
monotherapy, including any overlapping toxicity with the mFOLFOX6 regimen. The 
starting dose and dose escalation scheme may differ from that evaluated in Part B. It is 
expected that 2 or 3 dose levels of UCB6114 will be explored. The starting dose will be 
escalated stepwise in successive cohorts of 2 to 4 evaluable participants (mTPI design), until 
the RP2D-F is determined. Up to 27 participants may be enrolled. 
Part D 
Expansion module to explore the safety and antitumor activity of UCB6114 as monotherapy 
with the RP2D-M dosing regimen. It is planned to evaluate 15 participants with a selected 
recurrent/metastatic tumor type 1 (to be decided based on emerging internal and external 
data). Up to 15 additional participants may be enrolled depending on the observed antitumor 
activity (total sample size of up to 30 participants). 
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Table 4-1: 
Study modules for dose escalation and expansion 
Module Module description 
Part E 
Expansion module to explore the safety and antitumor activity of UCB6114 as monotherapy 
with the RP2D-M dosing regimen in an alternative selected tumor type (tumor type 2). It is 
planned to evaluate 15 participants with a selected recurrent/metastatic tumor type 2 (to be 
decided based on emerging internal and external data). Up to 15 additional participants may 
be enrolled depending on the observed antitumor activity (total sample size of up to 30 
participants). 
Part F 
Expansion module to explore the safety and antitumor activity of UCB6114 in combination 
with the SOC regimen tested in Part B (RP2D-T). It is planned to evaluate UCB6114 plus 
SOC in 15 participants with a selected recurrent/metastatic tumor type. Up to 15 additional 
participants may be enrolled depending on the observed antitumor activity (total sample size 
of up to 30 participants). 
Part G 
Expansion module to explore the safety and antitumor activity of UCB6114 in combination 
with the SOC regimen tested in Part C (RP2D-F). It is planned to evaluate 15 participants 
with a selected recurrent/metastatic tumor type. Up to 15 additional participants may be 
enrolled depending on the observed antitumor activity (total sample size of up to 30 
participants). 
iv=intravenous(ly); mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 on Day 1 + 
1200mg/m2/day on Day 1 and Day 2, and oxaliplatin 85mg/m2 on Day 1; mTPI= modified toxicity probability 
interval; QW=once weekly; Q2W=every 2 weeks; Q3W=every 3 weeks; PD=pharmacodynamics; 
PK=pharmacokinetics; RP2D-F=recommended Phase 2 dose of UCB6114 when used in combination with 
FOLFOX; RP2D-M=recommended Phase 2 dose for monotherapy; RP2D-T=recommended Phase 2 dose of 
UCB6114 when used in combination with TFD/TPI; sc=subcutaneous; SOC=standard of care; 
TFD/TPI=trifluridine/tipiracil 
In Part A, each cohort will include 3 to 6 participants. Dose escalation (or de-escalation) will be 
guided by safety assessments and available PK data. At each dose level, PD samples will be 
collected to evaluate the PK/PD relationship.  
In Part A, eligible participants will receive UCB6114 as an iv infusion every 2 weeks (Q2W) as 
monotherapy. UCB6114 will be administered as a flat dose (ie, not adjusted for weight or body 
surface area [BSA]) unless emerging data indicate that weight- or BSA-based dosing would be 
more appropriate. Doses of UCB6114, ranging from 100mg to 2000mg (corresponding to 
approximately 1 to 30mg/kg) (Table 6-5) may be explored. Five dose levels are planned; 
however, an additional 2 dose levels may be added based on emerging data. Dose escalation 
steps are currently planned at a maximum of 2.5-fold; however, may be adjusted based on 
observed PK in the preceding cohort(s) and will not exceed 5-fold. Up to 42 participants may be 
enrolled. 
The planned duration of treatment is 2 cycles. Participants may, however, remain on study for 
additional cycles if they are receiving therapeutic benefit (stable disease [SD], partial response 
[PR], or complete response [CR]) or until they fulfill one of the criteria for study discontinuation. 
Upon discontinuation of treatment, participants will be referred to appropriate follow-up care per 
the investigator’s judgment. 
Part A will include participants with tumor types associated with expression of GREM1 mRNA. 
These tumor types include bladder urothelial carcinoma, breast invasive carcinoma, colorectal 
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adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, lung 
adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, prostate 
adenocarcinoma, and stomach adenocarcinoma based on GREM1 expression data from Sneddon 
et al, 2006 and the Cancer Genome Atlas (The Cancer Genome Atlas, 2019). 
From Part A, a RP2D for UCB6114 monotherapy (RP2D-M) will be selected based upon the 
totality of information, including the safety profile, PK profile, and available antitumor activity 
and PD data. The start of any modules subsequent to Part A (monotherapy dose escalation) will 
be reliant on module-specific criteria and the approval of planned protocol amendments. 
Part A1 will be initiated after Cohort 5 of Part A (2000mg Q2W) has been determined to be 
 
(ie, DLT incidence <33%, see Section 4.1.2.4). Eligible participants with unresectable locally 
advanced or metastatic colorectal adenocarcinoma, gastric adenocarcinoma, adenocarcinoma of 
the gastroesophageal junction, or pancreatic cancer will receive iv infusion of UCB6114 as 
monotherapy. Four alternative dosing schedules (cohorts) have been planned and will explore 
shorter infusion time, and less frequent administration (Table 6-6). Each cohort will enroll 8 
participants including 1 sentinel participant. Up to 32 participants may be enrolled. 
Part B and Part C of ONC001 are planned to be initiated after Cohort 3 of Part A has completed 
the 28-day DLT assessment period and once the SMC has provided a recommendation to dose 
escalate to the next protocol-defined level in Part A of the study. For all dose levels, participants 
will be treated in cohorts of 2 to 4 (target of 3), each dose level will have a minimum of 3 and a 
maximum of 9 participants (Section 4.1.4.2.2 [Part B] and Section 4.1.5.2.2 [Part C]). 
In Part B, eligible participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the gastroesophageal junction 
will receive UCB6114 as an iv infusion in combination with orally administered TFD/TPI. The 
initial dose and schedule of UCB6114 will depend on the dose level evaluated in Cohort 3 of 
Part A (anticipated to be 500mg Q2W iv), the emerging safety profile of UCB6114 
monotherapy, and any predicted overlapping toxicities with TFD/TPI. Up to 3 dose levels 
(anticipated to be 500mg, 1000mg, and 2000mg administered Q2W iv) are planned 
(Section 4.3.3). Up to 27 participants are planned. Dose escalation decisions in this module will 
be guided by a model-based estimation of the probability of DLT in Cycle 1. 
In Part C, eligible participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the gastroesophageal junction 
will receive UCB6114 as an iv infusion in combination with mFOLFOX6 chemotherapy. The 
initial dose and schedule of UCB6114 will depend on the dose level evaluated in Cohort 3 of 
Part A (anticipated to be 500mg Q2W iv), the emerging safety profile of UCB6114 
monotherapy, and any predicted overlapping toxicities with mFOLFOX6. Up to 3 dose levels 
(anticipated to be 500mg, 1000mg, and 2000mg administered Q2W iv) are planned 
(Section 4.3.3). Up to 27 participants are planned. Dose escalation decisions in this module will 
be guided by a model-based estimation of the probability of DLT in cycle 1. 
In the expansion modules, the RP2D from the respective escalation modules (Part A through 
Part C) will be tested either as monotherapy in selected tumor types (Part D and Part E) or in 
combination with SOC (Part F and Part G). Participants recruited to these modules must have at 
least 1 measurable tumor lesion according to relevant Response Evaluation Criteria in Solid 
Tumors (RECIST). 
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Participants will continue treatment until disease progression, unmanageable toxicity, criteria for 
discontinuation are met, or withdrawal of consent. 
In the dose escalation modules, the decision to proceed to the next dose cohort will occur once 
all participants in the preceding cohort have been monitored for a minimum of 28 days (ie, 
1 cycle). However, all available safety data (both within the cohort and from preceding cohorts) 
will be taken into consideration when dose escalation decisions are made. 
In the expansion modules, response will be assessed after completion of 2 cycles of treatment 
(ie, 4 doses on Q2W dosing regimen) and at regular intervals thereafter. 
4.1.1 
Study oversight 
Study safety oversight will be performed via an SMC as well as regular safety conference calls in 
Part A , and by an SMC and an SSC, as well as regular safety conference calls, once modules 
subsequent to Part A commence. 
Safety monitoring committee  
A SMC will be established for Part A and will comprise key Sponsor personnel and Investigators 
from participating sites. Once modules subsequent to Part A commence, the members of the 
SMC will include Investigators who are actively enrolling study participants into the study.  
Responsibilities of the SMC include: 
• Review of safety data for study participants including review and provision of adjudication 
of individual DLTs, when applicable. 
• Review of available PK and PD biomarker data. 
• Make dose escalation recommendations, dosing schedule recommendations, 
recommendations to continue the study as planned or with protocol adjustments, if needed. 
• Determination of the MTD, if applicable. 
Study steering committee  
An SSC will be implemented prior to the start of modules subsequent to Part A. The SSC 
members will include the coordinating Investigator, supporting co-Investigators, and clinical 
experts not involved in the study. The medical, scientific, and clinical study expertise of the SSC 
will assist the Sponsor in identifying and resolving study related issues, such as study design, 
study implementation and conduct, and data analysis and reporting. In consultation with the 
SMC, the SSC will recommend to the Sponsor the dose and dosing regimen to be taken forward 
for Part B and Part C. 
4.1.2 
Part A – Monotherapy dose escalation 
In Part A of the study, 3 to 6 participants will be enrolled per dose level using a modified 
rolling-6 design. The rolling-6 design is an algorithm-based design in which a total of 
6 participants can be enrolled at the same dose level. The modification requires that each dose 
level incorporates a sentinel participant. The enrollment of a sentinel participant in each cohort 
has been included as an additional risk mitigation measure to monitor infusion related reactions 
and other early onset treatment related AEs. Each sentinel participant will be assessed for at least 
24 hours following second treatment administration before further participants within the dose 
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cohort can be enrolled. In the absence of a DLT observation in the sentinel participant after 16 
days, the remaining 5 participants may be enrolled concurrently (Figure 4-1). Should the sentinel 
participant experience a DLT, then participants 2 and 3 will be enrolled and observed for 16 days 
(Figure 4-2). Escalation can be performed when 3/3, 4/4, 5/5, 5/6, or 6/6 participants are 
evaluated without a DLT. When a single DLT has been observed in a given dose level, 
participants will be included at the same dose level, up to a total of 6 participants. De-escalation 
occurs when 2 or more participants experience a DLT at the first dose level. 
Dose escalation requires at least 3 participants to be treated and observed for at least 28 days 
after the first dose (assuming UCB6114 is dosed Q2W). If dosing is less frequent (due to missed 
or delayed doses or due to a planned change in schedule), at least 3 participants should be treated 
and observed for a minimum of 28 days (ie, 1 cycle), before dose escalation is considered. The 
second participant in any new cohort should also not be dosed until the first participant has 
received at least 2 doses and been observed for a minimum of 16 days (ie, 24 hours following the 
second treatment administration). All participants will remain in the hospital or study site’s 
standard monitoring facility for continuous monitoring for the first 24 hours following the first 
dose; at subsequent doses, the participant may remain at the hospital or study site’s standard 
monitoring facility at the investigator’s discretion. 
4.1.2.1 
SMC 
Once the last participant in a given cohort has completed the required 28-day DLT Observation 
Period, an SMC meeting will be convened to review all safety data, available PK data, and any 
available PD data. The SMC will decide whether to halt dose escalation, further expand the 
cohort to gain additional safety data, or determine the next dose level to be tested. Details are 
described in an SMC Charter. 
4.1.2.2 
Dose escalation criteria 
Dose-limiting toxicities observed in the full 28 days of Cycle 1 will be used to decide whether 
escalation to the next dose level may take place or whether cohort expansion or dose 
de-escalation should occur. However, all available safety data (both within the cohort and from 
preceding cohorts) will be taken into consideration when making such decisions. 
Dose-limiting toxicities may not be encountered in this study. There is no intention to continue 
dose escalation until an MTD can be established. The decision-making guidelines for dose 
escalation are shown in Figure 4-1 (no DLT was observed in the sentinel participant) and 
Figure 4-2 (a DLT was observed in the sentinel participant). The SMC will make dose escalation 
decisions based upon review of safety data and available PK data after all participants in a cohort 
complete at least the first treatment cycle (28 days) or have discontinued. 
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Figure 4-1: Dose escalation decision making: no DLT observed in sentinel 
participant 
 
DLT=dose-limiting toxicity; MTD=maximum tolerated dose 
Note: Figure 2 is shown in Figure 4-2. 
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Figure 4-2: Dose escalation decision making: DLT observed in sentinel 
participant 
 
DLT=dose-limiting toxicity; MTD=maximum tolerated dose 
4.1.2.3 
Dose de-escalation following initial dose level 
The SMC will determine if a dose de-escalation may be warranted, for example, if DLTs are 
observed in ≥2 participants in Cohort 1. 
4.1.2.4 
Dose-limiting toxicity determination and maximum tolerated dose 
definition 
Dose-limiting toxicity is defined as an AE that is at least possibly related to the study medication 
that occurs during Cycle 1 and fulfills any one of the following criteria: 
1. Grade 3 or 4 nonhematological toxicity according to the National Cancer Institute (NCI) 
Common Terminology Criteria for AEs (CTCAE Version 5.0) except for alopecia (of any 
severity or duration), or nausea, vomiting, or diarrhea that reverses to Grade ≤2 within 
24 hours with appropriate medical therapy. 
2. Grade 3 or 4 biochemical abnormality that persists despite maximal supportive treatment or 
biochemical abnormalities that is symptomatic and nontransient (does not return to baseline 
within 24 hours, with or without appropriate supplementation). 
3. Any Grade ≥3 hematological toxicity of >5 days duration or febrile neutropenia (absolute 
neutrophil count [ANC]<1000/mm3 with a single temperature of >38.3°C or sustained 
temperature ≥38°C for more than one hour), infection (documented clinically or 
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microbiologically) with Grade 3 or 4 neutropenia, thrombocytopenia with bleeding or 
requiring platelet transfusion, or Grade 4 thrombocytopenia. 
4. Prolonged Grade 2 diarrhea (>7 days) despite adequate antidiarrheal medication, or multiple 
Grade 1or 2 toxicities (eg, Grade 1 or 2 diarrhea, vomiting, rash, and fatigue) may also be 
considered dose-limiting if considered so by the investigator. 
Investigators, in consultation with the study physician or medically qualified designee, can 
declare a DLT if a participant is experiencing toxicity and treatment cannot be continued without 
exposing the participant to excessive risk. 
The MTD is considered to be the dose level immediately below that which results in a 
DLT incidence of 33% or higher. 
4.1.2.5 
Defining the recommended Phase 2 dose for monotherapy  
The RP2D-M will be defined when all participants in Part A have completed a minimum of 
28 days of treatment (ie, 1 Cycle) or have discontinued prematurely (Table 1-4). All safety, PK, 
available PD biomarker, ADA, and antitumor activity data will be used to select the RP2D-M. 
The RP2D-M will not exceed the MTD (if an MTD is established). Pharmacodynamic effects 
consistent with the mechanism of action of UCB6114 and/or clinical evidence of antitumor 
activity may also help determine the RP2D-M. 
4.1.3 
Part A1 – Dose optimization (alternative dosing schedules) 
Part A1 is a multicenter, non-randomized, open-label, dose optimization module of Study 
ONC001 to evaluate alternative dosing schedules and infusion times for UCB6114 administered 
as monotherapy in patients with unresectable locally advanced or metastatic colorectal cancer, 
gastric cancer, cancer of the gastro-esophageal junction, or pancreatic cancer.  
Part A1 may commence after the fifth cohort in Part A (Cohort 5) is considered sufficiently 
 
by the SMC (DLT rate less than 33%). The planned dose optimization scheme for Part A1 will 
assess the safety and tolerability of the drug new formulation and will explore shortening of the 
infusion time and less frequent dosing as follows:  
• Cohort 1: 2000mg Q2W (60-minute iv infusion), 28-day treatment cycle 
• Cohort 2: 2000mg Q2W (30-minute iv infusion), 28-day treatment cycle 
• Cohort 3: 3000mg Q3W (90-minute iv infusion), 21-day treatment cycle 
• Cohort 4: 4000mg Q4W (120-minute iv infusion), 28-day treatment cycle 
Details of each planned cohort are provided in Table 6-6. 
Up to 32 participants will be allocated 1:1:1:1 to one of the 4 cohorts, with each cohort enrolling 
8 study participants including 1 sentinel participant with an observation period of 48 hours.  
The enrollment of a sentinel participant in each cohort has been included as an additional risk 
mitigation measure to monitor infusion related reactions and other early onset treatment-related 
AEs. Each sentinel participant will be assessed for at least 48 hours following the first 
administration of UCB6114 in the first cycle and the SMC will convene before further 
participants within the cohort can be enrolled.  
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The SMC will also convene after 25%, 50% and 100% of study participants in Part A1 have 
completed the required 28-day observation period. If deemed necessary, an additional SMC 
meeting can convene after 75% of the participants have completed the required observation 
period. If 1 DLT, or more, (refer to Section 4.1.2.4 for the definition of DLTs) are reported for a 
cohort then, an ad-hoc SMC will convene to determine if the dosing schedule and study can 
continue as planned.  
If 3 or more participants experience DLT(s) in a given cohort, no further participants will be 
enrolled in the cohort and the dosing schedule will be considered to be unacceptably toxic.  
After consultation, the SMC will provide recommendations which could include to expand 
enrollment in a particular cohort to gain additional safety data, continue this Part with 
modifications or temporary suspension of enrollment in a particular cohort. Details are described 
in a SMC Charter. 
The planned duration of treatment is 2 cycles. Participants may, however, remain in the study for 
additional cycles if they are receiving therapeutic benefit (SD, PR, or CR) or until they fulfill one 
of the criteria for treatment discontinuation. Participants will continue treatment until disease 
progression, unmanageable toxicity, or withdrawal from the study. Upon discontinuation from 
treatment, participant will be referred to appropriate follow-up care per the Investigator’s 
judgment. 
4.1.4 
Part B – Dose escalation with TFD/TPI 
Part B is a single arm open-label multiple ascending dose-escalation module of ONC001 
evaluating UCB6114 in combination with TFD/TPI to identify the recommended Phase 2 dose of 
UCB6114 when used in combination with TFD/TPI (RP2D-T). Up to 27 participants with 
unresectable locally advanced or metastatic colorectal adenocarcinoma, gastric adenocarcinoma, 
or adenocarcinoma of the gastroesophageal junction will be enrolled. 
Part B of ONC001 is planned to be initiated after Cohort 3 of Part A has completed the 28-day 
DLT assessment period and once the SMC has provided a recommendation to dose escalate to 
the next protocol-defined level in Part A of the study.  
During the Treatment Period, UCB6114 will be administered in combination with TFD/TPI. 
UCB6114 will be administered as an iv infusion every 2 weeks (Q2W), while TFD/TPI will be 
administered orally twice daily (bid) within 1 hour of completion of morning and evening meals 
at home on Days 1 to 5 and Days 8 to 12 (28-day cycle). For the convenience of the participants, 
TFD/TPI can be administered at home to allow for the 12-hour interval between TFD/TPI doses 
associated with meals. For administration at home on Cycle 1 Day 1, eligibility must be 
confirmed within 3 days prior to Day 1 dosing as per the Schedule of Assessments. 
Trifluridine/tipiracil will be administered at the recommended standard of care dose. The starting 
dose of UCB6114 in Part B will depend on the dose level evaluated in Cohort 3 of Part A 
(anticipated to be 500mg Q2W iv) and the emerging safety profile of UCB6114 monotherapy, 
including any overlapping toxicity with TFD/TPI. 
Part B will be undertaken using the mTPI method. A target DLT rate of 25% with an equivalence 
interval (20% to 30%) will be used to estimate the MTD during dose escalation. For all dose 
levels, enrolled participants will be treated in cohorts of 2 to 4 participants (target of 3), who can 
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be treated in parallel. Each dose level may have more than one cohort and will have a minimum 
of 3 evaluable participants. 
It is expected that up to 3 dose levels of UCB6114 will be explored in combination with the 
standard TFD/TPI dosing regimen. However, additional dose levels may be added based on 
emerging data and recommendations of the SMC. Dose escalation steps are currently planned at 
a maximum of 2-fold. Escalating dose levels in Part B will not exceed a dose level tested and 
considered safe by the SMC to allow dose escalation in monotherapy (Part A). 
The decision to dose escalate, have no change in dose, or dose de-escalate in the next cohort will 
occur once all participants in the preceding cohort have been monitored for a minimum of 28 
days (ie, 1 cycle). All available safety data (both within the cohort and from preceding cohorts 
and other parts of the study) will be taken into consideration when dose escalation decisions are 
made. The dose justification is given below in Section 4.3.3. 
The planned duration of treatment is 2 cycles. Participants may, however, remain in the study for 
additional cycles if they are receiving therapeutic benefit (SD, PR, or CR) or until they fulfill one 
of the criteria for study discontinuation (Section 7.2). Participants will continue treatment until 
disease progression, unmanageable toxicity, or withdrawal of consent. Upon discontinuation of 
treatment, participants will be referred to appropriate follow-up care per the investigator’s 
judgment. 
From Part B, a RP2D-T for UCB6114 in combination with TFD/TPI will be determined based 
upon the totality of information, including the safety profile, PK data, PD biomarker data, and 
available antitumor activity. 
4.1.4.1 
Study oversight 
The SMC will convene after the last participant in a given cohort has completed the required 
28-day DLT Observation Period. The SMC will decide whether to halt dose escalation, further 
expand the dose level to gain additional safety data, or determine the next dose level to be tested. 
Safety conference calls with investigators and key Sponsor personnel will be held regularly.  
4.1.4.2 
Dose-limiting toxicity and maximum tolerated dose definition and 
determination 
4.1.4.2.1 
Definition of DLT 
Dose-limiting toxicity is defined as one of the following toxicities (according to the NCI CTCAE 
Version 5.0) occurring during the DLT assessment window (Days 1 to 28 of Cycle 1) that is at 
least possibly related to UCB6114: 
• Grade ≥4 neutropenia (ANC <500/μL) lasting ≥7 days 
− In the event of CTCAE Grade 4 neutropenia, full blood count must be performed on the 
seventh day after the onset of the event to determine if a DLT has occurred 
• Grade ≥3 neutropenia complicated by fever (≥38° C) or infection 
• Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion or Grade 4 
thrombocytopenia 
• Any Grade ≥3 non-hematological event with the following exceptions: 
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− Grade 3 nausea, vomiting, diarrhea, or fatigue that resolves to Grade ≤2 within 24 hours 
of implementing optimal supportive care 
− Grade 3 laboratory abnormality that is asymptomatic and also deemed by the investigator 
to not be clinically significant 
Investigators, in consultation with the medical monitor, can declare a DLT if a participant is 
experiencing toxicity and treatment cannot be continued without exposing the participant to 
excessive risk. 
4.1.4.2.2 
Determination of maximum-tolerated dose 
For every dose levels, participants will be treated in cohorts of 2 to 4 (target of 3), each dose 
level will have a minimum of 3 and a maximum of 9 participants. 
The target rate of DLTs is 25% (equivalence interval 20% to 30%). The target rate will define 
the MTD of the combination regimen (UCB6114 given in combination with TFD/TPI). 
The mTPI method relies upon a statistical probability algorithm, calculated using data from all 
participants treated in prior and current cohorts at the same dose level, to determine whether 
future cohorts should be dose escalated, have no change in dose, or be dose de-escalated. The 
dose escalation will stop if any of the following criteria is met: 
• The maximum sample size has been reached (27 participants total) 
• At least 9 participants have been accumulated on a dose that is predicted to be the MTD 
• All doses explored appear to be overly toxic and the MTD cannot be determined 
• The escalation would exceed a dose level tested and considered safe by the SMC in 
monotherapy (Part A) 
The mTPI design uses a Bayesian decision framework to inform dose-escalation and dose 
de-escalation decisions. These rules are conceptually similar to those used by the 3+3 design. 
The model-based dose-escalation decisions to help inform the final decision by the SMC can be 
precalculated under the mTPI design and are presented in a 2-way table (Table 4-2). 
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Table 4-2: 
Part B dose escalation/de-escalation schema for mTPI designa 
Number of DLTs 
Number of participants treated at dose level 
3 
4 
5 
6 
7 
8 
9 
0 
E 
E 
E 
E 
E 
E 
E 
1 
S 
S 
S 
S 
E 
E 
E 
2 
D 
D 
S 
S 
S 
S 
S 
3 
DR 
DR 
DR 
D 
S 
S 
S 
4 
 
DR 
DR 
DR 
DR 
DR 
D 
5 
 
 
DR 
DR 
DR 
DR 
DR 
6 
 
 
 
DR 
DR 
DR 
DR 
D=de-escalate to next lower dose; DLT=dose-limiting toxicity; DR=the current dose is unacceptably toxic; 
E=escalate to next higher dose; mTPI= modified toxicity probability interval; S=stay at current dose 
a Target toxicity=0.25 
Table 4-2 has the following interpretation (using 3 and 6 treated participants as examples): 
With 3 participants treated at current dose level: 
• 0 DLTs = escalate 
• 1 DLT = remain at the current dose 
• 2 DLTs = de-escalate 
• 3 DLTs = de-escalate and consider current dose as unacceptably toxic 
With 6 participants treated at current dose level: 
• 0 DLTs = escalate 
• 1 to 2 DLTs = remain at the current dose 
• 3 DLTs = de-escalate 
• >3 DLTs = de-escalate and consider current dose as unacceptably toxic 
4.1.4.3 
Definition of recommended Phase 2 dose in combination with 
TFD/TPI 
The RP2D-T will be defined after all participants evaluable for DLT assessment in Part B have 
completed a minimum of 28 days of treatment (ie, 1 cycle). The RP2D-T will not exceed the 
RP2D-M or the MTD (if an MTD is established). The definition of the RP2D-T will take into 
account the safety profile, PK, PD biomarkers, and any antitumor effect data. 
4.1.5 
Part C – Dose escalation with mFOLFOX6 
Part C is a single arm, open-label, multiple ascending dose-escalation module of ONC001 
evaluating UCB6114 in combination with a mFOLFOX6 to identify the recommended Phase 2 
dose of UCB6114 when used in combination with mFOLFOX6 (RP2D-F). Up to 27 participants 
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with unresectable locally advanced or metastatic colorectal adenocarcinoma, gastric 
adenocarcinoma, and adenocarcinoma of the gastroesophageal junction will be enrolled. 
Part C of ONC001 is planned to be initiated after Cohort 3 of Part A has completed the 28-day 
DLT assessment period and once the SMC has provided a recommendation to dose escalate to 
the next protocol-defined level in Part A of the study. Eligible participants will receive UCB6114 
as an iv infusion Q2W in combination with iv mFOLFOX6 (Q2W) on a 28-day cycle. A 
mFOLFOX6 regimen will be administered at the recommended standard of care dose: oxaliplatin 
85mg/m2 iv infusion on Day 1, leucovorin 400mg/m2 iv infusion on Day 1, 5-fluorouracil 
400mg/m2 iv bolus on Day 1, followed by 5-fluorouracil 1200mg/m2/day continuous infusion on 
Day 1 and Day 2 (2400mg/m2 over 46 hours). The starting dose of UCB6114 in Part C will 
depend on the dose level evaluated in Cohort 3 of Part A (anticipated to be 500mg Q2W iv), and 
the emerging safety profile of UCB6114 monotherapy, including any overlapping toxicity with 
the mFOLFOX6 regimen. 
Part C will be undertaken using the mTPI method. A target DLT rate of 25% with an equivalence 
interval (20% to 30%) will be used to estimate MTD during dose escalation. For all dose levels, 
enrolled participants will be treated in cohorts of 2 to 4 participants (target of 3), who can be 
treated in parallel. Each dose level may have more than one cohort and will have a minimum of 
3 evaluable participants. 
It is expected that up to 3 dose levels of UCB6114 will be explored in combination with the 
selected mFOLFOX6 dosing regimen. However, additional dose levels may be added based on 
emerging data and recommendations of the SMC. Dose escalation steps are currently planned at 
a maximum of 2-fold. Escalating dose levels in Part C will not exceed a dose level tested and 
considered safe by the SMC to allow dose escalation in monotherapy (Part A). 
The decision to dose escalate, have no change in dose, or dose de-escalate in the next cohort will 
occur once all participants in the preceding cohort have been monitored for a minimum of 
28 days (ie, 1 cycle). All available safety data (both within the cohort and from preceding cohorts 
and other parts of the study) will be taken into consideration when dose escalation decisions are 
made. The dose justification is given below in Section 4.3.3. 
The planned duration of treatment is 2 cycles. Participants may, however, remain in the study for 
additional cycles if they are receiving a therapeutic benefit (SD, PR, or CR) or until they fulfill 
one of the criteria for study discontinuation (Section 4.3.3). Participants will continue treatment 
until disease progression, unmanageable toxicity, or withdrawal of consent. Upon 
discontinuation from treatment, participants will be referred to appropriate follow-up care per the 
investigator’s judgment.  
From Part C, a RP2D-F for UCB6114 in combination with mFOLFOX6 will be determined 
based upon the totality of information, including the safety profile, PK data, PD biomarker data, 
and available antitumor activity. 
4.1.5.1 
Study oversight 
The SMC will convene after the last participant in a given cohort has completed the required 
28-day DLT Observation Period. The SMC will decide whether to halt dose escalation, further 
expand the dose level to gain additional safety data, or determine the next dose level to be tested. 
Safety conference calls with investigators and key Sponsor personnel will be held regularly. 
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4.1.5.2 
Dose-limiting toxicity determination and maximum tolerated dose 
definition 
4.1.5.2.1 
Definition of DLT 
Dose-limiting toxicity is defined as one of the following toxicities (according to the NCI CTCAE 
Version 5.0) occurring during the DLT assessment window (Days 1 to 28 of Cycle 1) that is at 
least possibly related to UCB6114: 
• Grade ≥4 neutropenia (ANC <500/μL) lasting ≥7 days 
− In the event of CTCAE Grade 4 neutropenia, full blood count must be performed on the 
seventh day after the onset of the event to determine if a DLT has occurred 
• Grade ≥3 neutropenia complicated by fever (≥38° C) or infection 
• Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion or Grade 4 
thrombocytopenia 
• Any Grade ≥3 non-hematological event with the following exceptions: 
− Grade 3 nausea, vomiting, diarrhea, or fatigue that resolves to Grade ≤2 within 24 hours 
of implementing optimal supportive care 
− Grade 3 laboratory abnormality that is asymptomatic and also deemed by the investigator 
to not be clinically significant 
Investigators, in consultation with the medical monitor, can declare a DLT if a participant is 
experiencing toxicity and treatment cannot be continued without exposing the participant to 
excessive risk. 
4.1.5.2.2 
Determination of maximum-tolerated dose 
For every dose levels, participants will be treated in cohorts of 2 to 4 (target of 3), each dose 
level will have a minimum of 3 and a maximum of 9 participants. 
The target rate of DLTs is 25% (equivalence interval 20% to 30%). The target rate will define 
the MTD of the combination regimen (UCB6114 given in combination with mFOLFOX6). 
The mTPI method relies upon a statistical probability algorithm, calculated using data from all 
participants treated in prior and current cohorts at the same dose level, to determine whether 
future cohorts should be dose escalated, have no change in dose, or be dose de-escalated. The 
dose escalation will stop if any of the following criteria are met: 
• The maximum sample size has been reached (27 participants total) 
• At least 9 participants have been accumulated on a dose that is predicted to be the MTD 
• All doses explored appear to be overly toxic and the MTD cannot be determined 
• The escalation would exceed a dose level tested and considered safe by the SMC in 
monotherapy (Part A) 
The mTPI design uses a Bayesian decision framework to inform dose-escalation and de-
escalation decisions. These rules are conceptually similar to those used by the 3+3 design. The 
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dose-escalation decisions can be pre-calculated under the mTPI design and are presented in a 
2-way table (Table 4-3). 
Table 4-3: 
Part C dose escalation/de-escalation schema for mTPI designa 
Number of DLTs 
Number of participants treated at dose level 
3 
4 
5 
6 
7 
8 
9 
0 
E 
E 
E 
E 
E 
E 
E 
1 
S 
S 
S 
S 
E 
E 
E 
2 
D 
D 
S 
S 
S 
S 
S 
3 
DR 
DR 
DR 
D 
S 
S 
S 
4 
 
DR 
DR 
DR 
DR 
DR 
D 
5 
 
 
DR 
DR 
DR 
DR 
DR 
6 
 
 
 
DR 
DR 
DR 
DR 
D=de-escalate to next lower dose; DLT=dose-limiting toxicity; DR=the current dose is unacceptably toxic; 
E=escalate to next higher dose; mTPI= modified toxicity probability interval; S=stay at current dose 
a Target toxicity=0.25 
Table 4-3 has the following interpretation (using 3 and 6 treated participants as examples): 
With 3 participants treated at current dose level: 
• 0 DLTs = escalate 
• 1 DLT = remain at the same dose 
• 2 DLTs = de-escalate 
• 3 DLTs = de-escalate and consider current dose as intolerable 
With 6 participants treated at current dose level: 
• 0 DLTs = escalate 
• 1 to 2 DLTs = remain at the same dose 
• 3 DLTs = de-escalate 
• >3 DLTs = de-escalate and consider current dose as intolerable 
4.1.5.3 
Defining the recommended Phase 2 dose in combination with 
mFOLFOX6  
The RP2D-F will be defined after all participants evaluable for DLT assessment in Part C have 
completed a minimum of 28 days of treatment (ie, 1 cycle). The RP2D-F will not exceed the 
RP2D-M or the MTD (if an MTD is established). The definition of the RP2D-F will take into 
account the safety profile, PK, PD biomarkers, and any antitumor effect data. 
4.1.6 
Part D – Monotherapy 1 expansion  
Part D can be initiated as soon as the RP2D-M is determined in Part A, or commencement may 
be delayed until evaluation of other schedules or routes of administration in Part A1. 
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4.1.7 
Part E – Monotherapy 2 expansion  
Part E can be initiated as soon as the RP2D-M is determined in Part A, or commencement may 
be delayed until evaluation of other schedules or routes of administration in Part A1. 
4.1.8 
Part F – Combination 1 expansion  
Part F can be initiated as soon as the RP2D-T is determined in Part B. 
4.1.9 
Part G – Combination 2 expansion  
Part G can be initiated as soon as the RP2D-F is determined in Part C. 
4.1.10 
Tumor type selection for modules post-Part A 
The tumor types to be explored in the modules following Part A will be selected based upon the 
following: 
• Data collected through Part A 
• Evolving preclinical and translational data 
• Literature data on the role of gremlin-1 in specific tumors 
• Feasibility of enrollment 
The protocol may be amended to replace the tumor types based on emerging data. 
4.2 
Scientific rationale for study design 
This is a modular study comprising dose escalation and expansion modules. 
The first dose escalation module of the study is an open-label, nonrandomized modified rolling-6 
design (an algorithm-based extension of the 3+3 design which is a standard practice in Phase 1 
oncology studies) in participants with advanced solid tumors, where UCB6114 will be 
administered as monotherapy. 
Two additional dose escalation modules will explore combination regimens (Part B and Part C). 
These will use the mTPI design to guide dose escalation (Ji and Wang, 2013). This design has a 
low risk of exposing participants to doses above the MTD and yields high probabilities for 
identifying the correct MTD. 
The planned monotherapy expansion modules and combination expansion modules will allow 
the simultaneous evaluation of multiple tumor types and standard of care regimens, replacing 
separate Phase 2 studies that would have followed after identification of the RP2D. Combining 
dose escalation and the expansion modules under one protocol will allow multiple hypotheses to 
be addressed (ie, different tumor types, doses) and potentially expedite development and 
approval of UCB6114. 
4.2.1 
Rationale for Part A 
The rationale for Part A is provided in Section 2.1.  
The tumor types for Part A were selected based on the reported prevalence of detectable 
expression and/or expression level of GREM1 mRNA and include bladder urothelial carcinoma, 
breast invasive carcinoma, colorectal adenocarcinoma, esophageal carcinoma, head and neck 
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squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic 
adenocarcinoma, prostate adenocarcinoma, and stomach adenocarcinoma. 
4.2.2 
Rationale for Part A1 
GREM1 mRNA expression has been reported in more than half of tissue samples from colorectal 
and pancreatic cancer (Sneddon et al, 2006). Upregulated gremlin-1 expression has been linked 
to a more advanced tumor stage and poor clinical prognosis in gastric cancer (Sun et al, 2020). In 
CRC, high levels of GREM1 expression were associated with a shorter disease-free survival 
when compared with low levels of GREM1 expression (Davis et al, 2015; Dutton et al, 2019). 
Part A1 will be conducted in participants with colorectal-, gastric-, gastroesophageal junction or, 
pancreatic cancer and will evaluate alternative dosing schedules and duration of infusion to allow 
for future combination regimens with UCB6114 and a range of other treatments. Part A1 will use 
modifications to the 5th dose-level in Part A (2000mg Q2W) should this be determined to be 
 
(i.e. DLT incidence <33%, see Section 4.1.2.4). 
4.2.3 
Rationale for Part B and Part C 
UCB nonclinical data showed that, in the ApcMin;Vil1-Grem-1 model of CRC in late stage, 
disease established mice, the combination of 5-fluorouracil and the murinized version of 
UCB6114, Ab7326 mIgG1, significantly prolonged mouse lifespan. This supports the evaluation 
of UCB6114 in selected gastrointestinal cancer types in combination with a fluoropyrimidine-
based chemotherapy. 
Trifluridine/tipiracil chemotherapy is used in different lines of treatment which depends on the 
tumor type, the patients’ comorbidities, and personal preferences. As no overlapping toxicity is 
expected, in Part B the dose escalation of UCB6114 will start in combination with therapeutic 
doses of the TFD/TPI chemotherapy, with the expectation that participants will benefit from the 
standard of care chemotherapy. 
The mFOLFOX6 chemotherapy regimen, consisting of leucovorin, 5-fluorouracil, and 
oxaliplatin, has been evaluated in CRC for more than 15 years and is commonly used in a variety 
of gastrointestinal cancers, including CRC and gastric- and gastroesophageal junction 
adenocarcinoma. The mFOLFOX6 chemotherapy regimen is used in different lines of treatment 
which depends on the tumor type, the patients’ comorbidities, and personal preferences. As no 
overlapping toxicity is expected, in Part C the dose escalation of UCB6114 will start in 
combination with therapeutic doses of the mFOLFOX6 chemotherapy, with the expectation that 
participants will benefit from the standard of care chemotherapy. 
4.2.4 
Dosing strategy 
The monotherapy dose escalation module (Part A) will systematically evaluate the safety, 
tolerability, and PK of UCB6114 at increasing dose levels. 
The planned dose escalation steps are given in Table 6-5. In the event that exposure is 
substantially lower than anticipated, dose escalations will still not exceed a 5-fold increase. 
Doses will be administered every 2 weeks by iv infusion. 
In Part A, the SMC will decide on the dose escalation steps (see Section 4.1.2.1). Based upon the 
emerging data, the SMC may decide to add up to 2 additional dose levels and/or schedules. 
Doses above 2000mg iv Q2W will be subject to a substantial amendment.  
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The combination dose escalation modules (Part B and Part C) will start with the Part A Cohort 3 
dose of UCB6114. Depending on the eventual determination of the RP2D-M from Part A, this 
starting dose could represent 25% to 100% of the RP2D-M. Doses of UCB6114 in the 
combination dose escalation modules will not exceed the MTD if an MTD is determined. 
Combination agents will be given at the approved doses and schedules. 
The RP2D-M will be used in the monotherapy expansion modules (Part D and Part E) and the 
RP2D in combination therapy will be used for the combination expansion modules (Part F and 
Part G). 
4.3 
Justification for dose 
4.3.1 
Starting dose in Part A 
The rationale to start at UCB6114 100mg administered iv Q2W in Part A is based on the 
following: 
• The maintenance of a predicted suppression of gremlin-1 associated with antitumor activity 
(prolonged survival; predicted 95% suppression across the dosing interval) observed in 
nonclinical pharmacology models assuming a low level of gremlin-1 (
) in human 
and a slow gremlin-1 turnover rate 
) based on a PK/PD model scaled to human 
developed using single ascending dose data from cynomolgus monkeys. 
• The low risk of UCB6114’s mechanism of action (antagonism of gremlin-1) and the class of 
molecule (fully human IgG4P), in combination with the lack of relevant adverse findings 
from the nonclinical 13-week GLP toxicity studies. 
When Ab7326 mIgG1 (murinized version of UCB6114) was dosed iv at 30mg/kg twice weekly 
(BIW) in the ApcMin/Vil1-Grem1 model, or 30mg/kg once weekly (QW) in the Vil1-Grem1 
model, a significantly increased survival over vehicle control was observed. Lower doses had 
reduced antitumor activity or had no effect, whereas higher doses did not appear to further 
increase survival. The human exposures at this dose level are anticipated to be lower than the 
exposures achieved at the efficacious doses identified in the nonclinical pharmacology models. 
These models are known to highly over-express gremlin-1 mRNA and may have much higher 
levels of gremlin-1 protein present than in patients with advanced solid tumors; therefore, the 
human exposures required for antitumor activity are anticipated to be lower. The median average 
concentration at steady state (Cav,ss) anticipated following 100mg iv Q2W is 20.4µg/mL, which 
corresponds to a concentration 10-fold greater than the cellular IC50 for the ID-1 reporter assay 
(an in vitro assay measuring the functional inhibition of BMP signaling by gremlin-1). The FIH 
starting dose is anticipated to have a >100-fold safety margin based on the outcome of the 13-
week GLP toxicity studies in cynomolgus monkeys and rats. Further details regarding dose 
modification are provided in Section 6.6. 
4.3.2 
Doses in Part A1 
Part A1 will be initiated after Cohort 5 of Part A, with dosing schedules that aim to maintain a 
similar exposure at steady state (average UCB6114 concentration at steady-state; Cav,ss; see 
Table 6-5) to the Part A Cohort 5 dose of 2000mg Q2W iv. Cohort 1 will assess safety, PK and 
PD of the new dose formulation. Cohorts 2 to 4 will assess shorter infusion time and less 
frequent administration. 
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4.3.3 
Starting doses for UCB6114 and standard of care regimens in Part B 
and Part C 
4.3.3.1 
UCB6114 dosing 
In both Part B and Part C, UCB6114 will be administered by iv infusion on Days 1 and 15 of 
each cycle. The starting dose of UCB6114 will depend on the dose level evaluated in Cohort 3 of 
Part A (anticipated to be 500mg Q2W iv), the emerging safety profile of UCB6114 monotherapy 
which may overlap with expected toxicities associated with TFD/TPI (Part B) or mFOLFOX6 
(Part C). The rationale for the UCB6114 starting dose in combination with TFD/TPI (Part B) or 
mFOLFOX6 (Part C) is based on: 
• Nonclinical safety studies of UCB6114, which demonstrated no toxicities (with the possible 
exception of reproductive findings in female rats) that would overlap with those commonly 
seen with cytotoxic chemotherapy.  
• A review of dosing targeted and cytotoxic drug combinations between 2010 and 2013 which 
showed that for combinations involving an antibody as the targeted agent, 69 out of 121 
studies (57%; 37 out of 68 drug combinations) could give both agents at 100% of the 
recommended dose (Nikanjam et al, 2016).  
• A nonclinical study of Ab7326 mIgG1 in the ApcMin;Vil1-Grem-1 mouse model, in which the 
lowest monotherapy dose that showed qualitative improvement in survival was 
15mg/kg BIW subcutaneously (sc) (for 6 weeks followed by 15mg/kg QW sc thereafter) 
when dosing from an age of 21 days. A clinical dose of UCB6114 of 1000mg Q2W iv is 
expected to provide similar exposure in humans as the 15mg/kg BIW dose achieved in mice. 
The combination UCB6114 start dose of 500mg Q2W iv is expected to provide an exposure 
approximately 50% of this. 
• A nonclinical study of Ab7326 mIgG1 in the ApcMin;Vil1-Grem-1 mouse model, in which 
30mg/kg BIW sc (for 6 weeks followed by 30mg/kg QW thereafter) given in combination 
with 5-fluorouracil increased survival relative to either monotherapy when dosing from an 
age of 35 days (which is close to the point where untreated mice are sacrificed on humane 
grounds). The combination UCB6114 start dose of 500mg Q2W iv is expected to provide an 
exposure approximately 25% of this. 
Considering the above points, a start dose of UCB6114 of 500mg Q2W iv in combination with 
TFD/TPI (Part B) or FOLOFX (Part C) is expected to have an adequate safety profile and is 
expected to provide approximately 25% of the exposure that was associated with increased 
survival in combination with 5-fluorouracil in the mouse model.  
As no significant difference in survival was observed between doses of 30 and 60mg/kg BIW sc 
of Ab7326 mIgG1 in the ApcMin;Vil1-Grem-1 mouse model, doses of UCB6114 higher than 
2000mg Q2W iv in humans are not likely warranted as monotherapy or in combination. 
Therefore, evaluation of 3 UCB6114 dose-levels escalated in combination with TFD/TPI 
(Part B) or mFOLFOX6 (Part C), anticipated to be 500mg, 1000mg, and 2000mg administered 
Q2W iv, is proposed. 
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4.3.3.2 
Standard of Care regimen dosing 
There are no planned escalations of the standard of care regimen doses. Dose modifications 
based on toxicity are described in Section 6.6.  
4.3.3.2.1 
Part B 
In Part B, TFD/TPI will be given orally bid on Days 1 to 5 and Days 8 to 12 of each 28-day 
treatment cycle. The starting dose of TFD/TPI in adults is 35mg/m2/dose administered orally bid 
on Days 1 to 5 and Days 8 to 12 of each 28-day cycle. The dosage is calculated according to 
body surface area (BSA) (Table 4-4). The dosage must not exceed 80mg/dose (based on the 
trifluridine component). 
Table 4-4: 
TFD/TPI dosage calculation 
Starting 
dose 
BSA (m2) 
Dose (mg) 
Tablets per dose 
Total daily 
dose (mg) 
15mg/6.14mg 
20mg/8.19mg 
35 mg/m2 
< 1.07 
35 
1 
1 
70 
1.07 to 1.22 
40 
0 
2 
80 
1.23 to 1.37 
45 
3 
0 
90 
1.38 to 1.52 
50 
2 
1 
100 
1.53 to 1.68 
55 
1 
2 
110 
1.69 to 1.83 
60 
0 
3 
120 
1.84 to 1.98 
65 
3 
1 
130 
1.99 to 2.14 
70 
2 
2 
140 
2.15 to 2.29 
75 
1 
3 
150 
≥2.30 
80 
0 
4 
160 
BSA=body surface area 
The tablets must be swallowed whole with a glass of water within 1 hour of completion of the 
morning and evening meals. Study participants will be instructed to swallow the required number 
of tablets at approximately the same times on each day. Study participants will be instructed to 
wash their hands before and after taking the drug. The TFD/TPI tablets may be dispensed to the 
study participants once predose assessments are completed and eligibility is confirmed, up to 
3 days prior to Day 1 (Table 1-7). The sites can, however, choose to do all assessments on Day 1, 
prior to dosing of any study medication. 
Participants must not retake doses of TFD/TPI that are vomited or were missed and should 
continue with the next scheduled dose. If tablets are handled by anyone other than the 
participant, this person must wear gloves. 
4.3.3.2.2 
Part C 
In Part C, mFOLFOX6 will be administered iv every 2 weeks in 28-day treatment cycles. Dosing 
will be based on calculated body surface area and will consist of oxaliplatin 85mg/m2 iv infusion 
on Day 1, leucovorin 400mg/m2 iv infusion on Day 1, 5-fluorouracil 400mg/m2 iv bolus on Day 
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1, followed by 5-fluorouracil 1200mg/m2/day continuous infusion on Day 1 and 2 (2400mg/m2 
over 46 hours). 
The recommended administration of mFOLFOX6 is shown in Table 4-5.  
Table 4-5: 
mFOLFOX6 dosing 
Drug 
Dose 
Administration 
Oxaliplatina 
85mg/m2 
iv in 250 to 500mL glucose 5% over 2 hours 
Leucovorina 
400mg/m2 
iv in 250mL glucose 5% over 2 hours  
5-Fluorouracil  
400mg/m2 
iv bolus 
5-Fluorouracil  
2400mg/m2 
iv over 46 hours via an infusor 
mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 
and Day 2, and oxaliplatin 85mg/m2 on Day 1; iv=intravenous(ly) 
a Oxaliplatin and leucovorin may be infused over the same two-hour period by using a Y-site connector placed 
immediately before the infusion site. 
Within the study, mFOLFOX6 is administered every 14 days in 28-day treatment cycles up to a 
maximum of 6 cycles. 
Antiemetic premedication prior to administration of chemotherapy is recommended and sites 
should follow their institutional standard of care.  
4.4 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population is defined separately for each study module and is presented in Table 5-1. 
Table 5-1: 
Study population 
Study module 
Population 
Part A: Monotherapy dose 
escalation 
Participants with recurrent or metastatic advanced solid tumors resistant or 
refractory to standard treatment from a variety of tumors types associated 
with gremlin-1 mRNA expression (ie, bladder urothelial carcinoma, breast 
invasive carcinoma, colorectal adenocarcinoma, esophageal carcinoma, 
head and neck squamous cell carcinoma, lung adenocarcinoma, lung 
squamous cell carcinoma, pancreatic adenocarcinoma, prostate 
adenocarcinoma and stomach adenocarcinoma) 
Part A1: Monotherapy dose 
optimization 
Participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, adenocarcinoma of the 
gastroesophageal junction, or pancreatic cancer 
Part B: Combination dose 
escalation with TFD/TPI 
Participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the 
gastroesophageal junction 
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Study module 
Population 
Part C: Combination dose 
escalation with 
mFOLFOX6 
Participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the 
gastroesophageal junction 
Part D: Monotherapy 
expansion  
Participants with recurrent or metastatic advanced solid tumor type 
selected  
Part E: Monotherapy 
expansion  
Participants with recurrent or metastatic advanced solid tumor type 
selected 
Part F: Combination 
therapy expansion  
Participants with recurrent or metastatic advanced solid tumor type 
selected 
Part G: Combination 
therapy expansion 
Participants with recurrent or metastatic advanced solid tumor type 
selected 
mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 and 
Day 2, and oxaliplatin 85mg/m2 on Day 1; mRNA=messenger ribonucleic acid; TFD/TPI=trifluridine/tipiracil 
5.1 
Inclusion criteria 
5.1.1 
Part A 
Participants are eligible to be included in Part A of the study only if all of the following criteria 
apply: 
Age 
1. Participant must be at least 18 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2a. Participant has a histologically and/or cytologically confirmed diagnosis of one of the 
following advanced solid tumor types: colorectal adenocarcinoma, esophageal carcinoma, 
head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell 
carcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, stomach adenocarcinoma, 
bladder urothelial carcinoma, or breast invasive carcinoma. 
3b. Participant has advanced disease (ie, unresectable locally recurrent or metastatic) and had 
access to approved therapies. 
4. Participant has measurable or non-measurable disease as defined by the relevant RECIST 
(Appendix 9, Section 11.9). 
5. Participant has a performance status of ≤1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Appendix 8, Section 11.8). 
6. Participant has discontinued all previous therapies for cancer (with exception of treatments 
defined in Section 6.5.1), including chemotherapy, radiotherapy, cancer-related hormonal 
therapy, or other investigational therapy for a minimum of 28 days or 5 half-lives (whichever 
is shorter) (6 weeks for mitomycin-C or nitrosoureas) prior to study enrollment and 
recovered from the acute effects of therapy. 
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7. Participant has an estimated life expectancy of ≥12 weeks. 
8. Participant has adequate bone marrow function, including the following: 
a. Absolute neutrophil count ≥1.5x109/L. 
b. Platelet count ≥100x109/L. 
c. Hemoglobin ≥9.0g/dL (or 5.5mmol/L). 
Participants with hemoglobin ≥8g/dL but <9g/dL may receive erythrocyte transfusions to 
achieve a hemoglobin level ≥9.0 g/dL. Initial treatment must not begin until 2 days after 
the erythrocyte transfusion and after the confirmation of hemoglobin ≥9.0g/dL. 
Contraception 
9. A male participant must agree to use contraception as detailed in Appendix 4 (Section 11.4) 
of this protocol during the treatment period and for at least 3 months after the last dose of 
study treatment and refrain from donating sperm during this period. 
10. A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 11.4]), not breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential as defined Appendix 4 (Section 11.4). 
OR 
b. A woman of childbearing potential who agrees to follow the contraceptive guidance in 
Appendix 4 (Section 11.4) during the treatment period and for at least 3 months after the 
last dose of study treatment. 
Informed consent 
11. Participant is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. 
5.1.2 
Part A1 
Participants are eligible to be included in Part A1 of the study only if all of the following criteria 
apply: 
Age 
1. Participant must be at least 18 years of age inclusive, at the time of signing the informed 
consent.  
Type of participant and disease characteristics 
2. Participant has histologically and/or cytologically confirmed diagnosis of one of the 
following advanced solid tumor types: colorectal adenocarcinoma, gastric adenocarcinoma, 
adenocarcinoma of the gastroesophageal junction, or pancreatic cancer. 
3. Participant has advanced disease (ie, unresectable locally recurrent or metastatic). 
4. Participant must have received and is refractory or intolerant to standard therapy appropriate 
for the tumor type. 
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5. Participant has measurable or non-measurable disease as defined by the relevant RECIST 
(Appendix 9, Section 11.9). 
6. Participant has a performance status of ≤1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Appendix 8, Section 11.8). 
7. Participant must have tumor lesion(s) or metastases amenable to biopsy, excluding bone 
metastases, as confirmed by a radiologist, if appropriate, and as deemed safe by the 
Investigator.  
8. Participant must consent to the mandatory pretreatment and on-treatment tumor biopsies. 
9. Participant has discontinued all previous therapies for cancer (with exception of treatments 
defined in Section 6.5.2), including chemotherapy, radiotherapy, cancer-related hormonal 
therapy, or other investigational therapy for a minimum of 28 days or 5 half-lives (whichever 
is shorter) (6 weeks for mitomycin-C or nitrosoureas) prior to start of study medication and 
recovered from the acute effects of therapy. 
10. Any clinically significant treatment-related toxicity from prior therapy must have resolved to 
Grade ≤1 prior to study entry, with the exception of alopecia. 
11. Participant has an estimated life expectancy of ≥12 weeks. 
Contraception 
12. A male participant must agree to use contraception as detailed in Appendix 4 (Section 11.4) 
of this protocol during the treatment period and for at least 3 months after the last dose of 
study treatment and refrain from donating sperm during this period. 
13. A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 11.4]), not breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential as defined in Appendix 4 (Section 11.4). 
OR 
b. A woman of childbearing potential who agrees to follow the contraceptive guidance in 
Appendix 4 (Section 11.4) during the treatment period and for at least 3 months after the 
last dose of study treatment. 
Informed consent 
14. Participant is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. 
5.1.3 
Part B 
Participants are eligible to be included in Part B of the study only if all of the following criteria 
apply: 
Age 
1. Participant must be at least 18 years of age inclusive, at the time of signing the ICF. 
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Type of participant and disease characteristics 
2. Participant has a histologically and/or cytologically confirmed diagnosis of one of the 
following advanced solid tumor types: colorectal adenocarcinoma, gastric adenocarcinoma, 
or adenocarcinoma of the gastroesophageal junction. 
3a. Participant has advanced disease (ie, unresectable locally advanced or metastatic).  
4a. Participants must have received, or be intolerant to, or deemed not suitable for, at least 2 
prior regimens of treatment, including the following standard of care anti-cancer treatments 
(where such treatments are available as standard of care): 
a. Participants with colorectal cancer: fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy, an anti-vascular endothelial growth factor biological therapy, and, if RAS 
wild-type, an anti-epidermal growth factor receptor (EGFR) therapy, or if microsatellite 
instability high/deficient mismatch repair (MSI-H/dMMR) immunotherapy (eg, 
nivolumab, pembrolizumab and ipilimumab).  
b. Participants with gastric or gastroesophageal junction adenocarcinoma: fluoropyrimidine, 
a platinum, either a taxane or irinotecan, ramucirumab, and, if appropriate, human 
EGFR 2/neu-targeted therapy. 
5. Participant has measurable or nonmeasurable disease as defined by the relevant RECIST. 
6. Participant has a performance status of ≤1 on the ECOG scale. 
7. Participant has discontinued all previous therapies for cancer (with exception of treatments 
defined in Section 6.5.3 ), including chemotherapy, radiotherapy, cancer-related hormonal 
therapy, or other investigational therapy for a minimum of 28 days or 5 half-lives (whichever 
is shorter) (6 weeks for mitomycin-C or nitrosoureas) prior to start of study medication and 
recovered from the acute effects of therapy. 
Any clinically significant treatment-related toxicity from prior therapy must have resolved to 
Grade ≤1 prior to study entry, with the exception of alopecia. 
8. Participant has an estimated life expectancy of ≥12 weeks. 
Contraception 
9. A nonsterilized male participant with female partners of reproductive potential must agree to 
use contraception during the Treatment Period and for at least 6 months after the final dose of 
study treatment and must refrain from donating sperm during this period. 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies: 
a. Not a woman of childbearing potential as defined in Appendix 4 (Section 11.4). 
OR 
b. A woman of childbearing potential who agrees to follow the contraceptive guidance in 
Appendix 4 (Section 11.4) during the Treatment Period and for at least 6 months after the 
final dose of study treatment. 
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Informed consent 
10. Participant is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
5.1.4 
Part C 
Participants are eligible to be included in Part C of the study only if all of the following criteria 
apply: 
Age 
1. Participant must be at least 18 years of age inclusive, at the time of signing the ICF. 
Type of participant and disease characteristics 
2. Participant has a histologically and/or cytologically confirmed diagnosis of one of the 
following advanced solid tumor types: colorectal adenocarcinoma, gastric adenocarcinoma, or 
adenocarcinoma of the gastroesophageal junction. 
3a. Participant has advanced disease (ie, unresectable locally advanced or metastatic) not 
amenable to curative treatment.  
4. Participants must have received, or be intolerant to, or deemed not suitable for at least 1 prior 
line of standard anti-cancer treatment in the locally advanced or metastatic setting. 
5. Participant has measurable or nonmeasurable disease as defined by the relevant RECIST. 
6. Participant has a performance status of ≤1 on the ECOG scale. 
7. Participant has discontinued all previous therapies for cancer (with exception of treatments 
defined in Section Section 6.5.4 ), including chemotherapy, radiotherapy, cancer-related 
hormonal therapy, or other investigational therapy for a minimum of 28 days or 5 half-lives 
(whichever is shorter) (6 weeks for mitomycin-C or nitrosoureas) prior to start of study 
medication. 
Any clinically significant treatment-related toxicity from prior therapy must have resolved to 
Grade ≤1 prior to study entry, with the exception of alopecia. 
8. Participant has an estimated life expectancy of ≥12 weeks. 
Contraception 
9. A nonsterilized male participant with female partners of reproductive potential must agree to 
use contraception during the treatment period and for at least 6 months after the final dose of 
study treatment and must refrain from donating sperm during this period. 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies: 
a. Not a woman of childbearing potential as defined in Appendix 4 (Section 11.4). 
OR 
b. A woman of childbearing potential who agrees to follow the contraceptive guidance in 
Appendix 4 (Section 11.4) during the Treatment Period and for at least 6 months after the 
final dose of study treatment. 
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Informed consent 
10. Participant is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
Inclusion criteria for Parts D, E, F, and G will be defined in a protocol amendment. 
5.2 
Exclusion criteria 
5.2.1 
Part A 
Participants are excluded from Part A of the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this study. 
2. Deleted. 
3. Participant has a known hypersensitivity to any components of the study medication or 
comparable drugs (eg, monoclonal antibodies, drugs targeting BMP signaling pathway). 
4. Active and clinically significant bacterial, fungal, or viral infection, known infections with 
hepatitis B, hepatitis C, known human immunodeficiency virus, or acquired 
immunodeficiency syndrome related illness.  
5. Deleted. 
6.  Participants with known tuberculosis (TB) infection, at high risk of acquiring TB infection, 
with latent TB infection, or current or history of nontuberculous mycobacteria infection. 
7a. Symptomatic central nervous system (CNS) malignancy or metastases. Screening of 
asymptomatic participants without history of CNS metastases is not required. Participants 
with asymptomatic CNS lesions should have completed standard therapy for their CNS 
lesions prior to study enrollment. 
8. Current hematologic malignancies, for example acute or chronic leukemia. 
9. Chronic underlying infection (for example, unhealed draining abscess, fistula) that, in the 
view of the investigator, should preclude the participant from enrolling in the study. 
10. Prior organ or allogeneic stem-cell transplantation. 
11. Moderate or severe cardiovascular disease including: 
a. Presence of cardiac disease, including a myocardial infarction within 6 months prior to 
study entry, unstable angina pectoris, New York Heart Association Class III/IV 
congestive heart failure, or uncontrolled hypertension. 
b. Documented major electrocardiogram (ECG) abnormalities at the investigator’s 
discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, 
second- or third-degree, atrioventricular block, bundle branch blocks, ventricular 
hypertrophy). 
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c. Major abnormalities documented by echocardiography (for example, moderate or severe 
heart valve function defect and/or left ventricular ejection fraction <50%), evaluation 
based on the institutional lower limit of normal. 
d. Participant has experienced any of the following during the last 6 months: 
coronary/peripheral bypass graft, cerebrovascular accident, transient ischemic attack, 
deep vein thrombosis, or symptomatic pulmonary embolism. 
12. Alanine transaminase (ALT) or aspartate aminotransferase (AST) are ≥2xULN (if liver 
metastases are present: ≥5xULN). 
13. Alkaline phosphatase (ALP) is ≥3xULN (if liver metastases are present: ≥5xULN). 
14. Bilirubin ≥1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%). 
15a. 
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
other than liver metastases (with the exception of Gilbert’s syndrome, asymptomatic 
gallstones, or biliary stent provided bilirubin levels do not exceed limits as per Exclusion 
Criterion #14). 
For study participants with a baseline result ≥2xULN for ALT, AST, or ≥3xULN ALP, or 
≥1.5xULN total bilirubin, the presence of liver metastases must be recorded in the electronic 
Case Report Form (eCRF). 
16b. QTc >450msec (note: The QTc is the QT interval corrected for heart rate according to 
Fridericia’s formula [QTcF]; it is either machine-read or manually over-read). 
Prior/Concomitant therapy 
17. Participant is taking a prohibited medication or has taken a prohibited medication as defined 
in Section 6.5.5. 
18. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) 
within 28 days prior to dosing. 
Prior/Concurrent clinical study experience 
19a. Current enrollment or past participation within the last 28 days before signing of consent in 
this or any other clinical study involving an IMP.  
Other exclusions 
20. Participant has impaired renal function as indicated by serum creatinine >1.5xULN. 
21. Participant has experienced any major surgery within 28 days prior to the first administration 
of the medication under investigation in the study. 
22a. International normalized ratio (INR), prothrombin time (PT), or activated partial 
thromboplastin time (aPTT) as follows:  
− In the absence of therapeutic intent to anticoagulate the participant: 
◦ 
INR >1.5xULN or PT >1.5xULN or aPTT >1.5xULN, or 
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◦ 
In the presence of therapeutic intent to anticoagulate the participant: INR or PT or 
aPTT not within therapeutic limits (according to the medical standards at the 
institution) or participant has not been on a stable dose of anticoagulant for at least 
2 weeks prior to dosing. 
5.2.2 
Part A1 
Participants are excluded from Part A1 of the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study. 
2. Participant has a known hypersensitivity to any components of the study medication or 
comparable drugs (eg, monoclonal antibodies, drugs targeting BMP signaling pathway). 
3. Active and clinically significant bacterial, fungal, or viral infection, known infections with 
hepatitis B, hepatitis C, known human immunodeficiency virus, or acquired 
immunodeficiency syndrome related illness.  
4.  Participants with known tuberculosis (TB) infection, at high risk of acquiring TB infection, 
with latent TB infection, or current or history of nontuberculous mycobacteria infection. 
5. Symptomatic central nervous system (CNS) malignancy or metastases. Screening of 
asymptomatic participants without history of CNS metastases is not required. Participants 
with asymptomatic CNS lesions should have completed standard therapy for their CNS 
lesions prior to study enrollment.  
6. Current hematologic malignancies, for example acute or chronic leukemia. 
7. Participants with evidence or history of bleeding diathesis. 
8. Chronic underlying infection (for example, unhealed draining abscess, fistula) that, in the 
view of the Investigator, should preclude the participant from enrolling in the study. 
9. Prior organ or allogeneic stem-cell transplantation. 
10. Moderate or severe cardiovascular disease including: 
a. Presence of cardiac disease, including a myocardial infarction within 6 months prior to 
study entry, unstable angina pectoris, New York Heart Association Class III/IV 
congestive heart failure, or uncontrolled hypertension. 
b.  Documented major electrocardiogram (ECG) abnormalities at the Investigator’s 
discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, 
second- or third-degree, atrioventricular block, bundle branch blocks, ventricular 
hypertrophy). 
c. Major abnormalities documented by echocardiography (for example, moderate or severe 
heart valve function defect and/or left ventricular ejection fraction <50%), evaluation 
based on the institutional lower limit of normal. 
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d. Participant has experienced any of the following during the last 6 months: 
coronary/peripheral bypass graft, cerebrovascular accident, transient ischemic attack, 
deep vein thrombosis, or symptomatic pulmonary embolism. 
Organ Function 
11. Participant has inadequate bone marrow function, including the following: 
a. ANC<1.5x109/L. 
b. Platelet count<100x109/L. 
c. Hemoglobin<9.0g/dL (or 5.5mmol/L). 
12. Prothrombin time or aPTT outside normal range, or international normalized ratio (INR) 
≥1.5. 
13. Participant has impaired renal function as indicated by serum creatinine >1.5x upper limit of 
normal (ULN) or calculated creatinine clearance of <50mL/min on the bases of the Cockroft-
Gault glomerular filtration rate estimation (Appendix 2 [Section 11.2 ] with formula). 
14. Alanine transaminase (ALT) or aspartate aminotransferase (AST) are ≥2xULN (if liver 
metastases present ≥5xULN). 
15. Bilirubin ≥1.5xULN 
16. Current or chronic history of liver disease, or known hepatic or biliary abnormalities other 
than liver metastases (with the exception of Gilbert’s syndrome, asymptomatic gallstones, or 
biliary stent provided bilirubin levels do not exceed limits as per Exclusion Criterion #12). 
17. QTc >450msec (note: The QTc is the QT interval corrected for heart rate according to 
Fridericia’s formula [QTcF]; it is either machine-read or manually over-read). 
Prior/Concomitant therapy 
18. Participant is taking a prohibited medication or has taken a prohibited medication as defined 
in Section 6.5.6. 
19. Participant is receiving therapeutic or prophylactic anticoagulation therapy. 
20. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) 
within 28 days prior to dosing. 
Prior/Concurrent clinical study experience 
21. Current enrollment in another clinical study, unless it is an observational (noninterventional) 
clinical study or the follow-up period of an interventional study. 
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5.2.3 
Part B 
Participants are excluded from Part B of the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study. 
2a. Participant has a known hypersensitivity to any study medications or components of the 
study medications or comparable drugs (eg, trifluridine or tipiracil hydrochloride, 
monoclonal antibodies, drugs targeting BMP signaling pathway). 
3. Participant is unable to swallow tablets. 
4. Participant has hereditary problems of galactose intolerance, total lactase deficiency, or 
glucose-galactose malabsorption. 
5. Participant has active and clinically significant bacterial, fungal, or viral infection, known 
infections with hepatitis B, hepatitis C, known human immunodeficiency virus, or acquired 
immunodeficiency syndrome related illness. 
6. Participant has known TB infection, is at high risk of acquiring TB infection, or has current 
or history of nontuberculous mycobacteria infection. 
7a. Participant has symptomatic CNS malignancy or metastases. Screening of asymptomatic  
participants without history of CNS metastases is not required. Participants with 
asymptomatic CNS lesions should have completed standard therapy for their CNS lesions 
prior to study enrollment. 
8. Participant has current hematologic malignancies, eg, acute or chronic leukemia. 
9. Participant has chronic underlying infection (eg, unhealed draining abscess, fistula) that, in 
the view of the investigator, should preclude the participant from enrolling in the study. 
10. Participant has prior organ or allogeneic stem-cell transplantation. 
11. Participant has moderate or severe cardiovascular disease including: 
a. Presence of cardiac disease, including a myocardial infarction within 6 months prior to 
study entry, unstable angina pectoris, New York Heart Association Class III/IV 
congestive heart failure, or uncontrolled hypertension. 
b. Documented major ECG abnormalities at the investigator’s discretion (for example, 
symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree 
atrioventricular block, bundle branch blocks, ventricular hypertrophy). 
c. Major abnormalities documented by echocardiography (for example, moderate or severe 
heart valve function defect and/or left ventricular ejection fraction <50%), evaluation 
based on the institutional lower limit of normal. 
d. Participant has experienced any of the following during the last 6 months: 
coronary/peripheral bypass graft, cerebrovascular accident, transient ischemic attack, 
deep vein thrombosis, or symptomatic pulmonary embolism. 
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12. Participant has experienced any major surgery within 28 days prior to the first administration 
of the medication under investigation in the study. 
13. Participant has serum potassium, magnesium, or calcium levels outside the institutional 
normal limits. 
Participants with electrolyte levels outside of the normal range will be eligible if these values 
are corrected upon retesting following any necessary supplementation. 
Organ function 
14. Participant has inadequate bone marrow function, including the following: 
a. ANC <1.5x109/L 
b. Platelet count <100x109/L 
c. Hemoglobin <9.0g/dL (or 5.5mmol/L) 
Participants with hemoglobin ≥8.0g/dL but <9.0g/dL may receive erythrocyte transfusions to 
achieve a hemoglobin level ≥9.0g/dL. Initial treatment must not begin until 2 days after the 
erythrocyte transfusion and after the confirmation of hemoglobin ≥9.0g/dL. 
15. Participant has impaired renal function as indicated by serum creatinine >1.5x upper limit of 
normal (ULN) or calculated creatinine clearance of <50mL/min on the bases of the Cockroft-
Gault glomerular filtration rate estimation (Appendix 2 [Section 11.2] with formula). 
16. Alanine transaminase or AST are ≥2xULN (if liver metastases are present: ≥5xULN). 
For study participants with a baseline result ≥2xULN for ALT and/or AST, the presence of 
liver metastases must be recorded in the eCRF. 
17. Bilirubin ≥1.5xULN 
18. Current or chronic history of liver disease or known hepatic or biliary abnormalities other 
than liver metastases (with the exception of Gilbert’s syndrome, asymptomatic gallstones, or 
biliary stent, provided bilirubin levels do not exceed limits as per Exclusion Criterion #17). 
19. International normalized ratio, PT, or aPTT as follows: 
a. In the absence of therapeutic intent to anticoagulate the participant, INR or PT or aPTT 
>1.5xULN, or 
b. In the presence of therapeutic intent to anticoagulate the participant, INR or PT or aPTT 
not within therapeutic limits (according to the medical standards at the institution) or 
participant has not been on a stable dose of anticoagulant for at least 2 weeks 
20b. QTc >450msec (note: The QTc is the QTcF; it is either machine-read or manually over-
read). 
Prior/Concomitant therapy 
21. Participant is taking a prohibited medication or has taken a prohibited medication as defined 
in Section 6.5.7  within 28 days of starting study treatment. 
22. Participant has received prior treatment with TFD/TPI. 
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23. Administration of a live, attenuated vaccine (eg, live attenuated influenza vaccine [LAIV], 
measles, mumps, and rubella [MMR], varicella; FluMist®) within 28 days of starting study 
treatment and for up to 3 months after the final dose of IMP or anticipation that such vaccine 
will be required during the study.  
Prior/Concurrent clinical study experience 
24. Current enrollment in another clinical study, unless it is an observational (noninterventional) 
clinical study or the follow-up period of an interventional study. 
5.2.4 
Part C 
Participants are excluded from Part C of the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study. 
2a. Participant has a known hypersensitivity to any study medications or components of the 
study medications or comparable drugs (eg, oxaliplatin, fluorouracil, calcium 
folinate/leucovorin, monoclonal antibodies, drugs targeting BMP signaling pathway). 
3. Participant has a history of hypersensitivity to oxaliplatin or other platinum-based drugs. 
4. Participant has active and clinically significant bacterial, fungal, or viral infection, known 
infections with hepatitis B, hepatitis C, known human immunodeficiency virus, or acquired 
immunodeficiency syndrome related illness. 
5. Participants has known TB infection, is at high risk of acquiring TB infection, or has current 
or history of nontuberculous mycobacteria infection. 
6a. Participant has symptomatic CNS malignancy or metastases. Screening of asymptomatic  
participants without history of CNS metastases is not required. Participants with 
asymptomatic CNS lesions should have completed standard therapy for their CNS lesions 
prior to study enrollment. 
7. Participant has current hematologic malignancies, eg, acute or chronic leukemia. 
8. Participant has chronic underlying infection (eg, unhealed draining abscess, fistula) that, in 
the view of the investigator, should preclude the participant from enrolling in the study. 
9. Participant has prior organ or allogeneic stem-cell transplantation. 
10. Participant has moderate or severe cardiovascular disease including: 
a. Presence of cardiac disease, including a myocardial infarction within 6 months prior to 
study entry, unstable angina pectoris, New York Heart Association Class III/IV 
congestive heart failure, or uncontrolled hypertension. 
b. Documented major ECG abnormalities at the investigator’s discretion (for example, 
symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree 
atrioventricular block, bundle branch blocks, ventricular hypertrophy). 
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c. Major abnormalities documented by echocardiography (for example, moderate or severe 
heart valve function defect and/or left ventricular ejection fraction <50%), evaluation 
based on the institutional lower limit of normal. 
d. Participant has experienced any of the following during the last 6 months: 
coronary/peripheral bypass graft, cerebrovascular accident, transient ischemic attack, 
deep vein thrombosis, or symptomatic pulmonary embolism. 
11. Participant has experienced any major surgery within 28 days prior to the first administration 
of the medication under investigation in the study. 
12. Participant has serum potassium, magnesium, or calcium levels outside the institutional 
normal limits. 
Participants with electrolyte levels outside of the normal range will be eligible if these values are 
corrected upon retesting following any necessary supplementation. 
Organ function 
13a. 
Participant has inadequate bone marrow function, including the following: 
a. ANC <2.0x109/L 
b. Platelet count <100x109/L 
c. Hemoglobin <9.0g/dL (or 5.5mmol/L) 
Participants with hemoglobin ≥8.0g/dL but <9.0g/dL may receive erythrocyte transfusions to 
achieve a hemoglobin level ≥9.0g/dL. Initial treatment must not begin until 2 days after the 
erythrocyte transfusion and after the confirmation of hemoglobin ≥9.0g/dL. 
14. Participant has impaired renal function as indicated by serum creatinine >1.5x upper limit of 
normal (ULN) or calculated creatinine clearance of <50mL/min on the bases of the Cockroft-
Gault glomerular filtration rate estimation (Appendix 2 [Section 11.2] with formula). 
15. Alanine transaminase or AST are ≥2xULN (if liver metastases are present: ≥5xULN). 
For study participants with a Baseline result ≥2xULN for ALT and/or AST, the presence of 
liver metastases must be recorded in the eCRF. 
16. Bilirubin ≥1.5xULN. 
17. Current or chronic history of liver disease or known hepatic or biliary abnormalities other 
than liver metastases (with the exception of Gilbert’s syndrome, asymptomatic gallstones, or 
biliary stent, provided bilirubin levels do not exceed limits as per exclusion criterion #16). 
18. International normalized ratio, PT, or aPTT as follows: 
a. In the absence of therapeutic intent to anticoagulate the participant, INR or PT or aPTT 
>1.5xULN, or 
b. In the presence of therapeutic intent to anticoagulate the participant, INR or PT or aPTT 
not within therapeutic limits (according to the medical standards at the institution) or 
participant has not been on a stable dose of anticoagulant for at least 2 weeks 
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19b. QTc >450msec (note: The QTc is the QTcF; it is either machine-read or manually over-
read). 
Prior/Concomitant therapy 
20. Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthetase gene 
polymorphism predisposing the participant to 5-fluorouracil toxicity. 
21. Participant is taking a prohibited medication or has taken a prohibited medication as defined 
in Section 6.5.8  within 28 days of starting study treatment. 
22. Administration of a live, attenuated vaccine (eg, LAIV, MMR, varicella; FluMist®) within 
28 days of starting study treatment and for up to 3 months after the final dose of IMP, or 
anticipation that such vaccine will be required during the study.  
Prior/Concurrent clinical study experience 
23. Current enrollment in another clinical study, unless it is an observational (noninterventional) 
clinical study or the follow-up period of an interventional study. 
Other exclusions  
24. Participant has known or suspected pernicious anemia or other anemias due to vitamin B12 
deficiency. 
Exclusion criteria for Parts D, E, F, and G will be defined in a subsequent protocol amendment. 
5.3 
Lifestyle restrictions 
No restrictions are required. 
5.4 
Screen failures 
Prior to dosing, the study physician or medically qualified designee will assess participant 
eligibility and confirm suitability for study treatment. Screen failures are defined as participants 
who consent to participate in the clinical study but are not subsequently assigned to study 
treatment. A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Due to the ongoing COVID-19 pandemic, or a potential re-emergence of COVID-19, some 
participants may be unable to complete Screening procedures (for instance, due to local 
pandemic restrictions or the need to self-isolate following close contact exposure). These 
participants should be considered screen failures. These and other individuals who do not fully 
meet the criteria for participation in this study (screen failure) may be rescreened at the 
discretion of the investigator and by agreement with the Sponsor on a case-dependent nature 
(dependent on the reason for the initial screen failure). 
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6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Treatments administered 
6.1.1 
Part A 
In Part A, UCB6114 will be administered as described in the Schedule of Activities (Table 1-4). 
A summary of the study treatment to be administered is provided in Table 6-1. 
Table 6-1: 
Treatments administered in Part A 
IMP 
UCB6114 
Type 
Drug 
Dose formulation 
UCB6114 
 
Unit dose strength(s) 
100mg/mL 
Dosage level(s) 
100mg, 250mg, 500mg, 1000mg, and 2000mg. Doses will be 
administered Q2W 
Route of administration 
iv infusion 
Use 
Experimental 
Sourcing 
IMP will be supplied by UCB Clinical Trial Supply or designee. 
Packaging and labeling 
Study intervention will be provided in 100mg/mL solution in glass vials. 
Each vial will be labeled as required per country requirement. 
IMP=investigational medicinal product; iv=intravenous(ly); Q2W=every 2 weeks 
6.1.2 
Part A1 
A new dose formulation will be used in Part A1. UCB6114 will be administered as described in 
the Schedule of Activities (Table 1-5 and Table 1-6) and as per defined cohort (Table 6-6). A 
summary of the study treatment to be administered is provided in Table 6-2. 
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Table 6-2: 
Treatments administered in Part A1 
IMP 
UCB6114 
Type 
Drug 
Dose formulation (new) 
UCB6114 
 
Unit dose strength(s) 
100mg/mL 
Dosage level(s) 
2000mg, 3000mg, 4000mg. Doses will be administered Q2W, Q3W, or 
Q4W as per defined cohort 
Route of administration 
iv infusion 
Use 
Experimental 
Sourcing 
IMP will be supplied by UCB Clinical Trial Supply or designee. 
Packaging and labeling 
Study intervention will be provided in 100mg/mL solution in glass vials. 
Each vial will be labeled as required per country requirement. 
IMP=investigational medicinal product; iv=intravenous(ly); Q1W=one weekly; Q2W=every 2 weeks, Q3W=every 
3 weeks, Q4W=every 4 weeks. 
6.1.3 
Part B 
UCB6114 and TFD/TPI will be administered as described in the Schedule of Activities for 
Part B (Table 1-7). A summary of the study treatments to be administered in Part B is provided 
in Table 6-3.  
Table 6-3: 
Study treatments in Part B 
Product Name 
UCB6114 
Lonsurf® 
Intervention name 
UCB6114 
Trifluridine/tipiracil (active ingredients: 
trifluridine and tipiracil hydrochloride) 
Type 
Drug 
Drug 
Dose formulation 
Solution for 
injection/infusion 
containing UCB6114 at 
100mg/mL (as in Part A); 
for excipients see below 
Film-coated tablets containing 
Trifluridine (15 or 20mg) and tipiracil 
(6.14mg or 8.19mg ); for excipients see 
below 
Unit dose strength(s) 
100mg/mL 
Lonsurf 15mg/6.14mg (white); 
Lonsurf 20mg/8.19mg (pale red) 
Dosage level(s) 
Planned dose levels: 
500mg Q2W 
1000mg Q2W 
2000mg Q2W 
35mg/m2/dose administered bid on 
Days 1 to 5 and Days 8 to 12 of each 
28-day cycle, not to exceed 80mg per 
dose. 
Route of administration 
iv infusion 
Oral 
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Product Name 
UCB6114 
Lonsurf® 
Use 
Experimental 
Experimental (combination product) 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Will be supplied by UCB 
Clinical Trial Supply or 
designee 
Provided centrally by the Sponsor or 
locally by the study site, subsidiary, or 
designee.  
Packaging and labeling 
UCB6114 will be provided 
as a 100mg/mL solution in 
glass vials. Each vial will be 
labeled as required per 
country requirements. 
Lonsurf will be provided in its original 
packaging. All IMP will be labeled as 
required per country requirements.  
Excipients  
Tablet core 
Lactose monohydrate 
Starch, pregelatinized (maize) 
Stearic acid 
Film coating 
Lonsurf 15mg/6.14mg film-coated 
tablets 
Hypromellose 
Macrogol (8000) 
Titanium dioxide (E171) 
Magnesium stearate 
Lonsurf 20mg/8.19mg film-coated 
tablets 
Hypromellose 
Macrogol (8000) 
Titanium dioxide (E171) 
Iron oxide red (E172) 
Magnesium stearate 
Printing ink 
Shellac 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
Titanium dioxide (E171) 
Indigo carmine aluminium lake (E132) 
Carnauba wax 
Talc 
Current/Former name or alias Not applicable 
TAS-102 
bid=twice daily; HCl=hydrochloride; IMP=investigational medicinal product; iv=intravenous(ly); NIMP=non-
investigational medicinal product; Q2W=every 2 weeks 
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6.1.4 
Part C 
UCB6114 and mFOLFOX6 chemotherapy will be administered as described in the Schedule of 
Activities for Part C (Table 1-8). UCB6114 must always be administered prior to mFOLFOX6 
chemotherapy.  
A summary of the study treatment to be administered in Part C is provided in Table 6-4.  
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Table 6-4: 
Treatments administered in Part C 
Product Name 
UCB6114 
Oxaliplatin 
Leucovorin 
Fluorouracil 
Intervention 
name 
UCB6114 
Part of mFOLFOX6 
chemotherapy regimen 
Part of mFOLFOX6 
chemotherapy regimen 
Part of mFOLFOX6 
chemotherapy regimen 
Type 
Drug 
Drug 
Drug 
Drug 
Dose 
formulation 
Solution for 
injection/infusion 
containing UCB6114 at 
100mg/mL, (as in Part A) 
for excipients see below 
Concentrate for solution 
for infusion containing 
oxaliplatin (5mg/mL), for 
excipients see below 
Solution for injection 
containing leucovorin 
(10mg/mL), for excipients 
see below 
Solution for injection 
containing fluorouracil 
(25 or 50mg/mL), for 
excipients see below 
Unit dose 
strength(s) 
100mg/mL 
5mg/mL 
10mg/mL 
25mg/mL; 
50mg/mL 
Dosage level(s) 
Planned dose levels: 
500mg Q2W 
1000mg Q2W 
2000mg Q2W 
85mg/m2 Q2W 
400mg/m2 Q2W 
400mg/m2 Q2W, followed 
by 1200mg/m2/day on 
Day 1 and 2 (2400mg/m2 
over 46 hours)  
Route of 
administration 
iv infusion 
iv infusion 
iv infusion 
iv bolus, then continuous 
infusion via infusor 
Use 
Experimental 
Experimental (as part of 
mFOLFOX6 
chemotherapy) 
Experimental (as part of 
mFOLFOX6 
chemotherapy) 
Experimental (as part of 
mFOLFOX6 
chemotherapy) 
IMP  
IMP  
IMP 
IMP 
IMP 
Sourcing 
Will be supplied by UCB 
Clinical Trial Supply or 
designee 
Provided centrally by the 
Sponsor or locally by the 
study site, subsidiary, or 
designee.  
Provided centrally by the 
Sponsor or locally by the 
study site, subsidiary, or 
designee.  
Provided centrally by the 
Sponsor or locally by the 
study site, subsidiary, or 
designee.  
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Table 6-4: 
Treatments administered in Part C 
Product Name 
UCB6114 
Oxaliplatin 
Leucovorin 
Fluorouracil 
Packaging and 
labeling 
UCB6114 will be provided 
in 100mg/mL solution in 
glass vials. Each vial will 
be labeled as required per 
country requirement. 
Oxaliplatin will be 
provided in its original 
packaging. All IMP will be 
labeled as required per 
country requirements. 
Leucovorin will be 
provided in its original 
packaging. All IMP will 
be labeled as required per 
country requirements. 
Fluorouracil will be 
provided in its original 
packaging. All IMP will 
be labeled as required per 
country requirements. 
Excipients  
Water for injection 
Sodium chloride 
Water for injection 
Sodium hydroxide 
Water for injection 
Current/Former 
name(s) or 
alias(es) 
Not applicable 
Eloxatin® 
Calcium folinate 
5-fluorouracil, 5-FU 
FU=fluorouracil; IMP=investigational medicinal product; iv=intravenous(ly); mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 
on Day 1 + 1200mg/m2/day on Day 1 and Day 2, and oxaliplatin 85mg/m2 on Day 1; Q2W=every 2 weeks 
 
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6.2 
Preparation, handling, storage, and accountability requirements 
6.2.1 
UCB6114 
The 100mg/mL solution will be diluted to a concentration calculated to give the planned dose 
over a constant infusion duration. Details of the dilution factors and the infusion rates to achieve 
this are given in the investigational medicinal product (IMP) Handling Manual. 
Study drug product (ie, IMP) must be stored under refrigerated conditions (2°C to 8°C/35.6°F to 
46.4°F). Further instructions regarding drug preparation and dosing will be contained in the 
IMP Handling Manual, which will be provided to each clinical site. 
The investigator (or designee) must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
temperature controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the IMP Handling Manual. 
Preparation, handling, storage and accountability requirements are described in the IMP 
Handling Manual. 
6.2.2 
TFD/TPI 
Please refer to the prescribing information or the Summary of Product Characteristics (SmPC) 
for details on formulations and storage. 
6.2.3 
mFOLFOX6 
Please refer to the prescribing information or SmPC for the individual components for details on 
formulations and storage.  
6.2.4 
Drug accountability 
Accountability logs will be used to record study medication dispensing and return information on 
a by-participant basis and will serve as source documentation during the course of the study. 
Details of any study medication lost, damaged (due to breakage or wastage), not used, partially 
used, disposed of at the study site, or returned to the Sponsor or designee must also be recorded 
on the appropriate forms. All supplies and pharmacy documentation must be made available 
throughout the study for UCB (or designee) to review. 
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The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of study medication until returned or destroyed. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The investigator must ensure that the study medication is used only in accordance with the 
protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws (in which case the site should provide the 
appropriate certification or confirmation of destruction), regulations, and UCB Standard 
Operating Procedures, or returned to UCB (or designee). Investigational medicinal product 
intended for the study cannot be used for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: Randomization and blinding 
This is an open-label study. 
6.4 
Treatment compliance 
Study participant compliance in Parts A, A1, and C will be ensured by the administration of 
study medication by designated site personnel. Drug accountability must be recorded on the 
accountability log. 
Study participant compliance for UCB6114 in Part B will be ensured by the administration of 
study medication by designated site personnel and drug accountability must be recorded on the 
accountability log. Study participant compliance for TFD/TPI in Part B will be evaluated through 
the use of a participant diary and the drug accountability log on which the number of TFD/TPI 
tablets dispensed and the number of unused tablets returned will be recorded. Drug 
accountability must be performed in the presence of the participant in order to obtain any 
explanations regarding discrepancies with the dosing regimen. 
Drug accountability must be recorded on the accountability log. 
6.5 
Concomitant medication(s)/treatment(s) 
Permitted and prohibited concomitant medications during Part A, Part A1, Part B, and Part C are 
defined below. Permitted concomitant medications for subsequent modules Part A1, Part D, 
Part E, Part F, and Part G will be described in subsequent protocol amendments. 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
during Part A 
The following concomitant medications are permitted during Part A of the study: 
• Medications intended solely for supportive care (eg, treatments for nausea, vomiting, and 
diarrhea) 
• Therapeutic use of steroids equivalent to prednisone 10mg/day 
• Bisphosphonate therapy 
• Hormonal contraceptives/hormonal replacement therapy 
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• Continuation of gonadotropin-releasing hormone (GnRH) agonist therapy for participants 
with prostate cancer 
• Continuation of antiestrogen therapy (eg, aromatase inhibitor) for participants with breast 
cancer 
6.5.2 
Permitted concomitant treatments (medications and therapies) 
during Part A1 
The following concomitant medications are permitted during Part A1 of the study: 
• Medications intended solely for supportive care (eg, treatments for nausea, vomiting, and 
diarrhea) 
• Therapeutic use of steroids equivalent to prednisone ≤10mg/day 
• Bisphosphonate therapy or therapy with RANK ligand inhibitor 
• Hormonal contraceptives/hormonal replacement therapy 
• Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the investigator. Palliative radiotherapy specifically refers to radiotherapy for 
symptom relief only. 
• Participants who experience infusion-associated symptoms may be treated symptomatically 
as per standard practice. 
6.5.3 
Permitted concomitant treatments (medications and therapies) 
during Part B  
The following concomitant medications and/or treatments are permitted during Part B of the 
study: 
• Medications intended solely for supportive care (eg, treatments for nausea, vomiting, and 
diarrhea). 
• Bisphosphonate therapy or therapy with RANK ligand inhibitor. 
• Hormonal contraceptives/hormonal replacement therapy. 
• Therapeutic use of steroids equivalent to prednisone ≤10mg/day. 
• Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the investigator. Palliative radiotherapy specifically refers to radiotherapy 
symptom relief only. 
• Participants who experience infusion-associated symptoms may be treated symptomatically 
as per standard practice. 
• Granulocyte colony-stimulating factor (G-CSF) or pegylated G-CSF for the management of 
neutropenia related toxicities. (Note: prophylactic pegylated G-CSF in Cycle 1 is not 
permitted.) 
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6.5.4 
Permitted concomitant treatments (medications and therapies) 
during Part C 
The following concomitant medications and/or treatments are permitted during Part C of the 
study: 
• Medications intended solely for supportive care (eg, treatments for nausea, vomiting, and 
diarrhea). 
• Bisphosphonate therapy or therapy with RANK ligand inhibitor. 
• Hormonal contraceptives/hormonal replacement therapy. 
• Therapeutic use of steroids equivalent to prednisone ≤10mg/day. 
• Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the investigator. Palliative radiotherapy specifically refers to radiotherapy 
symptom relief only. 
• Participants who experience infusion-associated symptoms may be treated symptomatically 
as per standard practice. 
• Granulocyte colony-stimulating factor (G-CSF) or pegylated G-CSF for the management of 
neutropenia related toxicities. (Note: prophylactic pegylated G-CSF in Cycle 1 is not 
permitted.) 
6.5.5 
Prohibited concomitant treatments (medications and therapies) 
during Part A 
The following concomitant medications are prohibited during Part A of the study: 
• Any concurrent anticancer treatment within 28 days or 5 half-lives (whichever is shorter) 
prior to first dose of study medication (eg, cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy], immunotherapy, biological therapy, or 
cytokine therapy [with the exception of erythropoietin]) 
• Any investigational drug within 28 days prior to start of study medication 
• Herbal remedies or vitamins used as anticancer treatments 
• Any herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to 
potentially interfere with major organ function (eg, hypericin) 
Concomitant treatment considered necessary for the participant’s well-being may be given at the 
discretion of the investigator but should be discussed with the study physician or medically 
qualified designee whenever possible. If there is a clinical indication for one of these 
medications specifically prohibited during the study, discontinuation from the study medication 
may be required. 
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6.5.6 
Prohibited concomitant treatments (medications and therapies) 
during Part A1 
The following concomitant medications are prohibited during Part A1 of the study: 
• Any concurrent anticancer treatment within 28 days or 5 half-lives (whichever is shorter) 
prior to first dose of study medication (eg, cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy], immunotherapy, biological therapy, or 
cytokine therapy [with the exception of erythropoietin]) 
• Any investigational drug within 28 days prior to start of study medication 
• Herbal remedies or vitamins used as anticancer treatments 
• Any herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to 
potentially interfere with major organ function (eg, hypericin) 
• Any anticoagulation therapy until after biopsies are obtained 
Concomitant treatment considered necessary for the participant’s well-being may be given at the 
discretion of the Investigator but should be discussed with the study physician or medically 
qualified designee whenever possible. If there is a clinical indication for one of these 
medications specifically prohibited during the study, discontinuation from the study medication 
may be required. 
6.5.7 
Prohibited concomitant treatments (medications and therapies) 
during Part B 
The following concomitant medications are prohibited during Part B of the study: 
• Any concurrent anticancer treatment within 28 days or 5 half-lives (whichever is shorter) 
prior to first dose of study medication (eg, cytoreductive therapy, radiotherapy 
immunotherapy, biologic therapy, or cytokine therapy [with the exception of erythropoietin]) 
• Treatment with mitomycin C or nitrosoureas within 6 weeks of starting study medication 
• Any investigational drug within 28 days prior to start of study medication 
• Herbal remedies or vitamins used as anticancer treatments 
• Any herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to 
potentially interfere with major organ function (eg, hypericin) 
Concomitant treatment considered necessary for the participant’s well-being may be given at the 
discretion of the investigator but should be discussed with the study physician or medically 
qualified designee whenever possible. If there is a clinical indication for one of these 
medications specifically prohibited during the study, discontinuation from the study medication 
may be required. 
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6.5.8 
Prohibited concomitant treatments (medications and therapies) 
during Part C 
The following concomitant medications are prohibited during Part C of the study: 
• Any concurrent anticancer treatment within 28 days or 5 half-lives (whichever is shorter) 
prior to first dose of study medication (eg, cytoreductive therapy, radiotherapy 
immunotherapy, biologic therapy, or cytokine therapy [with the exception of erythropoietin]) 
• Treatment with mitomycin C or nitrosoureas within 6 weeks of starting study medication 
• Any investigational drug within 28 days prior to start of study medication 
• Herbal remedies or vitamins used as anticancer treatments 
• Any herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to 
potentially interfere with major organ function (eg, hypericin) 
The following should be avoided during Part C of the study: 
• Concurrent administration of 5-fluorouracil and CYP2C9 substrates. Five-fluorouracil is a 
CYP2C9 inhibitor and possible drug interaction with 5-fluorouracil and CYP2C9 substrates 
has been reported.  
− Possible drug interaction with oxaliplatin, 5-fluorouracil, and warfarin has been reported. 
For participants maintained on warfarin, weekly INR is recommended until a stable 
warfarin dose is established, and then every 2 weeks. 
− Possible drug interaction with 5-fluorouracil and phenytoin or fosphenytoin has been 
reported and may occur at any time. Close monitoring is recommended; 5-fluorouracil 
may increase the serum concentration of these 2 agents. 
• Concomitant administration of medicinal product with a known potential to prolong the QT 
interval as QT interval prolongation and ventricular arrhythmias can occur with oxaliplatin. 
• Co-administration of medicinal products known to be nephrotoxic. 
Concomitant treatment considered necessary for the participant’s well-being may be given at the 
discretion of the investigator but should be discussed with the study physician or medically 
qualified designee whenever possible. If there is a clinical indication for one of these 
medications specifically prohibited during the study, discontinuation from the study medication 
may be required. 
6.5.9 
Vaccines 
Administration of live attenuated vaccines is not allowed during the conduct of the study and for 
up to 3 months after the final dose of IMP.  
Administration of non-live vaccines is allowed during the study at the discretion of the 
Investigator. 
Administration of any other vaccine not mentioned above may be allowed following discussion 
with the Medical Monitor. 
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6.5.10 
Rescue medication 
There are no absolute restrictions on the use of concomitant rescue medications for participants 
whose condition deteriorates during the course of the study. While the objectives of the study 
should be protected as much as possible through observance of restrictions detailed, the 
well-being of the participant will always take priority, and participants should be managed as 
deemed appropriate by the investigator. The anticipated use of any prohibited medications 
should be discussed with the study physician or medically qualified designee first, whenever 
possible. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded. 
6.6 
Dose modification 
6.6.1 
Part A and Part A1 
The justification for the UCB6114 start dose for Part A is presented in Section 4.3.1. 
In Part A, the decision to proceed to the next dose level (either an escalation or a de-escalation) 
will be made by the SMC based on safety, and available preliminary PK and/or PD data obtained 
in at least 3 participants at the prior dose level (Section 4.1.2.1 ). Further data obtained from any 
previous dose level may also contribute to this decision. 
The planned escalation scheme is given in Section 6.6.1.1. 
6.6.1.1 
Dose escalation scheme 
A summary of the planned UCB6114 dose levels for dose escalation in Part A is provided in 
Table 6-5. A dose range up to 2000mg Q2W iv was selected based on the following: 
1. Exposure and predicted gremlin-1 suppression levels associated with antitumor activity at 
different dose levels in nonclinical pharmacology models 
2. Pharmacokinetics of UCB6114 in cynomolgus monkeys scaled to humans 
3. Findings of 13-week GLP toxicity studies in cynomolgus monkeys and rats 
Table 6-5: 
Dose escalation steps and justification (Part A) 
Cohorta 
Dose (mg) 
[approximate 
mg/kgb] 
Predicted Cav,ss 
[90% prediction 
interval] (μg/mL)c 
Justification 
1 
100 [1.4] 
20.4 [13.4-31.0] 
The starting dose of 100mg Q2W iv was 
selected as described in Section 4.3.1. 
The anticipated safety margin is >100-fold. 
2 
250 [3.6] 
51.3 [33.5-77.5] 
Corresponds to a 2.5-fold increase over the first 
dose level and will give similar inhibition 
should the turnover half-life of gremlin-1 in 
humans be 
. 
3 
500 [7.1] 
102 [67.0-155.0] 
Corresponds to a 2-fold increase over the 
previous dose level. 
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Table 6-5: 
Dose escalation steps and justification (Part A) 
Cohorta 
Dose (mg) 
[approximate 
mg/kgb] 
Predicted Cav,ss 
[90% prediction 
interval] (μg/mL)c 
Justification 
4 
1000 [14.3] 
204 [134.0-310.0] 
The lowest dose to show qualitative 
improvement in survival in the 
ApcMin;Vil1-Grem-1 model was 15mg/kg BIW. 
A dose of 1000mg Q2W is expected to provide 
similar exposure in humans. 
Also, assuming a gremlin-1 level of 100ng/mL 
and a turnover half-life of 2h in humans, 
1000mg Q2W iv is predicted to inhibit 
approximately 95% of circulating gremlin-1. 
The anticipated safety margin is >10-fold at this 
dose level. 
5 
2000 [28.6] 
408 [268.0-620.0] 
A dose of 30mg/kg BIW in ApcMin;Vil1-Grem-1 
model showed improved survival compared 
with the control. A dose of 2000mg iv Q2W is 
expected to provide similar exposure in humans. 
No difference was observed between 30 and 
60mg/kg BIW in the ApcMin;Vil1-Grem-1 
model, and therefore, higher doses are likely not 
warranted. 
BIW=twice weekly; Cav,ss=average concentration at steady state; h=hour; iv=intravenous(ly); 
PK=pharmacokinetic(s); Q2W=every 2 weeks 
a Dose levels administered may be adapted according to emerging data, eg, dose escalation or de-escalation to an 
intermediate dose level. Not all dose levels listed may be evaluated in this study. 
b Approximate mg/kg doses based on a 70kg person. 
c Predicted Cav,ss was calculated from estimated cynomolgus monkey PK parameters following a single 
administration (UCB Research Study NCD3086) scaled to humans and predicted at steady state. The estimated 
between-subject variability of clearance (coefficient of variation of 26.3%) was assumed to apply to human study 
participants. 
The proposed dose escalation and dose schedule may be adapted based on the following: 
• Cohort-by-cohort safety assessment and available PK data 
• Any available PD biomarker data 
• Data collected in ongoing nonclinical studies 
Characterization of the dose-concentration-effect relationship (ranging from potential minimum 
effective doses to maximum effective doses) is important to determine the therapeutic window 
for UCB6114 for later clinical development. 
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After the  fifth cohort in Part A has been determined, an additional module (Part A1) has been 
included to evaluate alternative dosing schedules (see Table 6-6). The rationale for Part A1 
includes the following: 
• Evaluation of a less frequent (Q3W or Q4W) dosing schedule is considered desirable to 
enable UCB6114 to be combined with a range of other treatments or to reduce patient 
burden. 
• Administration with a shorter infusion time may be desirable to reduce patient’s burden. 
The dosing schedules planned in Part A1 are given in Table 6-6. 
Table 6-6: 
Planned dose optimization scheme for Part A1 
Cohort 
Dosing and infusion time 
Purpose 
Cohort 1a 
2000mg Q2W 
60-minute iv infusion (33.33mg/min) 
28-day treatment cycles 
To assess safety, PK and PD of 2000mg dose 
of new dose formulation. 
Cohort 2 
2000mg Q2W  
30-minute iv infusion (66.67mg/min) 
28-day treatment cycles 
To establish a shorter infusion time (30 
minutes) to reduce the burden/allow for easier 
combination with other anti-tumor agents. 
Cohort 3 
3000mg Q3W 
90-minute iv infusion (33mg/min) 
21-day treatment cycles 
To assess safety, PK and PD of less frequent 
dosing to allow combination with anti-tumor 
agents given in a 3-weekly cycle. 
Cohort 4 
4000mg Q4W 
120-minutes iv infusion (33mg/min) 
28-day treatment cycles 
To assess less frequent dosing to allow 
combination with SOC treatments given in a 
4-weekly cycle. 
a Reference, ie, same dosing schedule as in Part A Cohort 5 but with new dose formulation. All subsequent cohorts 
will receive the new dose formulation. 
iv=intravenous(ly); min=minute(s); PD=pharmacodynamics; PK=pharmacodynamics; Q2W=every 2 weeks; 
Q3W=every 3 weeks; Q4W=every 4 weeks, SOC=standard of care 
6.6.1.2 
Within participant dose modification in Part A 
For participants who experience dose-limiting toxicity, dose adjustments are permitted if it is 
considered in the best interest of the participant to continue therapy at the discretion of the 
investigator, in consultation with the Sponsor. 
Participants who fail to receive the second planned dose of UCB6114 within 7 days of the 
scheduled administration day, during the DLT Observation Period, for reasons not related to 
toxicity will be replaced by a new participant in that cohort. The replaced participant may still 
continue participation in the study. Safety data for replaced participants will be included in all 
summary data and any DLTs experienced by the replaced participant will contribute to 
determination of MTD (Part A) or suitability of the dosing schedule (Part A1). 
6.6.1.3 
Within participant dose modification in Part A1 
Dose adjustments and/or changes in dosing schedule are not permitted. 
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6.6.2 
Part B 
The justification for the UCB6114 start dose for Part B is presented in Section 4.3.3.2.1. 
In Part B, the decision to proceed to the next dose level (either an escalation or a de-escalation) 
will be made by the SMC as described in Section 4.1.4.1. Further data obtained from any 
previous dose level may also contribute to this decision. 
The planned dose escalation scheme is given in Section 6.6.2.1. 
6.6.2.1 
Dose escalation scheme 
A summary of the planned UCB6114 dose levels for dose escalation in Part B is provided in 
Table 6-7.  
Table 6-7: 
Dose escalation steps and justification (Part B) 
Dose 
Level 
Dose 
(mg) 
Justification 
1 
500 
The starting dose selected for Part B is the Part A Cohort 3 dose (anticipated to 
be 500mg Q2W iv); see Section 4.3.3.1 for details.  
2 
1000 The lowest dose to show a qualitative improvement in survival in the 
ApcMin;Vil1-Grem-1 model was 15mg/kg of Ab7326 mIgG1 administered BIW 
sc as monotherapy from an age of 21 days. A dose of 1000mg Q2W iv is 
expected to provide similar exposure in humans.  
A dose of 1000mg is expected to provide an exposure approximately 50% of 
that given in combination with 5-fluorouracil where survival relative to either 
monotherapy was increased in the ApcMin;Vil1-Grem-1 model when dosing 
from an age of 35 days (30mg/kg BIW sc [for 6 weeks followed by 30mg/kg 
QW thereafter]). 
3 
2000 A dose of 2000mg is expected to provide the same exposure in humans as that 
given in combination with 5-fluorouracil where survival relative to either 
monotherapy was increased in the ApcMin;Vil1-Grem-1 model when dosing 
from an age of 35 days.  
In a separate study where Ab7326 mIgG1 was administered as monotherapy 
from an age of 21 days, no difference was observed between 30 and 60mg/kg 
BIW sc in the ApcMin;Vil1-Grem-1 model, and therefore, higher doses of 
UCB6114 are likely not warranted. 
BIW=twice weekly; h=hour; iv=intravenous(ly); PK=pharmacokinetic(s); Q2W=every 2 weeks; 
sc=subcutaneous(ly) 
6.6.2.2 
UCB6114 dose modifications 
Study participants who experience Grade 4 (life-threatening) nonhematologic toxicity, including 
diarrhea and mucositis, which is at least possibly related to UCB6114, will be discontinued from 
treatment. 
Treatment with UCB6114 may temporarily be suspended for up to 3 weeks beyond the 
scheduled treatment day until toxicities are resolved to CTCAE Grade 2 or less. If UCB6114 is 
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held for more than 3 weeks beyond the scheduled treatment day, then the participant will be 
discontinued from treatment and will be followed up for safety and efficacy per the Schedules of 
Activities for Part A (Table 1-4), Part B (Table 1-7), and Part C (Table 1-8).  
For permitted adjustments of the infusion rate in case of AEs refer to the IMP Handling Manual. 
Participants who experience severe or life-threatening infusion-related events (CTCAE Grade 3 
or 4) will not receive further infusions. Hypersensitivity/infusion-related events should be 
managed per institutional guidelines. Premedication with steroids may be administered at the 
discretion of the investigator. 
6.6.2.3 
TFD/TPI dose modifications 
Dose modifications for TFD/TPI-related AEs are allowed as described below. A maximum of 
3 dose reductions are permitted to a minimum of 20mg/m2/dose. 
Participants who permanently discontinue TFD/TPI treatment due to TFD/TPI-related toxicity 
will have the option to continue treatment with UCB6114 alone if, in the view of the 
investigator, the participant is deriving benefit. 
In the case of hematological toxicities, TFD/TPI treatment may be interrupted or resumed 
according to the criteria stated in Table 6-8. In the case of hematological and nonhematological 
toxicities, the dose may be modified according to the criteria stated in Table 6-9. Reductions will 
be made in accordance with BSA (Table 6-10). 
Table 6-8: 
TFD/TPI dose interruption and resumption criteria for hematological 
toxicities 
Parameter 
Interruption criteria 
Resumption criteriaa 
Neutrophils 
<0.5x109/L 
≥1.5x109/L 
Platelets 
<50x109/L 
≥75x109/L 
TFD/TPI=trifluridine/tipriacil 
a Resumption criteria applied to the start of the next cycle for all participants regardless of whether the interruption 
criteria were met. 
 
Table 6-9: 
TFD/TPI dose modifications in case of hematological and non-
hematological toxicities 
Adverse reaction 
Recommended dose modifications 
Febrile neutropenia. 
CTCAE Grade 4 neutropenia (<0.5x109/L) or 
thrombocytopenia (<25x109/L) that results in more 
than 1 week’s delay in start of next cycle. 
CTCAE Grade 3 or Grade 4 nonhematologic AEs; 
except for Grade 3 nausea and/or vomiting 
controlled by antiemetic therapy or diarrhea 
responsive to antidiarrheal medicinal products. 
Interrupt dosing until toxicity resolves to Grade 1 
or baseline. 
When resuming dosing, decrease the dose level 
by 5mg/m2/dose from the previous dose level 
(Table 6-10). 
Dose reductions are permitted to a minimum 
dose of 20mg/m2/dose bid. 
Do not increase dose after it has been reduced. 
AE=adverse event; bid=twice daily; CTCAE= Common Terminology Criteria for Adverse Events; 
TFD/TPI=trifluridine/tipriacil 
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Table 6-10: TFD/TPI dose reductions according to body surface area 
Reduced dose 
BSA (m2) 
Dose (mg) 
Tablets per dose 
Total daily 
dose (mg) 
15mg/6.14mg 20mg/8.19mg 
Level 1 dose reduction: from 35mg/m2 to 30mg/m2 
30mg/m2 
<1.09 
30 
2 
0 
60 
1.09 to 1.24 
35 
1 
1 
70 
1.25 to 1.39 
40 
0 
2 
80 
1.40 to 1.54 
45 
3 
0 
90 
1.55 to 1.69 
50 
2 
1 
100 
1.70 to 1.94 
55 
1 
2 
110 
1.95 to 2.09 
60 
0 
3 
120 
2.10 to 2.28 
65 
3 
1 
130 
≥2.29 
70 
2 
2 
140 
Level 2 dose reduction: from 30mg/m2 to 25mg/m2 
25mg/m2 
<1.10 
25a 
2a 
1a 
50a  
1.10 to 1.29 
30 
2 
0 
60 
1.30 to 1.49 
35 
1 
1 
70 
1.50 to 1.69 
40 
0 
2 
80 
1.70 to 1.89 
45 
3 
0 
90 
1.90 to 2.09 
50 
2 
1 
100 
2.10 to 2.29 
55 
1 
2 
110 
≥2.30 
60 
0 
3 
120 
Level 3 dose reduction: from 25mg/m2 to 20mg/m2 
20mg/m2 
<1.14 
20 
0 
1 
40 
1.14 to 1.34 
25a 
2a 
1a 
50a 
1.35 to 1.59 
30 
2 
0 
60 
1.60 to 1.94 
35 
1 
1 
70 
1.95 to 2.09 
40 
0 
2 
80 
2.10 to 2.34 
45 
3 
0 
90 
≥2.35 
50 
2 
1 
100 
BSA=body surface area; TFD/TPI=trifluridine/tipriacil 
a At a total daily dose of 50mg, study participants should take 1x20mg/8.19mg tablet in the morning and 
2x15mg/6.14mg tablets in the evening. 
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6.6.3 
Part C 
The justification for the UCB6114 start dose for Part C is presented in Section 4.3.3.2.2. 
In Part C, the decision to proceed to the next dose level (either an escalation or a de-escalation) 
will be made by the SMC as described in Section 4.1.5.1). Further data obtained from any 
previous dose level may also contribute to this decision. 
The planned escalation scheme is given in Section 6.6.3.1. 
6.6.3.1 
Dose escalation scheme 
A summary of the planned UCB6114 dose levels for dose escalation in Part C is provided in 
Table 6-11.  
Table 6-11: Dose escalation steps and justification (Part C) 
Dose 
Level 
Dose 
(mg) 
Justification 
1 
500 
The starting dose selected for Part C is the Part A Cohort 3 dose (anticipated to 
be 500mg Q2W iv); see Section 4.3.3.1 for details.  
2 
1000 The lowest dose to show a qualitative improvement in survival in the 
ApcMin;Vil1-Grem-1 model was 15mg/kg of Ab7326 mIgG1 administered BIW 
sc as monotherapy from an age of 21 days. A dose of 1000mg Q2W iv is 
expected to provide similar exposure in humans.  
A dose of 1000mg is expected to provide an exposure approximately 50% of 
that given in combination with 5-fluorouracil where survival relative to either 
monotherapy was increased in the ApcMin;Vil1-Grem-1 model when dosing 
from an age of 35 days (30mg/kg BIW sc [for 6 weeks followed by 30mg/kg 
QW thereafter]). 
3 
2000 A dose of 2000mg is expected to provide the same exposure in humans as that 
given in combination with 5-fluorouracil where survival relative to either 
monotherapy was increased in the ApcMin;Vil1-Grem-1 model when dosing 
from an age of 35 days.  
In a separate study where Ab7326 mIgG1 was administered as monotherapy 
from an age of 21 days, no difference was observed between 30 and 60mg/kg 
BIW sc in the ApcMin;Vil1-Grem-1 model, and therefore, higher doses of 
UCB6114 are likely not warranted. 
BIW=twice weekly; h=hour; iv=intravenous(ly); PK=pharmacokinetic(s); Q2W=every 2 weeks; 
sc=subcutaneous(ly) 
6.6.3.2 
UCB6114 dose modifications 
Study participants who experience Grade 4 (life-threatening) nonhematologic toxicity, including 
diarrhea and mucositis, which is at least possibly related to UCB6114, will be discontinued from 
treatment. 
Treatment with UCB6114 may temporarily be suspended for up to 3 weeks beyond the 
scheduled treatment day until toxicities are resolved to CTCAE Grade 2 or less. If UCB6114 is 
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held for more than 3 weeks beyond the scheduled treatment day, then the participant will be 
discontinued from treatment and will be followed up for safety and efficacy per the Schedule of 
Activities.  
For permitted adjustments of the infusion rate in case of AEs, refer to the IMP Handling Manual. 
Participants who experience severe or life-threatening infusion-related events (Grade 3 or 4) will 
not receive further infusions. Hypersensitivity/infusion-related events should be managed per 
institutional guidelines. Premedication with steroids may be administered at the discretion of the 
investigator. 
6.6.3.3 
mFOLFOX6 dosing 
Please refer to the individual package inserts for details on formulations and storage. 
Antiemetic premedication prior to administration of chemotherapy is recommended and sites 
should follow their institutional standard of care.  
The recommended administration of mFOLFOX6 is shown in Table 6-12. 
Table 6-12: mFOLFOX6 dosing 
Drug 
Dose 
Administration 
Oxaliplatina 
85mg/m2 
iv in 250 to 500mL glucose 5% over 2 hours 
Leucovorina 
400mg/m2 
iv in 250mL glucose 5% over 2 hours  
5-Fluorouracil  
400mg/m2 
iv bolus 
5-Fluorouracil  
2400mg/m2 
iv over 46 hours via an infusor 
mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 
and Day 2, and oxaliplatin 85mg/m2 on Day 1; iv=intravenous(ly) 
a Oxaliplatin and leucovorin may be infused over the same two-hour period by using a Y-site connector placed 
immediately before the infusion site. 
Within the study, mFOLFOX6 is administered every 14 days in 28-day treatment cycles up to a 
maximum of 6 cycles.  
6.6.3.4 
mFOLFOX6 dose modifications 
Dose modifications for mFOLFOX6-related AEs are allowed as described below. A maximum 
of 2 dose level reductions are permitted.  
Participants who permanently discontinue treatment (all or individual drugs of the mFOLFOX6 
regimen) due to toxicity will be considered for continuation of treatment with UCB6114 if, in the 
view of the investigator, the participant is deriving benefit.  
Dose levels for individual drugs are as follows: 
• Oxaliplatin: 
− Starting dose: 85mg/m2 
− Dose Level -1: 65mg.m2 
− Dose Level -2: 50mg/m2 
• 5-fluorouracil iv bolus: 
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− Starting dose: 400mg/m2 
− Dose Level -1: 320mg/m2 
− Dose Level -2: 200mg/m2 
• 5-fluorouracil infusion over 46 hours: 
− Starting dose: 2400mg/m2 
− Dose Level -1: 2000mg/m2 
− Dose Level -2: 1600mg/m2 
No dose adjustments are required for leucovorin. 
6.6.3.4.1 
Dose modifications for neurological toxicity  
If neurological symptoms (ie, paresthesia, dysesthesia) occur, oxaliplatin dosage adjustments 
should be made as outlined in Table 6-13. No dose adjustments of 5-fluorouracil are 
recommended for neurotoxicity. 
Table 6-13: Dose modification for oxaliplatin-related neurological toxicity 
CTCAE (v5.0) 
Toxicity grade 
Duration of toxicity 
Transient 
(≥1 day and ≤14 days) 
Persistent 
(present at start of next treatment) 
1 
Maintain dose level 
Maintain dose level 
2 
Maintain dose level 
Reduce 1 dose level 
3 
1st time: reduce one dose level 
2nd time: reduce one dose level 
Discontinue 
4 
Discontinue 
Discontinue 
CTCAE=Common Terminology Criteria for Adverse Events  
6.6.3.4.2 
Dose modifications for hematological toxicity 
Recommended dose modifications for oxaliplatin and 5-fluorouracil for hematological toxicity 
are outlined in Table 6-14. 
Table 6-14: Dose modification for hematological toxicity 
Prior to Dosing  
(Day 1 or Day 15)  
Toxicity 
Dose level for subsequent cycles 
 
CTCAE (V5.0) 
Toxicity Grade 
ANC 
(x109/L) 
Oxaliplatin 
5-Fluorouracil 
If ANC <1.2 on Day 1 or Day 15, 
hold treatment and perform 
weekly blood counts. 
1 
≥1.2 
Maintain dose level 
Maintain dose level 
2 
1.0 to <1.2 
Maintain dose level 
Maintain dose level 
3 
0.5 to <1.0 
Reduce 1 dose level 
Maintain dose level 
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Table 6-14: Dose modification for hematological toxicity 
Prior to Dosing  
(Day 1 or Day 15)  
Toxicity 
Dose level for subsequent cycles 
If ANC is ≥1.2 within 2 weeks, 
proceed with treatment at a dose 
level according to the lowest 
ANC result of the delayed weeks. 
If ANC remains <1.2 after 2 
weeks, discontinue treatment. 
4 
<0.5 
Reduce 1 dose level 
Omit iv bolus and 
reduce infusion 
1 dose level 
 
CTCAE (V5.0) 
Toxicity Grade 
Platelets 
(x 109/L) 
Oxaliplatin 
5-Fluorouracil 
If platelets <75 on Day 1 or Day 
15, hold treatment. Perform 
weekly blood counts. 
If platelets ≥75 within 2 weeks, 
proceed with treatment at a dose 
level according to the lowest 
platelets result of the delayed 
weeks. 
If platelets remain <75 after 
2 weeks, discontinue treatment. 
1 
≥75 
Maintain dose level 
Maintain dose level 
2 
50 to <70 
Maintain dose level 
Maintain dose level 
3 
10 to <50 
Reduce 1 dose level 
Maintain dose level 
4 
<10 
Reduce 2 dose 
levels 
Maintain dose level 
ANC=absolute neutrophil count; CTCAE= Common Terminology Criteria for Adverse Events; iv=intravenous(ly) 
6.6.3.4.3 
Dose modifications for non-hematological, non-neurological toxicity 
Recommended dose modifications for non-hematological, non-neurological toxicity are outlined 
in Table 6-15. Along with dose modifications, supportive treatment should be initiated per 
institutional guidelines. 
Table 6-15: Dose modification for non-hematological, non-neurological toxicity 
Prior to Dosing 
(Day 1 or Day 15) 
Toxicity 
Dose level for subsequent 
cycles 
 
CTCAE (V5.0) 
Toxicity Grade 
Diarrhea 
Oxaliplatin 
5-Fluorouracil 
If diarrhea ≥2 on Day 1 or 
Day 15, hold treatment. 
Perform weekly assessments. 
If diarrhea is <Grade 2 within 
2 weeks, proceed with 
treatment at a dose level 
according to the highest 
Grade experienced. 
1 
Increase of <4 stools/day, 
or mild increase in 
colostomy output 
Maintain 
dose level 
Maintain dose 
level 
2 
Increase of 4 to 6 
stools/day, or moderate 
increase in colostomy 
output; limiting 
instrumental ADL 
Maintain 
dose level 
Maintain dose 
level 
3 
Increase of ≥7 stools/day; 
hospitalization indicated; 
severe increase in 
Maintain 
dose level 
Reduce 1 dose 
level of iv bolus 
and infusion 
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Table 6-15: Dose modification for non-hematological, non-neurological toxicity 
Prior to Dosing 
(Day 1 or Day 15) 
Toxicity 
Dose level for subsequent 
cycles 
If diarrhea remains ≥Grade 2 
after 2 weeks, discontinue 
treatment. 
colostomy output; 
limiting self-care ADL 
4 
Life threatening 
consequences; urgent 
intervention indicated 
Reduce 1 
dose level 
Reduce 1 dose 
level of iv bolus 
and infusion 
 
CTCAE (V5.0) 
Toxicity Grade 
Stomatitis/Mucositis 
Oxaliplatin 
5-Fluorouracil 
If stomatitis ≥Grade 2 on Day 
1 or Day 15, hold treatment. 
Perform weekly assessments.  
If stomatitis <Grade 2 within 
2 weeks, proceed with 
treatment at a dose level 
according to the highest 
Grade experienced. 
If stomatitis remains 
>Grade 2 after 2 weeks, 
discontinue treatment. 
1 
Minimal symptoms with 
normal oral intake 
Maintain 
dose level 
Maintain dose 
level 
2 
Moderate pain, analgesics 
indicated; altered oral 
intake 
Maintain 
dose level 
Maintain dose 
level 
3 
Severe pain; unable to 
adequately aliment or 
hydrate orally 
Maintain 
dose level 
Reduce 1 dose 
level of iv bolus 
and infusion 
4 
Life-threatening 
consequences, urgent 
intervention indicated 
Reduce 1 
dose level 
Reduce 1 dose 
level of iv bolus 
and infusion 
ADL=activities of daily living; CTCAE= Common Terminology Criteria for Adverse Events; iv=intravenous(ly) 
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6.7 
Criteria for study hold or dosing stoppage 
Detailed procedures for reporting SAEs and other safety events (including Rapid Alert 
Procedures) that may meet study or individual study part hold criteria are provided in 
Appendix 6 (Section 11.6). 
The study or individual study part will be immediately suspended (ie, any participant who has 
not received dose(s) of UCB6114 at the time of study/study part suspension will not be 
administered UCB6114)  if 1 or more study participants develop any of the following AEs 
deemed to be at least possibly related to UCB6114 administration by the investigator and the 
sponsor: 
• Death 
• Life-threatening organ failure requiring intervention to prevent death or permanent disability 
(eg, respiratory failure requiring ventilation, renal failure requiring dialysis, heart failure 
requiring hemodynamic support). 
The SMC will be consulted for both study/study module suspension and potential restart (details 
can be found in the SMC charter). 
The management of ongoing participants may be discussed on an individual basis with the 
inverstigator and the participants taking into account the benefit/ risk assessment, unless asked 
by the SMC and/or a regulatory authority/ies not to do so. 
Enrolment of new participants into the study or individual study module will not be restarted 
until: 
• Sponsor and the SMC have agreed a risk mitigation strategy which meets the requirements of 
any regulatory authority/ies to whom details of the AE have been submitted, and  
• Based on local policies, the Independent Ethics Committees (IECs)/Institutional Review 
Boards (IRBs) have been notified, and  
• Where applicable, regulatory authorities have been notified and have approved a substantial 
amendment for study restart. 
6.8 
Treatment after the end of the study 
The planned duration of study treatment is 2 cycles. Participants may, however, remain on study 
for additional cycles if they are receiving therapeutic benefit (SD, PR, or CR) or until they fulfill 
one of the criteria for study discontinuation. Upon discontinuation of treatment, participants will 
be referred to appropriate follow-up care per the investigator’s judgment. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
The IMP will be discontinued if any of the stopping criteria are met or if the participant is 
withdrawn from the study (see Section 7.2). 
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7.1.1 
Liver Chemistry Stopping Criteria 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the participant’s individual baseline values and underlying conditions. Participants 
who present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 
• Participants with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT ≥3xULN concurrent with a total bilirubin 
≥2xULN. 
• For participants with pre-existing ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above: 
− For participants without liver metastases: AST or ALT value ≥2 times the baseline values 
AND ≥3xULN 
− For participants with liver metastases: AST or ALT value ≥2 times the baseline values 
AND ≥8xULN 
Concurrent with 
• For participants with preexisting values of total bilirubin above the normal range: Total 
bilirubin ≥2 times the baseline values OR if the value reaches ≥3xULN (whichever is lower). 
The participant should return to the investigational site and be evaluated as soon as possible, 
preferably within 24 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment, and the possibility of hepatic 
neoplasia (primary or secondary) should be considered. In addition to repeating measurements of 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, gamma-glutamyl transferase, prothrombin time/international normalized ratio, 
and ALP. A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected. 
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be 
warranted. All cases confirmed on repeat testing as meeting the laboratory criteria defined above, 
with no other cause for liver function test abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal liver function tests. Such 
potential Hy’s Law cases should be reported as SAEs. 
Interruption of the study medication should be considered by the investigator when a participant 
meets one of the conditions outlined above. 
7.1.2 
QTc Stopping Criteria 
A participant who meets either bulleted criterion based on the average of triplicate ECG readings 
will be withdrawn from study medication. 
• QTc >500msec OR Uncorrected QT >600msec 
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• Change from baseline of QTc >60msec 
For participants with underlying bundle branch block, follow the discontinuation criteria listed in 
Table 7-1. 
Table 7-1: 
Bundle Branch Block discontinuation criteria 
Baseline QTc with Bundle Branch Block 
Discontinuation QTc threshold with Bundle 
Branch Block 
< 450msec 
> 500msec 
450 to 480msec 
≥ 530msec 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator, study physician, or medically qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
See the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B 
(Table 1-7), and Part C (Table 1-8) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.3 
Other criteria for discontinuation of study medication 
Participants must discontinue study treatment if they experience any of the following: 
1. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
2. The participant experiences unacceptable toxicity. 
− For information on dose delays due to drug-related toxicity, see Section 6.6.1 (Part A and 
Part A1), Section 6.6.2 (Part B), and Section 6.6.3 (Part C). Participants will discontinue 
treatment, unless, in the opinion of the investigator, they are experiencing clinical benefit 
and it is in their best interest to continue treatment. For these participants, treatment may 
continue at a reduced dose at the discretion of the investigator and Sponsor. 
3. The participant has documented evidence of progressive disease. 
− Participants with progressive disease before the end of Cycle 1 may be discontinued from 
study medication at the discretion of the investigator. Participants with progressive 
disease beyond Cycle 1 will be discontinued from study medication. In cases where 
progression is not clear and, in the opinion of the investigator, the participant may be 
having clinical benefit, the participant may continue treatment, but must be reimaged 
within 2 cycles of treatment. 
4. The participant, for any reason, requires treatment with another therapeutic agent or modality 
for his/her cancer (with the exception of palliative bone-directed radiotherapy). In this case, 
discontinuation from the study treatment must occur before introduction of the new agent or 
modality. 
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5. Participant takes prohibited concomitant medications as defined in this protocol. 
Participants who discontinue the study medication and/or study early will have end-of-study 
(SFU) procedures performed as shown in the Schedules of Activities for Part A (Table 1-4), Part 
A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). 
See the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B 
(Table 1-7), and Part C (Table 1-8) for data to be collected at the time of study treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.4 
Temporary discontinuation of study medication 
A treatment dose may be withheld if a participant experiences toxicity as described in 
Section 6.6.1.2  (Part A), Section 6.6.1.3 Part A1), Section 6.6.2.2 (Part B), and Section 6.6.3.1 
(Part C). 
Participants who fail to receive the second planned dose of UCB6114 within 7 days of the 
scheduled administration day during the DLT Observation Period for reasons not related to 
toxicity will be replaced by a new participant in that cohort. 
Treatment with UCB6114 may temporarily be suspended for up to 3 weeks beyond the 
scheduled treatment day until toxicities are resolved to CTCAE Grade 2 or less. If UCB6114 is 
held for more than 3 weeks beyond the scheduled treatment day, then the participant will be 
discontinued from treatment and will be followed up for safety per schedule of assessment.  
7.2 
Participant discontinuation/withdrawal from the study 
The criteria for enrollment must be followed explicitly. A Treatment Allocation/Enrolment Plan 
and management process (IVRS) may be utilized to ensure strict compliance. 
Participants are free to withdraw from the study at any time, without prejudice to their continued 
care. 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety or compliance reasons. 
Participants should be withdrawn from the study if any of the following events occur: 
1. Participant withdraws his/her consent. 
2. Participant develops an illness or comorbidity that would interfere with his/her continued 
participation.  
3. The investigator considers it in the best interest of the participant to be withdrawn. If this 
decision is made because of an SAE or a clinically significant laboratory value, then 
appropriate supportive measures are to be taken. UCB or its designee is to be alerted 
immediately. 
4. Participant is noncompliant with the study visit schedule. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
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If any participant withdraws/is withdrawn from the study, the site will attempt to contact the 
participant and facilitate completion of the SFU Visit and the Final Visit. However, participants 
will not be followed up if they have withdrawn their consent to do so.  
The primary reason for withdrawal from the study should be documented on the appropriate 
eCRF page. 
Investigators should inform the study physician or medically qualified designee in the event that 
a participant is withdrawn from the study. 
Participants who withdraw from the study before receiving study medication will be replaced. 
7.3 
Lost to follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for an 
SFU and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator, study physician, or 
medically qualified designee must make every effort to regain contact with the participant (at 
least 1 phone call and 1 written message to the participant), and document his/her effort (date 
and summary of the phone call and copy of the written message in the source documents), to 
complete the final evaluation. All results of these evaluations and observations, together with 
a narrative description of the reason(s) for removing the participant, must be recorded in the 
source documents. The eCRF must document the primary reason for withdrawal. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up documented in the eCRF. 
7.4 
COVID-19 Pandemic 
In the context of the COVID-19 pandemic, investigators should have individualized benefit-risk 
discussions with study participants during Screening and the course of the study. Such 
discussions should take into consideration the ongoing assessment of the study participant’s 
medical status as well as the COVID-19 pandemic status in the geographic region. Investigators 
must elicit from the participant any suspected or known exposure to COVID-19 or a confirmed 
COVID-19 positive diagnosis. To accommodate potential COVID-19 restrictions, the study 
procedures may be adapted. Such adaptations may include replacing in-clinic visits with video 
consultations, flexibility in the timing and/or location of assessment collection, and any other 
changes deemed necessary until such restrictions are lifted. Clinical sites may arrange for virtual 
study visits or home visits to continue collection of safety and PK data. Participants who miss 
doses due to a positive COVID-19 diagnosis or a known exposure may continue in the study if, 
in the opinion of the investigator, they are experiencing clinical benefit and it is in their best 
interest to continue treatment. A study participant may resume treatment after missing doses due 
to COVID-19 pandemic restrictions, exposure, or infection provided that the protocol-defined 
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study drug discontinuation criteria are not met. In such cases, the investigator should assess all 
available medical information prior to re-initiating dosing. In the event of a temporary dosing 
stop due to COVID-19, participants who were enrolled prior to stop may receive home or virtual 
visits to continue collection of safety and PK data. Adverse events associated with COVID-19 
are discussed in Section 9.2.  
Any changes to the study to manage the impact of COVID-19 will be communicated to the 
regulatory authorities according to local guidance. 
8 
STUDY AND SITE DISCONTINUATION  
The investigator or UCB have the right to stop or terminate the study at any time, for any ethical, 
medical, or scientific reason, while considering the rights, safety, and well-being of the 
participant(s).  
Study site participation may be discontinued if UCB, the investigator, the IRB/ethical review 
board, or the regulatory authority deems it necessary for any scientific, medical, or ethical 
reason. The study will be discontinued if UCB, while considering the rights, safety, and 
wellbeing of the participant(s), deems it necessary for any scientific, medical, or ethical reason. 
9 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedules of Activities for Part A 
(Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). Study 
procedures and their timing for modules subsequent to Parts A, A1, B, and C will be described in 
a planned protocol amendment. 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedules of 
Activities for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and 
Part C (Table 1-8), is essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a Screening log to record details of all 
participants screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for Screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 and 
Table 1-6), Part B (Table 1-7), or Part C (Table 1-8), as applicable. 
In Part A, the maximum amount of blood collected from each participant during Screening will 
be approximately 8 to 10mL. In the case of liver function abnormalities considered potential 
Hy’s Law cases where the liver-specific ALP must be separated from the total ALP in 
participants with bone metastases, an additional volume of 2mL of blood will be collected. 
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The maximum amount of blood collected from each participant over the duration of Cycle 1 of 
Part A are indicated in Table 9-1. 
Table 9-1: 
Total blood volume collected during Cycle 1 of Part A 
Sample 
Number of samples 
Volume of sample 
Total blood 
volume 
Hematology 
4 
<2mL 
8mL 
Biochemistry 
4 
<2mL 
8mL 
Coagulation 
2 
<2mL 
4mL 
Pregnancy (if applicable)a 
1 
2mL 
2mL 
Pharmacodynamics (PD) 
12 
various (2.5 to 20mL) 
83.5mL 
Immunogenicity (ADA) 
3 
5mL 
15mL 
Total 
38 
- 
180.5mL 
ADA=antidrug antibody 
Note: Repeat or unscheduled samples may be taken in addition, for safety reasons or for technical issues with the 
samples. 
a This volume could be increased by 2mL per visit if serum pregnancy test is performed instead of urine for second 
pregnancy assessment during this cycle. 
The maximum amount of blood collected from each participant during Cycle 2 of Part A will be 
approximately 82.5mL. This volume could be increased by up to 4mL if serum pregnancy test is 
performed instead of urine pregnancy test. 
The maximum amount of blood collected from each participant during Cycle 3 of Part A will be 
approximately 72.5mL, and the maximum amount of blood collected from each participant from 
Cycle 4 onwards will be approximately 52.5mL. This volume could be increased by up to 4mL 
per cycle if serum pregnancy test is performed instead of urine pregnancy test 
The maximum amount of blood collected from each participant during the SFU of Part A will be 
approximately 51.5mL. 
In Part A1,  
• The maximum amount of blood collected from each participant during Screening will be 
approximately 42 to 44mL (if pregnancy test is applicable). In the case of liver function 
abnormalities considered potential Hy’s Law cases where the liver-specific ALP must be 
separated from the total ALP in participants with bone metastases, an additional volume of 
2mL of blood will be collected. 
• The maximum amount of blood collected from each participant over the duration of Cycle 1 
is indicated in Table 9-2. 
• The maximum amount of blood collected from each participant during Cycle 2 will be 
approximately 51.5mL for Cohorts 1, 2 and 4, and 47.5mL for Cohort 3. This volume could 
be increased by up to 2mL if serum pregnancy test is performed instead of urine pregnancy 
test. 
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• The maximum amount of blood collected from each participant during Cycle 3 will be 
approximately 60.5mL for Cohorts 1 and 2, and 56.5mL for Cohorts 3 and 4. This volume 
could be increased by up to 2mL per cycle if serum pregnancy test is performed instead of 
urine pregnancy test. If the on-treatment biopsy is not performed an additional volume of up 
to 9mL could be collected for additional PK and circulating Gremlin-1 assessment. 
• The maximum amount of blood collected from each participant from Cycle 4 onwards will 
be approximately 46.5mL for Cohorts 1 and 2, and 42.5mL for Cohorts 3 and 4. This volume 
will be increased by up to 7mL (2mL per cycle if serum pregnancy test is performed instead 
of urine pregnancy test and 5mL every third cycle [Cycle 6, Cycle 9] for immunogenicity).  
• The maximum amount of blood collected from each participant during the SFU Visit will be 
approximately 47.5mL. 
Table 9-2: 
Total blood volume collected during Cycle 1 of Part A1 
Cohorts 
 
 
Sample 
 
 
Volume of 
sample 
Cohorts 1, 2, 4 
Cohort 3 
N° of 
samples 
Total blood 
volume 
N° of 
samples 
Total blood 
volume 
Hematology 
<2mL 
2 
<4mL 
1 
<2mL 
Biochemistry 
<2mL 
2 
<4mL 
1 
<2mL 
Coagulation 
<2mL 
1 
2mL 
1 
2mL 
Pregnancy (if 
applicable)a  
2mL 
1 
2mL 
1 
2mL 
PD 
various (2.5 to 
20mL) 
7 
43.5mL 
4 
16mL 
Immunogenicity (ADA) 
5mL 
1 
5mL 
1 
5mL 
Total 
- 
- 
80.5mL 
- 
49mL 
ADA=antidrug antibody; N°=number; PD=pharmacodynamics; PK=pharmacokinetics 
a This volume could be increased by 2mL per visit if serum pregnancy test is performed instead of urine for second 
pregnancy assessment during this cycle. 
Note: Repeat or unscheduled samples may be taken in addition, for safety reasons or for technical issues with the 
samples. 
In Parts B and C, the maximum amount of blood collected from each participant during 
Screening will be approximately 38.5mL. In the case of liver function abnormalities considered 
potential Hy’s Law cases where the liver-specific ALP must be separated from the total ALP in 
participants with bone metastases, an additional volume of 2mL of blood will be collected. 
The maximum amount of blood collected from each participant over the duration of Cycle 1 of 
Parts B and C is indicated in Table 9-3. 
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Table 9-3: 
Total blood volume collected during Cycle 1 of Parts B and C 
Sample 
Number of samples 
Volume of sample 
Total blood 
volume 
Hematology 
4 
<2mL 
8mL 
Biochemistry 
4 
<2mL 
8mL 
Coagulation 
2 
<2mL 
4mL 
Pharmacodynamics (PD) 
4 
various (4 to 20mL) 
32mL 
Immunogenicity (ADA) 
1 
5mL 
5mL 
Total 
19 
- 
77mLa 
Note: Repeat or unscheduled samples may be taken in addition, for safety reasons or for technical issues with the 
samples. 
a This volume could be increased by 2mL per visit at which serum pregnancy test is performed  
The maximum amount of blood collected from each participant during Cycle 2 will be 
approximately 101mL. This volume could be increased by up to 2mL if serum pregnancy test is 
performed instead of urine pregnancy test. 
The maximum amount of blood collected from each participant during subsequent cycles and the 
SFU will be approximately 44mL. This volume could be increased by up to 2mL per cycle if 
serum pregnancy test is performed instead of urine pregnancy test. 
9.1 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedules of Activities for 
Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C 
(Table 1-8). Safety assessments for Parts A1, D, E, F, and G will be described in a protocol 
amendment. 
9.1.1 
Physical examination 
The investigator or other designated clinician will perform a complete physical examination at 
Screening and on Cycle 1 Day 1 predose (Part A, Part A1 and Part C) or within 3 days prior to 
administration of any IMP (Part B). Physical examination will be symptom-directed at all other 
visits. 
A complete physical examination will include, at a minimum, head, eyes, ears, nose, and throat; 
general abdomen; lymph nodes; and cardiovascular, respiratory, gastrointestinal, neurological, 
musculoskeletal, hepatic, and genitourinary (as clinically indicated) systems. Weight will also be 
measured and recorded. Height will only be recorded at Screening. 
Signs and symptoms of concomitant disease and/or conditions should also be assessed. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Clinically relevant findings or worsening of previous findings will be recorded in the eCRF as an 
AE. 
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9.1.2 
Vital signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiration rate. Vital sign 
measurements should be recorded prior to collection of PK samples. 
9.1.3 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, and QT intervals. Refer to Section 7.1.2 for QTc withdrawal 
criteria and any additional QTc readings that may be necessary. 
All ECG recordings should be taken with the study participant resting in the supine position for 
at least 5 minutes before the recording. When coinciding with blood sample draws for PK, 
ECG assessment should be performed prior to blood sample collection, such that the blood 
sample is collected at the nominal time. 
The 3 ECG tracings should be obtained as closely as possible in succession, within 2 to 
10 minutes at each time point. 
All ECGs will be evaluated for any clinically relevant changes by the investigator. 
Electrocardiograms may be collected for central reading. During the visit, the assessment of the 
ECG by the investigator or designee will be used to determine eligibility and continuation in the 
study. 
9.1.4 
Echocardiograms 
Echocardiograms will be collected from all participants according to the Schedules of Activities 
for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C 
(Table 1-8). Left ventricular ejection fraction will be measured and recorded in the eCRF 
expressed as a percentage. 
9.1.5 
Clinical safety laboratory assessments 
Hematology, blood chemistry, coagulation, and urinalysis will be collected at the time points 
described in the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 and 
Table 1-6), Part B (Table 1-7), and Part C (Table 1-8) and analyzed at a local laboratory. See 
Appendix 2 (Section 11.2) for the list of clinical laboratory tests to be performed. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant’s condition. 
Chemistry, hematology, and coagulation (where applicable) results should be available for 
review prior to infusion of treatment. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 24 hours after the final dose of study medication should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator or study physician or medically qualified designee. 
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If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 11.2), must be 
conducted in accordance with the laboratory manual and the Schedules of Activities for Part A 
(Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). 
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
9.1.6 
Pregnancy testing 
Procedures for pregnancy testing and contraceptive use are provided in Appendix 4 
(Section 11.4). Pregnancy testing should be collected as described in the Schedules of Activities 
for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C 
(Table 1-8). 
For female participants of childbearing potential, a serum pregnancy test with sensitivity of at 
least 25mIU/mL will be performed on 2 occasions prior to starting study therapy, as follows: 
once at the start of Screening and once at the Day 1 Cycle 1 visit immediately before the 
investigational product administration. 
Following a negative pregnancy test result at Screening, appropriate contraception must be 
commenced, and another negative pregnancy test result will then be required at the Day 1 
Cycle 1 Visit before the participant may receive the study treatment. 
Serum or urine pregnancy tests will also be routinely repeated twice at every treatment cycle 
during the active Treatment Period, at the Final Visit, and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected. In the case of a positive 
pregnancy test, the participant will be withdrawn from treatment but may remain in the study 
(Section 9.2.5). 
9.2 
Adverse events and serious adverse events 
Planned time points for AE and SAE reporting are provided in the Schedules of Activities for 
Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6),Part B (Table 1-7), and Part C (Table 1-8). 
Reporting of AEs and SAEs for Parts D, E, F, and G will be described in a protocol amendment. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 11.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The investigator, study physician, or medically qualified designee are responsible for detecting, 
documenting, and recording events that meet the definition of an AE or SAE and remain 
responsible for following up AEs that are serious, considered related to the study treatment 
(UCB6114, TFD/TPI [Part B], any individual component of mFOLFOX6 [Part C], or more than 
1 of the treatments) or study procedures, or that caused the participant to discontinue the study 
treatment or study (see Section 7). 
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All non-serious events of COVID-19 or associated with COVID-19 should be reported as either 
“suspected COVID-19” or “confirmed COVID-19” utilizing the standard AE form. If additional 
assessments (e.g. additional labs) are performed by the site, they should be reported on 
unscheduled visit CRF pages per standard practice. 
All serious events of COVID-19 or associated with COVID-19 should be reported as either 
“suspected COVID-19” or “confirmed COVID-19”, along with additional relevant data, to UCB 
Patient Safety utilizing the electronic SAE form and in accordance to the timelines outlined 
within the protocol.  
9.2.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 
and Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no study medication was taken but specific study 
procedures were conducted. This includes all AEs not present prior to the initial visit and all AEs 
that recurred or worsened after the initial visit. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 11.3). The investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
The investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the investigator is certain that they are in no way associated with the study 
medication), up to the Safety Follow-up Visit for each participant, and to also inform participants 
of the need to inform the investigator of any SAE within this period. Serious AEs that the 
investigator thinks may be associated with the study medication must be reported to UCB 
regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 11.3). 
9.2.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
9.2.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and non-serious AEs of special interest (as defined in 
Section 9.2.6 and Section 9.2.7, respectively), will be followed until resolution, stabilization, the 
investigator determines that it is no longer clinically significant, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3. Further information on follow-up 
procedures for AEs and SAEs is given in Appendix 3 (Section 11.3). 
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9.2.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
9.2.5 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study treatment and until 3 months after the last study treatment 
administration. 
If a pregnancy is reported, the investigator must immediately inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 11.4). 
Female participants should be withdrawn from the study as soon as pregnancy is known (by 
positive pregnancy test), and the following should be completed: 
• The participant should return for a Safety Follow-up Visit. 
• The participant should immediately stop the intake of the study medication or be 
down-titrated as instructed at the Safety Follow-up Visit. 
• A Final Visit should be scheduled 3 months after the participant has discontinued her study 
medication. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
9.2.6 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. 
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For UCB6114, the following event requires immediate reporting (within 24 hours regardless of 
seriousness) to UCB: 
• Hy’s Law 
− Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the 
biochemical abnormality (ie, without waiting for any additional etiologic investigations 
to have been concluded). Follow-up information should be reported if an alternative 
etiology is identified during investigation and monitoring of the participant. 
− Study participants who have evidence of liver metastases may be considered to have an 
alternate etiology for the described laboratory abnormalities. 
9.2.7 
Adverse events of special monitoring 
An AE of special monitoring is a product-specific AE, adverse reaction, or safety topic requiring 
special monitoring by UCB. 
For UCB6114, no AEs of special monitoring have been identified. 
9.2.8 
Anticipated serious adverse events 
To date, no humans have been exposed to UCB6114. Thus, no serious AEs with a possible 
causal relationship to the IMP (ie, suspected serious adverse reactions [SARs]) have been 
observed in humans. Therefore, all suspected SARs will be considered unexpected and will be 
reported as such. 
Death due to disease progression will not be recorded as a SAE and will be recorded in the 
survival eCRF. However, if death might be due to other causes, it should be timely reported as a 
SAE. 
9.2.9 
Infusion-related reactions (hypersensitivity reactions) 
Participants should be observed for at least 6 hours after the start of the first infusion and for 
2 hours after the start of the subsequent infusions for symptoms like fever and chills or other 
infusion-related symptom. Interruption or slowing the rate of the infusion may help control such 
symptoms. The infusion may be resumed when symptoms abate. 
If an infusion-related reaction occurs, the participant must be treated according to the best 
available medical practice. 
Participants should be instructed to report any delayed reactions to the investigator immediately. 
Ensure that medications to treat infusion-related reactions, and cardiopulmonary resuscitative 
equipment are available for immediate use prior to initiation of UCB6114. 
In the event of an infusion-related reaction, temporarily stop the drug until resolution, then 
resume at a reduced infusion rate. 
If an infusion is interrupted, it can be restarted if the investigator considers it appropriate to do 
so. In such instances, the total infusion time may exceed the planned infusion time in order to 
administer the entire planned dose. The chronology of these events should be recorded accurately 
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in the source data and eCRF. In addition, the PK sampling times should be adjusted to preserve 
the relationship of sampling times to the start of the infusion. 
If an infusion-related reaction or anaphylaxis occurs, a blood sample will be collected from the 
study participant as soon as possible, while the event is ongoing, to investigate the nature of the 
reaction. Evaluation of drug-related hypersensitivity reaction may consist of diagnostic testing 
and continued monitoring. Further tests may include, but are not limited to cytokine 
measurements, immunoglobulin E levels, tryptase, complement parameters such as C3a, C5a 
measurements when there is a suspicion of Type I or III hypersensitivity reaction. 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor. 
Premedication to prevent the onset of infusion-related reactions may be allowed for individual 
study participants based on the Investigator recommendations and after consultation with the 
Sponsor and should be recorded in the eCRF. 
Procedures for reporting infusion-related reactions are the same as those for AEs and SAEs, as 
described in Appendix 3 (Section 11.3). 
9.3 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect, as early as possible, any 
safety concern(s) related to the study medication so that investigators, study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The study physician or medically qualified designee/equivalent will conduct an ongoing review 
of safety data as they become available and perform ongoing SAE reconciliations in 
collaboration with the Patient Safety representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory or electrocardiogram [ECG] results) for which data will be 
periodically reviewed during the course of the study. For information regarding the SMC, see 
Section 4.1.1 (all parts),  Section 4.1.2.1 (Part A), Section 4.1.3 (Part A1), Section 4.1.4.1  (Part 
B), and Section 4.1.5.1  (Part C). 
9.4 
Treatment of overdose 
For this study, any dose of UCB6114 >20% above the prescribed dose within a 24-hour time 
period will be considered an overdose. Overdose events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms. 
No specific information is available on the treatment of overdose for UCB6114. 
UCB6114 will not be self-administered by the study participant. In the event of inadvertently 
administering an overdose of UCB6114, the investigator should: 
1. Contact the study physician or medically qualified designee immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until UCB6114 
can no longer be detected systemically (at least 28 days). 
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4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study physician or medically qualified designee based on the clinical 
evaluation of the participant. 
For this study, overdose of the SOC combination therapies in Part B (TFD/TPI) and Part C 
(mFOLFOX6) refers to the administration of a quantity of medicinal product given per 
administration or per day that is above the recommended dose according to the authorized 
product information. This shall also take into account cumulative effects due to overdose. Please 
refer to the respective product information or SmPC for overdose management information. 
9.5 
Pharmacokinetics 
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Table 9-4: 
Blood collection time points for PK analysis for Part A 
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Table 9-4:
Blood collection time points for PK analysis for Part A
Table 9-5: 
Blood collection time points for PK analysis for Part A1 
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Table 9-6: 
Blood collection time points for PK analysis for Part B and Part C 
9.6 
Efficacy assessments 
Planned time points for all tertiary/exploratory antitumor activity assessments are provided in the 
Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B 
(Table 1-7), and Part C (Table 1-8). Primary, secondary, and tertiary/exploratory antitumor 
activity assessments for Parts A1, D, E, F, and G will be described in a protocol amendment. 
9.6.1 
Tumor assessments 
Tumor assessments will be performed as outlined in the Schedules of Activities for Part A 
(Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). The 
same imaging technique used to characterize each identified and reported lesion at Baseline will 
be employed in subsequent tumor assessments. 
Screening tumor assessments must be performed within 42 days prior to the first dose of 
UCB6114, and include at a minimum a computed tomography (CT) or magnetic resonance 
imaging (MRI) scan of the chest, abdomen, and pelvis (if relevant), and any other areas of 
known or suspected disease. A CT or MRI scan that is dated prior to consent for this study may 
be used as the Screening assessment, where this has been performed as per standard care or at the 
end of a prior research study 
Thereafter, tumor assessments of the chest, abdomen, and pelvis (if applicable) and any other 
areas of disease found at Screening, or newly suspected at follow-up, are to be performed 
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between Days 21 and 28 of every even-numbered cycle and at the SFU Visit unless the 
participant has already withdrawn due to progressive disease or if the previous tumor assessment 
was within 6 weeks of SFU Visit.  
Bone lesions can be assessed with CT and MRI. Further tests may be required for assessing bone 
lesions and they will be performed at the investigator’s discretion and per clinical practice. 
The method of tumor assessment should follow the RECIST (Version 1.1) criteria detailed in 
Appendix 9 (Section 11.9). If subcutaneous masses or nodes are palpable (eg, bulky) and are 
assessable by both clinical and radiographic techniques, the radiographic (CT/MRI) technique 
should be used for the assessment of target and non-target lesions. Assessment is to be performed 
at the site by appropriately qualified personnel (radiologist and clinical investigator) and results 
are to be recorded in the eCRF. 
In the event of CR or PR, the tumor assessment should be confirmed. The confirmation 
assessment is done at least 4 weeks after the response is recorded, typically at the next scheduled 
assessment time point. If bone lesion assessments are a part of the tumor assessment, the bone 
assessments should be repeated at the time of the confirmation scan. 
Any redacted scan data may be collected for verification/central reading. 
9.6.2 
ECOG Performance Status 
Measures of ECOG Performance Status will be taken at visits outlined in the Schedules of 
Activities for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and 
Part C (Table 1-8). ECOG Performance Status will be determined according to the table 
provided in Appendix 8 (Section 11.8) 
9.7 
Genetics 
Planned time points for all genetic assessments are provided in the Schedules of Activities for 
Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and Part C 
(Table 1-8). Genetic assessments for Parts A1, D, E, F, and G will be defined in a protocol 
amendment. 
Where local regulation and IEC allow, an 8.5mL blood sample for deoxyribonucleic acid (DNA) 
isolation will be collected from participants and may be used to perform genetic analysis to help 
understand a participant’s response to UCB6114. 
See Appendix 5 (Section 11.5) for information regarding genetic research. Details on processes 
for collection and shipment of these samples can be found in the laboratory manual. 
9.8 
Pharmacodynamics 
Planned time points for all tertiary/exploratory PD assessments are provided in the Schedules of 
Activities for Part A (Table 1-4), Part A1 (Table 1-5 and Table 1-6), Part B (Table 1-7), and 
Part C (Table 1-8). All tertiary/exploratory PD assessments for Parts  D, E, F, and G will be 
defined in a protocol amendment. 
Blood samples for PD analysis will be collected at the time points discussed in the following 
sections. 
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Blood samples of various volumes may be collected for analysis in a range of PD assays 
(Table 9-1). In Part A, the number of blood samples and total volume collected per cycle and at 
the SFU Visit will be as follows: 
• In Cycle 1, up to 12 blood samples totaling approximately 83.5mL 
• In Cycle 2, up to 5 blood samples totaling approximately 35.5mL 
• In Cycle 3, up to 5 blood samples totaling approximately 35.5mL 
• In Cycle 4, up to 4 blood samples totaling approximately 15.5mL 
• At the SFU Visit, up to 5 blood samples totaling approximately 35.5mL 
In Part A1, the number of blood samples and total volume collected per cycle and at the SFU 
Visit will be as follows: 
• In Screening, up to 4 blood samples totaling approximately 36 mL in each Cohort 
• Cycle 1, up to 7 blood samples totaling approximately 43.5mL in Cohorts 1, 2, 4 and up to 4 
blood samples totaling approximately 16mL in Cohort 3 
• In Cycle 2, up to 4 blood samples totaling approximately 31.5mL in each Cohort 
• In Cycle 3 up to 5 blood samples totaling approximately 35.5mL in each Cohort 
• From Cycle 4 onwards and at the SFU Visit up to 4 blood samples totaling approximately 
31.5mL in each Cohort 
One additional sample for circulating gremlin-1 (4mL) may be taken on the day of the on-
treatment biopsy if taking place on a day where no circulating gremlin-1 sample is scheduled. 
In Parts B and C, the number of blood samples and total volume collected per cycle and at the 
SFU Visit will be as follows: 
• In Screening, up to 3 blood samples totaling approximately 32.5mL 
• In Cycle 1, up to 4 blood samples totaling approximately 32mL 
• In Cycle 2, up to 6 blood samples totaling approximately 56mL 
• From Cycle 3 onwards, up to 3 blood samples totaling approximately 28mL 
• At the SFU Visit, up to 3 blood samples totaling approximately 28mL 
Tumor biopsies will also be collected during the study (see Section 9.8.7). 
9.8.1 
Blood samples for circulating gremlin-1 
Whole blood samples of approximately 4mL per time point will be collected and processed to 
serum for measurement of total circulating gremlin-1 levels. Sampling time points throughout 
the study are outlined in the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 
and Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). Sampling collection times relative to 
dosing are detailed in Table 9-7 (Part A), in Table 9-8 (Part A1) and Table 9-9 (Part B and 
Part C). 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. 
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Table 9-7: 
Sample time points for serum gremlin-1 analysis in Part A 
Cycle 
Day 
Sampling time relative to dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 2 
+24h 
Postdose on Cycle 1 
Day 1 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles (up 
to and including 
Cycle 4) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
Note: The time window for blood sample collection at the 24h PD time point postdose (Cycle Day 2) is ± 0.5h. 
Table 9-8: 
Sample time points for serum gremlin-1 analysis in Part A1 
Cyclea 
Day 
Sampling time relative to dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 1 
End of infusion (+15min) 
Postdose  
Day 1 
+4h (+1h) 
Postdose  
Day 15b 
Within 0.5h prior to dosing/day of 
visit 
Predose/NA 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Cycle 3  
Day 1 
Within 0.5h prior to dosing 
Predose 
Day 1 
+4h (+1h) 
Postdose 
Cycle 4 onwards 
Day 1 
Baseline 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
a An additional sample should also be collected on the day of the on-treatment biopsy (only if taking place on a day 
where no serum gremlin-1 samples are scheduled) 
b Predose for a 2-weekly cycle (Cohorts 1 and 2) but on day of visit for a 3-weekly or a 4-weekly cycle (Cohorts 3 
and 4) 
h=hour; NA=not applicable; SFU=Safety Follow-Up  
 
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Table 9-9: 
Sample time points for serum gremlin-1 analysis in Part B and 
Part C 
Cycle 
Day 
Sampling time relative to 
dosing with UCB6114 
Sampling time 
Screening 
Once between 
Day -28 and -1 
NA 
NA 
Cycle 1 
Day 15 
Within 0.5h prior to dosing 
Predose 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Cycle 3 (onward)a 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
a To be completed in cycle 3 and thereafter in even cycles only (ie, Cycle 4, 6) 
9.8.2 
Blood samples for serum protein analysis and blood transcriptomics 
In Part A and Part A1, whole blood samples of approximately 5mL per time point will be 
collected and processed to serum for analysis of protein markers. An additional whole blood 
sample of 2.5mL per time point may also be collected for potential transcriptomic analysis. 
Samples for analysis of protein markers or potential transcriptomic analysis will not be obtained 
in Part B or Part C. 
Sampling time points for these assays are detailed in Table 9-10 (Part A) and Table 9-11 
(PartA1). 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. 
Table 9-10: Sample time points for serum protein analysis and blood 
transcriptomics in Part A 
Cycle 
Day 
Sampling time relative to 
dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles (up 
to and including 
Cycle 4) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
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Table 9-11: Sample time points for serum protein analysis and blood 
transcriptomics in Part A1 
Cycle 
Day 
Sampling time relative to dosing Sampling time 
2-weekly and 4-weekly cycles (Cohorts 1, 2 and 4) 
Screening 
Day-14 to -1 
Baseline 
 
Cycle 1 
Day 15 
Within 0.5h prior to dosing 
(Cohorts 1 and 2)/on day of visit 
(Cohort 4) 
Predose(Cohorts 1 and 2)/ 
NA (Cohort 4) 
Subsequent cycles  
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of 
visit 
On day of visit 
NA 
3-weekly cycles (Cohort 3) 
Screening 
Day-14 to -1 
Baseline 
 
Cycle 2 onwards  
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of 
visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
 
9.8.3 
Blood samples for circulating tumor DNA analysis 
Whole blood samples of approximately 20mL per time point will be collected and processed for 
analysis of circulating tumor DNA (ctDNA).  
Sampling time points are detailed in Table 9-12 (Part A), Table 9-13 (Part A1) and Table 9-14 
(Part B and Part C). 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. 
Table 9-12: Sample time points for ctDNA analysis in Part A 
Cycle 
Day 
Sampling time relative to 
dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles (up 
to and including 
Cycle 3) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
ctDNA=circulating tumor DNA; h=hour; NA=not applicable; SFU=Safety Follow-Up 
 
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Table 9-13: Sample time points for ctDNA analysis in Part A1 
Cycle 
Day 
Sampling time relative to 
dosing 
Sampling time 
2-weekly and 4-weekly cycles (Cohorts 1, 2 and 4) 
Screening 
Day-14 to -1 
Baseline 
 
Cycle 1 
Day 15 
Within 0.5h prior to dosing 
(Cohorts 1 and 2)/on day of visit 
(Cohort 4) 
Predose(Cohorts 1 
and 2)/ NA (Cohort 
4) 
Subsequent cycles  
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
3-weekly cycles (Cohort 3) 
Screening 
Day-14 to -1 
Baseline 
 
Cycle 2 onwards  
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
 
Table 9-14: Sample time points for ctDNA analysis in Part B and Part C 
Cycle 
Day 
Sampling time relative to 
dosing with UCB6114 
Sampling time 
Screening 
Once between 
Day -28 and -1 
NA 
NA 
Cycle 1 
Day 15 
Within 0.5h prior to dosing 
Predose 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Cycle 3 (onward) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
ctDNA=circulating tumor DNA; h=hour; NA=not applicable; SFU=Safety Follow-Up 
9.8.4 
Blood samples for serum bone turnover markers 
In Parts A, B, and C, whole blood samples of approximately 4mL per time point will be collected 
and processed to serum for analysis of circulating markers of bone turnover. Sampling time 
points throughout the study are outlined in the Schedules of Activities for Part A (Table 1-4), 
Part B (Table 1-7), and Part C (Table 1-8).  
Sampling collection time points relative to dosing are detailed for Part A in Table 9-15 and for 
Parts B and C in Table 9-16. 
Instructions pertaining to sample collection processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study.  
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Table 9-15: Blood samples for serum bone turnover markers in Part A 
Cycle 
Day 
Sampling time relative to 
dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles (up 
to and including 
Cycle 4) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
Table 9-16: Blood samples for serum bone turnover markers in Parts B and C 
Cycle 
Day 
Sampling time relative to 
dosing with UCB6114 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles 
(from cycle 3 onwards) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
9.8.5 
Urine samples for urinary bone turnover markers 
In Parts A, B, and C, urine samples of approximately 30mL per time point will be collected for 
analysis of urinary markers of bone turnover. Sampling time points throughout the study are 
outlined in the Schedules of Activities for Part A (Table 1-4), Part B (Table 1-7), and Part C 
(Table 1-8). 
Sampling collection times relative to dosing are detailed for Part A in Table 9-17 and for Parts B 
and C in Table 9-18. 
Instructions pertaining to sample collection processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. 
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Table 9-17: Urine samples for urinary bone turnover markers in Part A 
Cycle 
Day 
Sampling time relative to 
dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles (up 
to and including 
Cycle 4) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
Table 9-18: Urine samples for urinary bone turnover markers in Parts B and C 
Cycle 
Day 
Sampling time relative to 
dosing with UCB6114 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Subsequent cycles 
(from cycle 3 onwards) 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit 
On day of visit 
On day of visit 
NA 
h=hour; NA=not applicable; SFU=Safety Follow-Up 
9.8.6 
Blood samples for genetic analysis 
An 8.5mL blood sample will be taken predose Cycle 1 Day 1 (Part A) or at Screening (Part A1, 
Part B and Part C) for genetic analysis as described in Section 9.7. 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. A description of genetic analyses performed in 
this study is provided in Appendix 5 (Section 11.5). 
9.8.7 
Tumor biopsy for PD assessments and predictive biomarker 
assessments 
In participants with a tumor that is accessible to biopsy and who have given informed consent, 
biopsies may be performed unless tissue collection carries a high risk of mortality or is otherwise 
contraindicated (to be determined at the discretion of the investigator).  
• During Part A, these biopsies will be optional and collected at Screening and on Day 22.  
• During Part A1, these biopsies will be mandatory and collected at the following time points:  
− After eligibility assessment and before study drug administration (Baseline) between 
Day-28 and Day -1. 
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− Within 2 weeks post Cycle 1 Day 15 for 2- or 4- weekly dosing schedule (ie, between 
Cycle 1 Day 15 and Cycle 2 Day 1 for Cohorts 1, 2 and 4) and within 2 weeks post 
Cycle 2 Day 1 for a 3-weekly dosing schedule (ie, between Cycle 2 Day 1 and Cycle 2 
Day 15 for Cohort 3). 
Note: An additional blood sample each for PK and cGremlin-1 should be collected on the 
day of biopsy but only in cases where samples for these endpoints are not already 
scheduled to be taken on the Day. 
In addition, if a historical tumor biopsy specimen had been obtained prior to the study 
participant’s entry into the study (eg, time of diagnosis), permission will be requested at the 
time of informed consent to use the biopsy for PD analysis. 
• Tumor biopsies will not be obtained in Part B or Part C. 
Biopsies will be performed according to standard clinical practice for the participant’s indication 
and will be collected as outlined in the Schedules of Activities for Part A and Part A1 
(Section 1.3). 
Biopsy samples may be processed to RNA and/or formalin fixed and paraffin embedded. 
Ribonucleic acid samples may be used for transcriptomic analysis. Formalin-fixed and 
paraffin-embedded tissue may be used for transcriptomic analysis, immunohistochemistry, 
and/or protein expression analysis. 
Excess tumor samples that remain after PD assessments have been performed may be retained 
while research on UCB6114 or study medications of this class continues, but no longer than 
20 years (or other period according to local regulations). Tumor samples may be analyzed for 
additional biomarkers specifically related to the mechanism of action of UCB6114 or cancer 
biology as warranted by new preclinical discoveries and reports in the scientific literature. 
Biopsy procedure in Part A1 
The most suitable lesion(s) to be biopsied should discussed between the oncologist, radiologist, 
and/or colleague performing biopsy of cutaneous metastases or endoscopic biopsy, as 
appropriate.  
Tumor biopsies are mandatory, however biopsies are to be performed, and the potentially 
required local anesthesia administered, only if considered to be of low risk to the participant, as 
determined by the Investigator and the health care professional performing the biopsy.  
It is preferred that up to 5 cores per biopsy, 18-gauge in diameter and ≥1cm in length will be 
obtained during each procedure, if considered safe and feasible. A single baseline biopsy core 
transferred to neutral buffered formalin (NBF) will constitute a successful biopsy. If an initial 
attempt at a biopsy is unsuccessful, the patient will be given an option to proceed with a repeated 
attempt. If the baseline biopsy remains unsuccessful no further biopsies will be performed but 
the patient may remain on the study and receive study medication.  
If the study participant chooses not to undergo biopsies subsequent to the baseline biopsy, he/she 
will be withdrawn from the study. Feasibility for the subsequent biopsies will be assessed by the 
Investigator/the health care professional performing the biopsy and should include a 
consideration of patient safety. If the subsequent biopsy is deemed to be unsafe and/or not 
feasible , the study participant may remain on study and receive study medication.  
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The lesion from which each biopsy is taken will be documented in the Tissue Acquisition Form, 
and, if possible, an attempt will be made to collect the on-treatment biopsies from the same 
lesion as the Baseline biopsy.  
The use of imaging to facilitate biopsies will be decided by members of the Interventional 
Radiology team and may include ultrasound, CT scan, or MRI. Should a CT scan be needed for 
biopsy, the number of scans for each procedure will be limited to the minimum number and 
duration required to safely obtain the biopsy. 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the biopsy manual for this study. 
9.8.8 
Historical tumor samples 
If available, samples from study participants’ stored historical tumor biopsy specimen from the 
time of diagnosis or subsequent surgery may be sent to the analyzing laboratory. These samples 
will be analyzed for transcriptional and/or protein expression and the results may be compared 
with those obtained from the on-study biopsies where available. 
9.9 
Biomarkers 
Collection of samples for other biomarker research is also part of this study and is described in 
Section 9.8. 
Planned tertiary/exploratory biomarker assessments for Parts D, E, F, and G will be defined in a 
protocol amendment. 
9.10 
Immunogenicity 
Antibodies to UCB6114 will be evaluated in serum samples collected from all participants 
according to the Schedules of Activities for Part A (Table 1-4), Part A1 (Table 1-5 and 
Table 1-6), Part B (Table 1-7), and Part C (Table 1-8). On dosing days, these samples will be 
collected predose. These samples will be tested by the Sponsor or Sponsor’s designee. All 
tertiary/exploratory ADA assessments for Parts D, E, F, and G will be described in a protocol 
amendment. 
Serum samples will be screened for antibodies binding to UCB6114 and the titer of confirmed 
positive samples will be reported. 
The detection and characterization of antibodies to UCB6114 will be performed using validated 
assays by or under the supervision of the Sponsor.  
In Part A, a total of 3 samples of 5mL of blood will be collected for ADA analysis during the 
first cycle of treatment, for a total of 15mL (Table 9-19). One sample of 5mL of blood will be 
collected for ADA analysis during Cycles 2, 3, and 4. If a participant continues on study beyond 
Cycle 4, an additional 5mL blood sample for ADA analysis (with concomitant sample for PK 
analysis) will be collected every 3 months (Cycle 7, Cycle 10, etc). An additional 5mL blood 
sample for ADA will be taken at the SFU Visit. 
In Part A1, 1 sample of 5mL of blood will be collected for ADA analysis on Day 1 of the first 
3 cycles (Cycles 1 to 3) and on Day 1 of every third cycles thereafter (ie, Cycle 6, Cycle 9; 
Table 9-20). An additional 5mL blood sample for ADA will also be taken at the SFU Visit. 
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In Part B and Part C, 1 sample of 5mL of blood will be collected for ADA analysis during 
Cycle 1 and Cycle 2 (Table 9-21). From Cycle 3 onwards, an additional 5mL sample for ADA 
analysis (concomitant to a sample for PK analysis) will be collected in even-numbered cycles 
only (Cycle 4, Cycle 6, etc). An additional 5mL blood sample for ADA will also be taken at the 
SFU Visit. 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. 
Table 9-19: Blood sample time points for ADA analysis in Part A 
Cycle 
Day 
Sampling time relative to 
dosing 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Day 15 
Within 0.5h prior to dosing 
Predose 
Day 22 
On day of visit (taken at same 
time ±5min as PK sample is 
collected) 
On day of visit 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Cycle 3 
Day 1 
Within 0.5h prior to dosing 
Predose 
Cycle 4 
Day 1 
Within 0.5h prior to dosing 
Predose 
Cycle 7 (onward) 
Every 3 months 
Within 0.5h prior to dosing 
Predose 
SFU Visit  
On day of visit 
On day of visit 
NA 
ADA=antidrug antibody; h=hour; NA=not applicable; SFU=Safety Follow-up  
Table 9-20: Blood sample time points for ADA analysis in Part A1 
Cycle 
Day 
Sampling time relative to 
dosing with UCB6114 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Cycle 3a onwards 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit  
On day of visit 
NA 
On day of visit 
ADA=antidrug antibody; h=hour; NA=not applicable; SFU=Safety Follow-Up 
a Cycle 3 and every third cycle thereafter (ie, Cycle 6, Cycle 9 etc.) 
 
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Table 9-21: Blood sample time points for ADA analysis in Part B and Part C 
Cycle 
Day 
Sampling time relative to 
dosing with UCB6114 
Sampling time 
Cycle 1 
Day 1 
Baseline 
Predose 
Cycle 2 
Day 1 
Within 0.5h prior to dosing 
Predose 
Cycle 3 (onward)a 
Day 1 
Within 0.5h prior to dosing 
Predose 
SFU Visit  
On day of visit 
NA 
On day of visit 
ADA=antidrug antibody; h=hour; NA=not applicable; SFU=Safety Follow-Up 
a To be completed in cycle 3 and thereafter in even cycles only (i.e., Cycle 4, 6).  
10 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and further details will be included in the Statistical 
Analysis Plan for each module. 
10.1 
Definition of analysis sets 
Enrolled Set 
The Enrolled Set (ES) consists of all study participants who sign the Informed Consent Form. 
Safety Set 
The Safety Set (SS) will be used primarily for the analysis of safety data and will consist of all 
study participants who receive 1 or more full or partial doses of any study treatment. 
Per-protocol Set 
The Per-protocol Set (PPS) will include all study participants in the SS who do not have 
important protocol deviations that may substantially affect antitumor activity. The PPS will be 
the primary analysis set for the analysis of the exploratory antitumor activity endpoints.  
Pharmacokinetic Set 
The Pharmacokinetic Set (PKS) will include all study participants in the SS who have at least 
1 evaluable PK concentration (ie, a sample which is above the lower limit of quantitation and for 
which the date and time of the sample and prior date and time of dosing are known). Additional 
participants or specific samples may be excluded from the PKS at the discretion of the Advanced 
Modeling and Simulation Scientist/Quantitative Clinical Pharmacology scientist. 
Pharmacokinetic analysis will be performed on the PKS. 
ADA Set 
The ADA Set (ADAS) will include all study participants in the SS who have at least 1 evaluable 
ADA assessment.  
Immunogenicity analyses will be performed on the ADAS. 
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Pharmacodynamic Set 
The Pharmacodynamic Set (PDS) will include all study participants in the SS who have at least 
1 evaluable PD assessment (where appropriate, the sample should be above the lower limit of 
quantitation and the date and time of the sample should be known). 
Pharmacodynamic analysis will be performed on the PDS. 
DLT Evaluable Set 
The DLT Evaluable Set (DES) will include all study participants who, during the DLT 
assessment period:  
• Receive the planned dose of UCB6114 (Part A and Part A1) 
• Receive the planned dose of UCB6114 and at least 80% of the planned dose of TFD/TPI 
(Part B)  
• Receive the planned dose of UCB6114 and at least 80% of the planned dose of mFOLFOX6 
(Part C) 
• Stopped treatment because of a DLT (any part of the study) 
The DES will be used by the SMC for all dose escalation/de-escalation decision making. 
10.2 
General statistical considerations 
All analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, Cary, NC, US).  
Descriptive statistics will be used to provide an overview of the Baseline, safety, PK, PD, and 
other exploratory results. For categorical and ordinal variables, the number and percentage of 
participants in each category will be presented. The denominator for the percentages will be 
based on the number of participants appropriate for the purpose of analysis. Unless otherwise 
noted, all percentages will be expressed to 1 decimal place. For continuous variables, descriptive 
statistics will include, but will not be limited to, the number of participants, mean, median, 
standard deviation, minimum, and maximum. 
Definitions of Baseline for each variable, as applicable, will be included in the SAPs for each 
module. 
No formal hypothesis testing will be performed in Part A, Part A1, Part B or Part C. 
10.3 
Planned safety and other analyses 
10.3.1 
Safety analyses 
Safety will be assessed by clinical review of all relevant parameters including AEs, SAEs, 
laboratory values, vital signs, echocardiograms, ECG results and physical examination. Eastern 
Cooperative Oncology Group performance status will also be assessed from a safety perspective. 
Unless specified otherwise, the safety analyses will be conducted for the SS defined in 
Section 10.1. The results of these analyses will be presented by study part. For the dose 
escalation modules of the study (Part A, B, and C) tabulations will be provided by dose level and 
overall. For the dose optimization module of the study (Part A1) tabulations will be provided by 
cohort and overall. For the expansion modules (Parts D, E, F, and G), tabulations will be 
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provided by tumor type and overall. Some safety analyses may be performed based on the dose 
escalation, optimization, and expansion modules combined. 
Summary tables and listings will be provided for all reported TEAEs, defined as AEs that start 
on or after the first administration of study treatment up until the SFU visit. A pre-treatment AE 
which increases in severity on or after the first dose of study treatment will also be counted as a 
TEAE. The reported AE term will be assigned a standardized preferred term using the current 
version of the Medical Dictionary for Regulatory Activities (MedDRA). 
The causal relationship between the occurrence of an AE and study medication will be judged by 
the investigator. In the event that a participant experiences repeat episodes of the same AE, then 
the event with the highest CTCAE severity grade and strongest causal relationship to study 
medication will be used for purposes of incidence tabulations. 
An overview of the number and percentage of participants who experience TEAEs will be 
presented. This summary will include the number and percentage of participants with any 
TEAEs, serious TEAEs, related TEAEs (related to UCB6114, TFD/TPI [Part B], any individual 
component of mFOLFOX6 [Part C], or more than 1 of the treatments [Part B and Part C]), 
discontinuation due to TEAEs, CTCAE Grade 3 or 4 TEAEs, DLTs, AEs leading to death, and 
TEAEs leading to death; event counts will also be included against each of these categories. 
In addition, the following summaries will be presented by MedDRA System Organ Class, High 
Level Term and Preferred Term: 
• Incidence of all TEAEs, serious TEAEs, and non-serious TEAEs 
• Incidence of TEAEs by maximum relationship and maximum CTCAE severity grade 
• Incidence of TEAEs leading to a temporary interruption and/or reduction in study treatment 
• Incidence of TEAEs leading to discontinuation of study treatment 
• Incidence of fatal TEAEs by relationship 
• Incidence of adverse events of special interest (AESIs) (Hy’s Law – see Section 9.2.6) 
• Incidence of infusion-related (hypersensitivity) reactions 
For the dose escalation and optimization modules, the observed DLT rate in each dose cohort 
will be calculated by the crude proportion of participants who experience DLT. Multiple 
concurrent AEs leading to DLT will be considered a single DLT. 
Deaths that occur on study (defined as during treatment or within 30 days of treatment 
discontinuation) will be reported in a participant listing, which will include the primary cause of 
death and the number of days between the date of the final dose of study medication and death. 
Observed values and changes from Baseline in clinical chemistry, hematology, urinalysis, and 
coagulation parameters will be summarized at each visit. In addition, for each of these 
parameters, the Baseline value, the minimum, maximum, average, and last post-Baseline value 
for each participant will be summarized by cycle using descriptive statistics. These post-Baseline 
summary measures will be calculated based on laboratory assessments performed at the 
scheduled time points common to all cycles of study treatment.  
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Laboratory values will be assigned severity grades when available using the NCI CTCAE 
criteria. Directional shifts in laboratory toxicity grades (comparing Baseline grade with worst 
post-Baseline grade) will be analyzed using standard shift tables, presenting the number and 
proportion of participants and their maximum grade shift. For analytes without a CTCAE 
severity grade assigned, the shift table will present directional shifts from Baseline to above or 
below the laboratory standard normal range using the maximum increase and/or decrease 
observed throughout the course of treatment/observation. 
In addition, serial vital signs measurements will be obtained during participant’s UCB6114 
treatment and postdose (per the Schedules of Activities for Part A [Table 1-4], Part A1 
[Table 1-5 and Table 1-6], Part B [Table 1-7], and Part C [Table 1-8]). On the first day of each 
participant’s UCB6114 treatment, vital signs will be taken in conjunction with serial PK 
sampling. For each participant, the vital signs change from the predose value will be summarized 
in a descriptive manner.  
In Part A, vital signs will be measured at multiple time points on treatment days (predose, 10min 
and 30min after the start of the infusion, at the end of infusion, and at 1 hour after the end of the 
infusion). In addition, on Cycle 1 Day 1, vital signs will also be assessed at 2 hours and 8 hours 
after the end of the infusion. On non-dosing visits, vital signs will be measured prior to PK 
sampling. 
In Part A1, vital signs will be measured at multiple time points on treatment day (predose, 
10 minutes and 30 minutes after the start of the infusion, at the end of the infusion and 2 hours 
after the end of the infusion. In addition, on Cycle 1 Day 1, vital signs will also be assessed at 5 
hours after the end of the infusion.  
In Part B and Part C, on Day 1 of Cycle 1, vital signs will be measured at multiple time points 
(per the Schedules of Activities for Part B [Table 1-7], and Part C [Table 1-8]). At all other 
scheduled visits (Day 8, 15, and 22 of Cycle 1 and Days 1 and 15 of all subsequent cycles of 
study treatment), vital signs will be measured prior to UCB6114 dosing on treatment days.  
Observed vital sign measurements and changes from Baseline will be summarized by visit and 
timepoint using descriptive statistics. In addition, for each of the vital signs, the Baseline value, 
the minimum, maximum, average and last post-Baseline value for each participant will be 
summarized by cycle using descriptive statistics. These post-Baseline summary measures will be 
calculated based on vital sign measurements performed at the scheduled time points common to 
all cycles of study treatment. 
For the multiple vital sign measurements on Day 1 of Cycle 1, changes from the predose value 
will be calculated at each postdose time point and summarized using descriptive statistics.  
In Part A, on Days 1 and 15 of Cycle 1, ECGs will be performed at multiple time points relative 
to the dose of study treatment (predose, end of infusion, and 8 hours post end of infusion prior to 
PK sampling). At all other dosing visits (Days 1 and 15 of all subsequent cycles of study 
treatment), ECGs will be performed predose. On non-dosing visits, ECGs will be performed 
prior to PK sampling. 
In Part A1, ECGs will be performed at Screening; during Cycle 1 prior to dosing, at the end of 
the infusion, and 2 hours after the end of infusion; during each subsequent cycle prior to dosing 
with UCB6114 on Day 1. 
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In Part B and Part C, on Days 1 and 15 of Cycle 1, ECGs will be performed at multiple time 
points relative to dosing with UCB6114 (predose, end of infusion, and 2 hours post end of 
infusion prior to PK sampling). At all other UCB6114 dosing visits, ECGs will be performed 
prior to dosing with any study medication and as per Schedule of Activities.  
Observed values and changes from Baseline for these ECG parameters will be listed and 
summarized by visit using descriptive statistics. The mean of the triplicate measurements taken 
for each parameter will be used in the summary. In addition, for each of the ECG parameters, the 
Baseline value, the minimum, maximum, average and last post-Baseline value for each 
participant will be summarized by cycle using descriptive statistics. These post-Baseline 
summary measures will be calculated based on ECG measurements performed at the scheduled 
time points common to all cycles of study treatment. 
All summaries and listings of ECG data will be based on the local (site) 12-lead ECG 
measurements. 
Electrocardiograms will also be collected for central reading, the data from which will be 
analyzed and reported separately.  
Physical examination data will be listed only. 
Prior and concomitant medications will be coded to the generic term using the current version of 
the World Health Organization Drug Dictionary and will be tabulated by cohort and listed by 
participant.  
10.3.2 
Analysis of Baseline and Demographic Variables 
Descriptive summaries of demographic and Baseline characteristics for participants in the SS 
will be presented. For the dose escalation modules (Parts A, B and C) and the dose optimization 
module (Part A1), Baseline and demographic data will be tabulated by cohort and overall. For 
Part B and Part C, summaries may be presented by tumor type depending on the number of 
participants with specific tumor types. For the expansion modules (Parts D, E, F and G), 
participants will be tabulated by tumor type and overall. 
10.3.3 
Other analyses 
10.3.3.1 
Analysis of PK endpoints 
UCB6114 concentrations in blood will be listed for the SS and summarized descriptively for the 
PKS at each scheduled assessment by dose level. Where possible, key and other PK parameters 
will be determined after single and multiple doses using noncompartmental analysis and will also 
be summarized descriptively. Key and other PK parameters are described in Table 10-1 and will 
be calculated where possible. 
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Table 10-1: Pharmacokinetic parameters 
10.3.3.1.1 
Dose dependency 
The dose-dependency of PK parameters may be assessed. 
10.3.3.1.2 
Population PK 
The PK of UCB6114 administered as monotherapy in Part A and Part A1 may be assessed using 
a population analysis approach. 
 
10.3.3.2 
Analysis of genetic endpoints 
Possible relationships between variations in DNA sequence and the PD effects of UCB6114 will 
be explored using summary statistics and graphs. 
The analysis method and results for all genetic analysis will be reported separately to the main 
clinical study report. 
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10.3.3.3 
Analysis of PD endpoints 
The PD variables from blood samples and optional tumor samples will be summarized 
descriptively by cancer type, dose level/schedule, treatment cycle, and overall. The relationship 
of PD variables with the tumor response to UCB6114 will be explored using summary statistics 
and graphs. 
The analysis methods and results for all PD variables will be reported separately to the main 
clinical study report. 
10.3.3.4 
Analysis of biomarker endpoints 
Biomarkers examined in this study will be analyzed as described in Section 10.3.3.3. 
10.3.3.5 
Analysis of immunologic endpoints 
The ADA antibody status from the samples, participant classification according to ADA 
antibody status, changes from Baseline in titer over time, and the incidence of treatment-
emergent ADA positivity will be summarized by timepoint. Potential relationships between 
ADA and PK, PD, antitumor activity, and safety will also be explored.  
Hypersensitivity reactions are referenced in Section 10.3.1.  
10.4 
Planned efficacy/outcome analyses 
10.4.1 
Analysis of antitumor activity/outcome endpoint 
The analysis of the primary antitumor activity/outcome endpoint in the expansion modules (Parts 
D, E, F, and G) will be the same as the analysis of the exploratory antitumor activity/outcome 
endpoints in the dose escalation modules and will be further described, as applicable, in a 
planned protocol amendment. 
10.4.1.1 
Antitumor activity endpoint definitions 
The following are definitions of the antitumor activity endpoints: 
Objective response rate (ORR) is defined as the percentage of participants with a best overall 
response (BOR) of complete response (CR) or partial response (PR). 
Disease control rate (DCR) is defined as the percentage of participants with a BOR of CR, PR, or 
SD. 
Best overall response is defined for each study participant as the best overall tumor response 
designation, as determined by the investigator according to relevant RECIST criteria, recorded 
between the first dosing date and the date of documented disease progression or the date of 
subsequent anticancer therapy (systemic medication, surgery, or radiotherapy for cancer), 
whichever occurs first. Complete response or PR determinations included in the BOR assessment 
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must be confirmed by a second scan ≥4 weeks after the criteria for response are first met. In 
addition, for a BOR of SD, tumor measurements must have met the criteria for stable disease 
(SD)at least once after the start of study treatment at a minimum interval of no less than 6 to 8 
weeks. Table C in Section 11.9 (Appendix 9) provides the derivation of BOR when confirmation 
of CR and PR responses are required.  
Duration of response (DOR) will be calculated for participants who achieve a CR or a PR and 
is defined as the time in days from the start date of the response to the first date that recurrent or 
progressive disease is objectively documented. For participants who die without objective 
disease progression, DOR will be censored on the date of death, regardless of cause. For 
participants who discontinue early without documented objective progressive disease, DOR will 
be censored at the date of their last available (scheduled or unscheduled) tumor assessment at 
which a lack of objective disease progression was determined. A sensitivity analysis will be 
performed taking into account both objective progressive disease and clinical disease 
progression, as determined by the investigator, in the calculation of DOR. 
Progression-free survival (PFS) is defined as the time in days from first dosing date to the date 
of the first documented objective disease progression or death due to any cause, whichever 
occurs first. Participants who died without a documented objective disease progression will be 
considered to have progressed on the date of their death. Participants who did not progress or die 
will be censored on the date of their last available (scheduled or unscheduled) tumor assessment. 
Participants who did not have any on-study tumor assessments and did not die will be censored 
on the date of their first dose of study treatment. Participants who discontinued early without 
documented objective disease progression or death will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who started anti-cancer therapy without a prior 
documented objective disease progression will be censored on the date of their last available 
(scheduled or unscheduled) tumor assessment prior to the initiation of the subsequent anti-cancer 
therapy. A sensitivity analysis will be performed taking into account both objective progressive 
disease and clinical disease progression, as determined by the investigator, in the calculation of 
PFS. 
Overall Survival (OS) is defined for all participants in the study as the time in days from the 
date of first dosing to the date of death from any cause. Participants will be followed up to 
ascertain their survival status at the SFU Visit (within 30 days after their final dose of study 
treatment) and at the Final Visit (3 months after their final dose of study treatment); they will not 
be followed up beyond this time point. For participants who discontinued early from the study or 
discontinued study treatment due to disease progression and were not known to have died, OS 
will be censored on the date of last contact. 
10.4.1.2 
Analysis of the antitumor activity endpoints 
Unless specified otherwise, the antitumor activity analyses will be conducted using the PPS with 
sensitivity analyses conducted using the SS (see Section 10.1). The results of these analyses will 
be presented for each study part. 
Tumor response data, as determined using RECIST criteria, will be tabulated. Tabulations will 
be presented by dose level for each cohort. 
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Exploratory analyses of selected antitumor activity endpoints may be performed based on 
subgroups of participants in the SS. Data permitting, the subgroups will be defined based on 
participant, disease, and treatment history information (eg, extent of prior anti-cancer therapy). 
For the antitumor activity endpoints ORR and DCR, the proportion of participants achieving 
response, and, if data allow, the exact 95% confidence interval for this proportion will be 
estimated using the Clopper-Pearson method and presented for the response rates. 
Duration of response, PFS and OS will be summarized descriptively using the Kaplan-Meier 
method with 95% CIs calculated using Greenwood’s formula. Duration of response and PFS 
rates at specific timepoints (3 months, 6 months, 12 months, etc.) will also be derived from the 
Kaplan-Meier estimation and presented together with associated 95% CIs. 
A full discussion of statistical methodology will be provided in the SAPs for each module. 
10.5 
Handling of protocol deviations 
After all data have been verified/coded/entered into a database, a data review will be performed. 
The purpose of this review will be to check all protocol deviations, define the PPS, and check the 
quality of the data. The review will also help decide how to manage problems in the participants’ 
data (eg, missing values, withdrawals, dropouts, and protocol deviations). Accepted deviations 
from theoretical time points will be described in the appropriate documents and included in the 
Trial Master File. After the pre-analysis review, resolution of all issues, and documentation of all 
decisions, the database will be locked. 
10.6 
Handling of dropouts or missing data 
Participants who withdraw from the study before receiving study medication will be replaced 
and will not be included in the safety or antitumor activity assessments. Safety analyses will be 
conducted on all participants who have received at least 1 dose of the study medication, 
regardless of whether they are deemed evaluable for the assessment of a dose level (ie, they 
receive the planned dose during Cycle 1 [2 treatment administrations]). 
Any participant who is discontinued from the study before receiving all doses of UCB6114 in 
Cycle 1 will be deemed nonevaluable for assessment of a dose level and will be replaced unless 
they experience a DLT before withdrawal. 
In the context of the COVID-19 pandemic, participants who miss doses due to a positive 
COVID-19 diagnosis or known or expected exposure may continue in the study if, in the opinion 
of the investigator, they are experiencing clinical benefit and it is in their best interest to continue 
treatment (see  Section 7.1.4).  
Nonevaluable participants may be replaced to ensure that at least 3 participants receive all 
assigned doses of therapy at each dose level/cohort, unless accrual to that cohort has stopped due 
to DLTs. 
Further details on any imputation of missing data will be included in the SAPs for each module. 
10.7 
Planned interim analysis and data monitoring 
No formal interim analysis will be conducted during this study; however, the SMC will regularly 
review all the safety, tolerability, and PK data as well as any available biomarker and ADA data 
for the dose escalation modules (Part A, Part B, Part C). 
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In Part A, Part B, and Part C, at the end of each cohort, the SMC will review all available safety, 
PK, ADA and biomarker data prior to any dose escalation/de-escalation decision. The 
composition and operation of the SMC will be clearly outlined in the SMC Charter. The PK data 
will be summarized after each cohort, in order to support escalation to the next proposed dose 
level. 
In Part A1, the SMC will review all the safety and tolerability of the sentinel participant in each 
cohort (48 hours following first UCB6114 administration). The SMC will also review available 
safety, tolerability, and PK data as well as any available biomarker and ADA data once 25%, 
50% and 100% study participants in Part A1 have completed the required 28-day observation 
period. 
Before starting any subsequent study part, the Sponsor will review all available safety, 
tolerability, PK, and PD biomarker endpoints from other final or ongoing study part.  
10.8 
Determination of sample size 
10.8.1 
Dose escalation modules 
The number of participants likely to be enrolled in Parts A, B, and C depends on how many dose 
levels are needed to define the RP2D-M and the RP2D for combination therapy. 
In Part A, up to 42 eligible participants will be enrolled across 5 cohorts/dose levels. This 
assumes that all 5 planned dose levels are evaluated, that 1 dose level is added based on 
emerging data, and that, on average, each cohort includes an additional participant due to drop-
out/replacement and/or the modified rolling-6 design. 
In Part A1, up to 32 eligible participants will be enrolled across 4 alternative dosing schedules; 8 
participants per cohort is considered sufficient to protect against unacceptable level of toxicity. 
The probability of declaring a dose schedule (cohort) too toxic, given a toxicity rate greater than 
the maximum tolerable toxicity rate (33%) is approximately 90% (Mokdad et al, 2018). 
However, the probability is reduced to 80% when the dose optimization module is considered 
independent of Part A. An administrative decision to stop enrolling into Part A1 may be made by 
the Sponsor at any time. 
In Part B and Part C, up to 27 eligible participants will be enrolled. In both parts, it is expected 
that up to 3 dose levels of UCB6114 will be explored in combination with the standard TFD/TPI 
or FOLFOX dosing regimen, respectively. However, additional dose levels may be added based 
on emerging data and recommendations of the SMC. In each part of the study, between 3 and 9 
participants are expected to be enrolled per dose level depending on the observed 
toxicity/observation of DLTs. An administrative decision to stop enrolling into Part B or Part C 
may be made by the Sponsor at any time. 
10.8.2 
Expansion modules 
Participant numbers for Parts D, E, F, and G are based primarily on pragmatic considerations 
rather than formal statistical power considerations. A minimum sample size of 15 participants is 
proposed per expansion module (may be expanded to 30 participants). This sample size will 
allow the safety and antitumor activity of UCB6114 to be evaluated with reasonable confidence 
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prior to commencement of further clinical studies. Furthermore, based on well-established 
statistical principles (Gehan, 1961): 
• If no responses are seen in the first 15 consecutive participants enrolled, the chances of a 
response rate >20% are <4%. 
• If no responses are seen in 30 consecutive participants enrolled, the chances of a response 
rate >10% is <5%. 
For Parts F and G, in which UCB6114 will be evaluated in combination with another 
agent/regimen, response rates may be higher depending on the participant population and 
combination agent/regimen chosen. 
Accordingly, a clinically meaningful improvement in the response rate will be defined for 
Parts F and G based upon the tumor type, line of therapy, and current SOC response probability. 
A 2-stage design (Simon, 1989) will be used to expand the cohorts should the observed response 
rate exceed the SOC expected response plus the clinically meaningful improvement threshold. 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
11.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
International Council for Harmonisation (ICH)-Good Clinical Practice (GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the investigator/UCB will forward copies of the protocol, ICF, IB, 
investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
participant-related documents to be used for the study to the IRB/IEC for its review and 
approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to participants or others, and any protocol deviations, to 
eliminate immediate hazards to participants. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. 
For minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
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requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
11.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the investigator and/or contract research organization 
(CRO) agreements, as applicable. 
11.1.3 
Informed consent process 
Participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the investigator (or 
study physician or medically qualified designee). Each participant will have the opportunity to 
discuss the study and its alternatives with the investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (investigator, study physician, or medically qualified designee). The 
participant or his/her legal representative must receive a copy of the signed and dated ICF. As 
part of the consent process, each participant must consent to direct access to his/her medical 
records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
If the ICF is amended during the study, the investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form. 
11.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the participant number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its study physician or medically qualified 
designee, representatives of the relevant IRB/IEC, or representatives of regulatory authorities 
will be allowed to review that portion of the participant’s primary medical records that directly 
concerns this study (including, but not limited to, laboratory test result reports, ECG reports, 
admission/discharge summaries for hospital admissions occurring during a participant’s study 
participation, and autopsy reports for deaths occurring during the study). 
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
11.1.5 
Committees structure 
The SMC will comprise key Sponsor personnel and investigators from participating sites (see 
Section 4.1.1). Full details of the exact SMC composition will be provided in the SMC Charter. 
11.1.6 
Data quality assurance 
All participant data relating to the study will be recorded in eCRF unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. The investigator will contact UCB for 
authorization prior to the destruction of any study records or in the event of accidental loss or 
destruction of any study records. The investigator will also notify UCB should he/she relocate or 
move the study-related files to a location other than that specified in the Sponsor’s trial master 
file. 
11.1.6.1 
Electronic Case Report Form completion 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the eCRF. 
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Detailed instructions will be provided in the eCRF Completion Guidelines. 
11.1.7 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic records, charts, diaries, x-rays, laboratory results, printouts, pharmacy records, 
care records, ECG, or other worksheets. Source documents should be kept in a secure, limited 
access area. 
Source documents that are computer-generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the participant’s source documents. The 
investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
11.1.8 
Study and site closure 
Study site participation may be discontinued if UCB, the investigator, the IRB/ethical review 
board, or the regulatory authority deems it necessary for any scientific, medical, or ethical 
reason. 
The study will be discontinued if UCB, while considering the rights, safety, and wellbeing of the 
participant(s), deems it necessary for any scientific, medical, or ethical reason. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local regulatory authorities, the Sponsor ‘s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study medication development 
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11.1.9 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This will allow the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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11.2 
Appendix 2: Clinical laboratory tests 
• Chemistry, hematology, and coagulation (as described in the Schedules of Activities for 
Part A [Table 1-4], Part A1 (Table 1-5 and Table 1-6), Part B [Table 1-7], and Part C 
[Table 1-8]) results should be available for review prior to administration of treatment. 
• The tests detailed in the table below will be performed by the local or central laboratory. If 
the local or central laboratory results are used to make either a study treatment decision or 
response evaluation, the results must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of this protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
RBC Indices: 
MCV 
MCH 
MCHC 
WBC Count with 
Differential: 
Absolute neutrophils 
Absolute lymphocytes 
Absolute monocytes 
Absolute eosinophils 
Absolute basophils 
Coagulation 
aPTT and either PT or INR 
Clinical 
Chemistry1 
ALT 
AST 
Alkaline 
phosphatase 
Bicarbonate 
Sodium 
Potassium 
Magnesium 
Chloride 
Calcium 
Total bilirubin 
BUN or urea  
Glucose 
(non-fasted) 
Phosphorus or 
phosphate  
Total protein 
Uric acid 
Amylase 
Albumin 
 
 
 
GGT 
Cholesterol 
Creatine kinase 
CRP 
LDH 
Lipase 
Triglycerides 
Serum creatinine 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal, including 
crystals) 
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Laboratory 
Assessments 
Parameters 
Other Tests 
Pregnancy tests: 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only) 
• 
Serum or urine hCG pregnancy test (as needed for women of childbearing 
potential)  
Bone Turnover Markers: 
• 
Blood BAP, blood CTx, urinary NTx and urinary CtxII (see Section 9.8) 
Tumor markers  
• 
eg, PSA, CA125, CA19-9 
• 
If routinely measured, results of tumor markers will also be recorded in the 
eCRF when available during the participant’s participation in the study. 
All study-required laboratory assessments will be performed by a local laboratory. 
The results of each test must be entered into the eCRF. 
NOTES: 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 . All cases confirmed on repeat testing as meeting the laboratory 
criteria defined in Section 7.1.1, with no other cause for liver function test abnormalities identified at the time, 
should be considered potential Hy’s Law cases irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal liver function tests. Such potential Hy’s Law cases should be 
reported as SAEs. 
ALT=alanine aminotransferase; aPPT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BAP=bone alkaline phosphatase; BUN=blood urea nitrogen; eCRF=electronic Case Report Form; CRP=C-
reactive protein; CTx=C-terminal telopeptide; GGT=gamma glutamyl transferase; hCG=human chorionic 
gonadotropin; INR=international normalized ratio; LDH=lactate dehydrogenase; NTX=N-terminal telopeptide; 
PSA=prostate specific antigen; PT=prothrombin time; RBC=red blood cell; ULN=upper limit of normal; 
SAE=serious adverse event; WBC=white blood cell 
Investigators must document their review of each laboratory safety report. 
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The formula for the Cockroft-Gault glomerular filtration rate estimation is as follows: 
 
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11.3 
Appendix 3: Adverse events – Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study medication, whether or not considered related to the study 
medication. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study medication. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, coagulation, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study medication administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study medication or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the antitumor activity assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of antitumor 
activity will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
 
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Events NOT Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
Hospitalization for convenience/assessments and for convalescence is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical events: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
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• 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records 
to UCB/CRO in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
study physician or medically qualified designee. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical records 
before submission to the study physician or medically qualified designee. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
Each must be categorized using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v 5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_8.5x11.pdf). 
 
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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study medication administration will be 
considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed products, in 
his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to UCB. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to UCB. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by a UCB 
representative to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
An AE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the participant is lost to follow-up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to UCB within 24 hours of receipt of the 
information. 
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Reporting of SAEs 
SAE Reporting to UCB via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to UCB will be the electronic data collection 
tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the paper 
SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then 
the site can report this information on a paper SAE form (see next section) or to the study 
physician or medically qualified designee by telephone. 
• 
Contacts for SAE reporting can be found on page 3. 
 
SAE Reporting to UCB via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the UCB. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found on page 3. 
 
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11.4 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered women of childbearing potential: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
− A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
− Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during this study: 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in the table below when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition, male participants must refrain from donating sperm for the duration of the study and 
after the final dose of study medication as follows: 
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1. For 3 months if participating in Part A or Part A1 of the study;  
2. For 6 months if participating in Part B or Part C of the study. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration for 
the duration of the study and, after the final dose of study medication as follows:  
1. For 3 months if participating in Part A or Part A1 of the study;  
2. For 6 months if participating in Part B or Part C of the study. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 
It is currently unknown whether trifluridine/tipiracil (Lonsurf®) may reduce the effectiveness of 
hormonal contraceptives, and therefore women using hormonal contraceptives should add a 
barrier contraceptive method. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationa  
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User Independentb 
 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.  
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study medication. The reliability of sexual 
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abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study medication, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized 
during the treatment period and after the final dose of study medication, as follows: 
1. For at least 3 months if participating in Part A or Part A1 of the study;  
2. For at least 6 months if participating in Part B or Part C of the study. 
Pregnancy testing 
• Women of childbearing potential should only be included after a confirmed menstrual period 
and a negative highly sensitive serum pregnancy test. 
• Additional pregnancy testing should be performed at each visit during the treatment period 
and within 30 days after the final dose of study medication and as required locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• Pregnancy testing, with a sensitivity of at least 25mIU/mL will be performed. 
Male participants with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study medication. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be at least 12 months after the delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female participants who become pregnant 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study medication or be withdrawn from the study OR may request continuation 
of study medication. 
• The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate, and the information 
will be forwarded to the Sponsor. Generally, the follow-up will be at least 12 months after 
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the delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study medication by the 
investigator will be reported to the Sponsor as described in Section 9.2.5. While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
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11.5 
Appendix 5: Genetics 
Use and analysis of DNA 
• Genetic variation may impact a participant’s response to study medication, susceptibility to, 
and severity and progression of disease. Variable response to study medication may be due to 
genetic determinants that impact the mechanism of action of the drug; disease etiology; 
and/or molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for potential DNA analysis. 
• DNA samples may be used for research related to UCB6114 and/or advanced solid tumors 
(locally recurrent or metastatic). They may also be used to develop tests/assays including 
diagnostic tests related to UCB6114 and/or interventions of this drug class and/or advanced 
solid tumors (locally recurrent or metastatic). Genetic research may consist of the analysis of 
one or more candidate genes or the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate). 
• DNA samples may be analyzed if it is hypothesized that this may help further understand the 
clinical data or help resolve issues with the clinical data; for example, PK outliers or potential 
safety observations. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to UCB6114 or study medications of this class to understand the participant’s 
solid tumor or related conditions. 
• The results of any genetic analyses will be reported separately. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
• The samples will be retained while research on UCB6114 or study medications of this class 
continues, but no longer than 20 years (or other period according to local regulations). 
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11.6 
Appendix 6: Rapid Alert Procedures 
The aim of the Rapid Alert process is to stop the exposure to the study medication or concerned 
study procedure as soon as possible, following a confirmed or suspected safety issue, preventing 
its reoccurrence in other study participants as described in the Rapid Alert Team charter. Upon 
occurrence of an SAE and/or another safety event which may constitute a study/study part hold 
criterion, irrespective of its relationship with the study medication or the study conduct, the 
investigator should notify the study Sponsor as soon as possible (ideally within 2 hours of 
becoming aware of the event) by the following process: 
1. A phone call to the study physician to alert them a safety event has been identified. 
2. If the investigator is not able to reach the study physician, they should call the 24-hour rapid 
response helpline number. Upon receipt of a call from an investigator, the 24/7 helpline will 
contact a physician from UCB who will return the call to the investigator. 
3. Additionally,  
a. For UCB’s RAVE® (ACQUIRE) study, complete the eCRF (S)AE page 
OR 
b. For non UCB’s RAVE (ACQUIRE) study or as back-up if UCB’s RAVE® (ACQUIRE) is 
down, send a completed “Investigator (S)AE Report Form for Development Drug (For Rapid 
Alert Studies)” to the fax/email for Rapid Alert provided at the front of the protocol.  
The form should include assessed seriousness, severity, and causality and should be filed in 
the Study Investigator’s File. 
Both the phone call and the completed form from the Investigator are crucial in assessing the 
safety of the study medication and in determining whether the event requires immediate 
action to place the study or individual study parts on hold and/or expedite reporting to the 
regulatory authorities. The (S)AE form should be completed in English and provided even if 
the data are incomplete, or if it is obvious that more data will be needed in order to draw any 
conclusions about the diagnosis or causality. Additional information (eg, laboratory reports) 
received by the investigator must be provided within 24 hours. All documents in the local 
language must be accompanied by a translation in English, or the relevant information 
included in the same document must be summarized in English in the (S)AE form. 
During the call between the Investigator and the UCB physician the safety issue will be 
discussed to determine if there is sufficient evidence to declare a protocol hold criterion has been 
met for the entire study or for an individual study part. If the investigator and UCB physician 
agree a stopping criterion has not been met, dosing of the study may continue as per the study 
protocol and the discussion between the investigator and the UCB physician should be 
documented. 
In all other circumstances, the investigator will be instructed to suspend dosing and the UCB 
physician will arrange an urgent, internal UCB Rapid Alert Team meeting. The Rapid Alert 
Team will review the information provided at the call along with the (S)AE form to determine 
whether or not a protocol hold criterion for the entire study or for an individual study part has 
been met. If it is determined that no criterion have been met, UCB will contact the investigator 
and inform them to recommence dosing. If it is determined a hold criterion has been met, UCB 
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will contact all investigators and notify them of the formal hold (please refer to Section 6.7 for 
further details). 
If the investigator believes a protocol stopping criterion has been met for the entire study or for 
an individual study part, and they are unable to contact UCB prior to the next dose being due, 
they should postpone any further dosing until they have obtained feedback from UCB. In these 
circumstances dosing may be restarted if UCB and the investigator subsequently agree that no 
stopping criteria have been met. 
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11.7 
Appendix 7: Country-specific Requirements 
Not applicable. 
11.8 
Appendix 8: ECOG Performance Status Scale 
ECOG Performance Status will be determined according to the following table: 
Grade 
ECOG performance status scale 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (eg, light housework, office work) 
2 
Ambulatory and capable of all selfcare 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 for more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group 
11.9 
Appendix 9: RECIST v1.1 guidelines 
Guidelines here have been adapted from Eisenhauer, 2009. 
11.9.1 
Measurability of tumor at Baseline 
At Baseline, tumor lesions/lymph nodes will be categorized measurable or nonmeasurable as 
follows: 
Measurable Lesions 
Tumor lesions (extra/non-nodal lesions) 
Lesions that can be accurately measured in ≥1 dimension (longest diameter in the plane of 
measurement) with a minimum size of 
• 10mm or greater when assessed by CT or MRI (slice thickness no greater than 5mm) 
• 10mm or greater when assessed by caliper (lesions which cannot be accurately measured 
with calipers should be recorded as nonmeasurable) 
• 20mm by chest X-ray 
Malignant lymph nodes (nodal lesions) 
Malignant lymph nodes with the short axis 15mm or greater when assessed by CT (CT slice 
thickness recommended to be no greater than 5mm) 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
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Nonmeasurable lesions 
Nonmeasurable lesions will be considered as follows: 
• All other lesions, including small lesions (extra/ non-nodal lesions) with longest diameter 
less than 10mm 
• Malignant lymph nodes (nodal lesions) with ≥10 to <15mm short axis 
• Truly nonmeasurable lesions: such as pleural or pericardial effusions, ascites, inflammatory 
breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, clinical 
lesions that cannot be accurately measured with calipers, abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability  
• Bone disease: Bone disease is nonmeasurable with the exception of soft tissue components 
that can be evaluated by CT or MRI and meet the definition of measurability at Baseline. 
• Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
• Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be 
recorded either as target or non-target disease. Cystic lesions thought to represent cystic 
metastases can be measurable lesions, if they meet the specific definition above. If non-cystic 
lesions are also present in the same patient, these are preferred as target lesions. 
• Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
Recording Tumor Assessments 
All sites of disease must be assessed at Baseline. Baseline assessments should be done as close 
as possible to and prior to study start. For an adequate baseline assessment, all required scans 
must be done within 42 days prior to treatment and all disease must be documented 
appropriately. If a baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
To assess objective response or future progression, overall tumor burden at Baseline should be 
estimated and compared to subsequent assessments.  
Baseline documentation of target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total and 
representative of all involved organs should be identified as target lesions at Baseline. Target 
lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements. Record the longest diameter of each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded. The sum of the diameters 
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(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at Baseline will 
be the basis for comparison to assessments performed during the study. 
• If two target lesions coalesce, the measurement of the coalesced mass is used. If a large target 
lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded. If a target 
lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to 
have disappeared; otherwise a default value of 5 mm should be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should still be 
recorded. 
Baseline documentation of nontarget lesions 
All nonmeasurable disease is nontarget. All measurable lesions not identified as target lesions are 
also included as non-target disease. Measurements are not required but rather assessments will be 
expressed as ABSENT, INDETERMINATE (not evaluable), PRESENT/NOT INCREASED 
(present), INCREASED (unequivocal progression). Multiple non-target lesions in one organ may 
be recorded as a single item on the eCRF (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
11.9.2 
Objective response status at each evaluation 
Disease sites must be assessed using the same technique used at baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made, the case must be 
discussed with the radiologist to determine if substitution is possible. If not, subsequent objective 
statuses are indeterminate. 
Target lesions 
• Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease. All target nodes must decrease to normal size (short axis <10 mm). All target 
lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under Baseline of the sum of 
diameters of all target measurable lesions. The short diameter is used in the sum for target 
nodes, while the longest diameter is used in the sum for all other target lesions. All target 
lesions must be assessed. 
• Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed. 
Stable can follow PR only in the rare case that the sum increases by <20% from the nadir, but 
enough that a previously documented 30% decrease no longer holds. 
• Progressive disease: 20% increase in the sum of diameters of target measurable lesions above 
the smallest sum observed (over Baseline if no decrease in the sum is observed during 
therapy), with a minimum absolute increase of 5 mm. 
• Indeterminate. Progression has not been documented, and one or more target measurable 
lesions have not been assessed; or assessment methods used were inconsistent with those 
used at Baseline; or one or more target lesions cannot be measured accurately (eg, poorly 
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visible unless due to being too small to measure); or one or more target lesions were excised 
or irradiated and have not reappeared or increased. 
Nontarget lesions 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker levels. All 
lymph nodes must be ‘normal’ in size (<10 mm short axis). 
• NonCR/Nonprogressive disease: Persistence of any nontarget lesions and/or tumor marker 
level above the normal limits. 
• Progressive disease: Unequivocal progression of pre-existing lesions. Generally, the overall 
tumor burden must increase sufficiently to merit discontinuation of therapy. In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target disease 
should be rare. 
• Indeterminate: Progression has not been determined and one or more non-target sites were 
not assessed or assessment methods were inconsistent with those used at Baseline. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates progressive disease. If a new 
lesion is equivocal, for example due to its small size, continued assessment will clarify the 
etiology. If repeat assessments confirm the lesion, then progression should be recorded on the 
date of the initial assessment. A lesion identified in an area not previously scanned will be 
considered a new lesion. 
FDG-PET scanning can be used to complement CT scanning in assessments of progression 
(particularly possible “new” disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
• Negative FDG-PET at Baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease based on a new lesion. 
• No FDG-PET at Baseline and a positive FDG-PET at follow-up: 
− If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is progressive disease. 
− If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of progressive disease will be the date of the initial 
abnormal FDG-PET scan). 
− If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not progressive 
disease. 
Supplemental Investigations 
• If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate. If no disease is identified, objective status is CR. 
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• If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Subjective progression 
Participants requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as progressive disease on tumor assessment eCRFs. This 
should be indicated on the Study Medication Discontinuation eCRF page as Clinical Progression. 
Every effort should be made to document progressive disease even after discontinuation of 
treatment. 
Evaluation of Response for an Individual Assessment Time Point 
In order to determine tumor response, the sum of all target lesions is calculated at Baseline and at 
each subsequent time point (every 2 cycles in this study). Initially, a separate response for target 
lesions is determined using Table A. Finally, the best overall response is determined as a 
composite of the target and non-target responses using Table B. 
Table A 
Objective Response Status at each Evaluation for Participants with Nontarget 
Disease Only 
Nontarget diseases 
New Lesions 
Objective status 
CR 
No 
CR 
NonCR/nonprogressive disease 
No 
NonCR/nonprogressive 
disease 
Indeterminate 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
progressive disease 
Any 
Yes 
progressive disease 
 
Table B 
Overall Response (Target and Nontarget) at Each Assessment Time Point 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
NonCR/nonprogressive disease 
No 
PR 
CR 
Indeterminate or Missing 
No 
PR 
PR 
NonCR/nonprogressive disease, 
Indeterminate or Missing 
No 
PR 
SD 
NonCR/nonprogressive disease, 
Indeterminate or Missing 
No 
Stable 
Indeterminate or 
Missing 
Nonprogressive disease 
No 
Indeterminate 
Progressive disease 
Any 
Yes or No 
Progressive disease 
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Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Any 
Progressive disease 
Yes or No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this circumstance, 
the best overall response can be interpreted as in Table B. 
Table C 
Best overall response when confirmation of CR and PR required 
Overall response  
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
Stable Disease, progressive 
disease, or PRa 
CR 
Stable Disease 
Stable disease provided minimum 
criteria for stable disease duration 
met, otherwise, progressive 
disease 
CR 
Progressive Disease 
Stable disease provided minimum 
criteria for stable disease duration 
met, otherwise, progressive 
disease 
CR 
NE 
Stable disease provided minimum 
criteria for stable disease duration 
met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
Stable Disease 
Stable Disease 
PR 
Progressive Disease 
Stable disease provided minimum 
criteria for stable disease duration 
met, otherwise, progressive 
disease 
PR 
NE 
Stable disease provided minimum 
criteria for stable disease duration 
met, otherwise, NE 
NE 
NE 
NE 
CR=complete response; NE=nonevaluable; PR=partial response 
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 progressive disease at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for stable disease was met. 
However, sometimes “CR” may be claimed when subsequent scans suggest small lesions were likely still present 
and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
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11.10 
Appendix 10: Abbreviations and Trademarks 
ADA 
antidrug antibody 
ADAS 
ADA Set 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
bid 
twice daily 
BIW 
twice a week 
BMP 
bone morphogenetic protein 
BOR 
best overall response 
BSA 
body surface area 
CNS 
central nervous system 
CR 
complete response 
CRF 
Case Report form 
CRC 
colorectal cancer 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DCR 
disease control rate 
DES 
DLT Evaluable Set 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report form 
EGFR 
epidermal growth factor receptor 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
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FIH 
first in human 
FOLFOX 
oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) regimen 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GLP 
Good Laboratory Practice 
GnRH 
gonadotropin-releasing hormone 
HMPS 
hereditary mixed polyposis syndrome 
HPA 
hypothalamic-pituitary-adrenal 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG4 
human immunoglobulin G4 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
iv 
intravenous(ly) 
LAIV 
live attenuated influenza vaccine 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFOLFOX6 
modified FOLFOX 6 regimen (leucovorin 400mg/m2 on Day 1, 
5-fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 and 
Day 2, and oxaliplatin 85mg/m2 on Day 1) 
MMR 
measles, mumps, and rubella 
MoA 
mechanism of action 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
NBF 
neutral buffered formalin 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
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PD 
pharmacodynamic(s) 
PDS 
Pharmacodynamic Set 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PKS 
Pharmacokinetic Set 
PPS 
Per-protocol Set 
PR 
partial response 
PT 
prothrombin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QW 
once weekly 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RP2D-F 
recommended Phase 2 dose of UCB6114 when used in combination 
with FOLFOX 
RP2D-M 
recommended Phase 2 dose for monotherapy 
RP2D-T 
recommended Phase 2 dose of UCB6114 when used in combination 
with TFD/TPI 
SAE 
serious adverse event 
SAR 
serious adverse reactions 
sc 
subcutaneous(ly) 
SD 
stable disease 
SFU 
Safety Follow-Up 
SLIT1/2 
slit guidance ligand 1/2 
SMC 
Safety Monitoring Committee 
SmPC 
Summary of Product Characteristics 
SOC 
standard of care 
SS 
Safety Set 
SSC 
Study Steering Committee 
TFD/TPI 
trifluridine/tipiracil 
ULN 
upper limit of normal 
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11.11 
Appendix 11: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment 5 (14 Jan 2022) 
Overall Rationale for the Amendment 
The overall rationale for Amendment 5 is to provide details for the conduct of Part A1 (dose 
optimization module), as summarized in the table below. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Addition of text pertaining to dose 
optimization module Part A1 throughout 
the document, including the synopsis, 
objectives and endpoints, schema, 
schedules of activities, background, 
design, benefit-risk assessment, dose 
selection, selection and withdrawal 
criteria, treatments administered, 
concomitant medications, dose 
modifications, study assessments and 
procedures, statistical analyses, and 
appendices. When applicable, sections, 
tables and figures have been renumbered. 
Addition to 
provide details for 
the conduct of 
Part A1 of the 
study 
Global 
Part A1 ‘dose adaptation module’ was 
renamed ‘dose optimization module’ for 
clarity. 
Clarification 
1.1 Synopsis 
3 Objectives and endpoints 
Global 
In secondary and tertiary endpoints, the 
wording ‘dose level’ was replaced by 
‘cohort’ to cover both dose level in Part A 
and dosing schedule in Part A1.  
The changes were also applied throughout 
the document, where relevant.  
Update of the 
endpoints to 
include Part A1’s 
endpoints 
4.1 Overall design 
The description of the Safety Monitoring 
Committee (SMC) and Study Steering 
Committee (SSC) are applicable for all 
study parts; thus, the information has been 
moved up in a separate section. 
Subsequent sections have been 
renumbered. 
Treatment duration text was updated to 
include “criteria for discontinuation are 
met”, in line with the text provided in the 
study synopsis (new text in bold). 
Simplification of 
the text 
 
 
 
 
 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
4.2.3 Rationale for Part B and Part C 
The rationale for selected indication for 
Part B and Part C was the same as for 
Part A1 and the corresponding text was 
moved from Section 4.2.3 to Section 
4.2.2.  
It was clarified that Ab7326mIgG1 is the 
murinized version of UCB6114. 
Clarification 
5.2.3 Part B 
5.2.4 Part C 
A correction was made in the exclusion 
criteria for Part A (criterion #7a), Part B 
(criterion #7a) and Part C (criterion #6a): 
“Screening of symptomatic asymptomatic 
participants without history of CNS 
metastases is not required”.  
Correction 
9.2.8 Anticipated serious adverse 
events 
Clarification that death due to disease 
progression will not be recorded as a SAE 
but will be recorded in a survival 
electronic case report form (eCRF). 
Clarification  
9.2.9 Infusion-related reactions 
(hypersensitivity reactions) 
Clarifications of the procedures to be 
performed in case an infusion-related 
reaction occurs.  
Clarification 
10 Statistical considerations 
Clarification that a SAP will be developed 
for each module.  
Clarification  
10.4 Analysis of the anti-tumor 
activity endpoints 
Timepoints at which the duration of 
responses and PFS will be derived has 
been corrected to be in line with the 
statistical analysis plan. 
Correction 
Global 
Correction of spelling, grammar, or 
typographical errors. 
Correction 
Document history 
Type of amendment for protocol 
amendment 3.1 has been changed from 
‘substantial’ to ‘Not applicable’ as the 
substantial/nonsubstantial classification is 
irrelevant in US. 
Correction 
 
Amendment 4 (17 June 2021) 
Overall Rationale for the Amendment 
The overall rationale for Amendment 4 is to incorporate regulatory agency-required local 
protocol amendments in 1 global amendment and perform some additional adjustments to the 
protocol. Summary of changes is given in the table below (changes already performed in one of 
the previous local amendments are identified by a footnote). 
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This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Addition of the IND number. 
Addition of the 
IND number. 
Synopsis Table 1-2: Objectives and 
endpoints for the dose escalation 
modules in Part B and Part C 
3. Objectives and endpoints 
Table 3-2: Objectives and endpoints 
for the dose escalation modules in 
Part B and Part C 
Pharmacodynamic endpoint related to 
protein marker levels has been updated as 
follows: 
“Change in protein marker levels in blood 
and tumor tissue by scheduled assessment 
and dose level”. 
Correction as no 
tumor biopsies are 
requested in Parts 
B and C of the 
study. 
4.1.1.4 Dose-limiting toxicity 
determination and maximum 
tolerated dose definition (Part A) 
Update of the definition of DLTs to 
confirm that they include any AE at least 
possibly related to the study medication 
and fulfilling the specified criteria.a 
Correction. 
4.1.1.4 Dose-limiting toxicity 
determination and maximum 
tolerated dose definition (Part A) 
Revision of the DLT definition for Part A 
(update of the febrile neutropenia 
definition as per CTCAE v5.0 and 
addition of Grade 4 thrombocytopenia).a 
Correction. 
4.1.3.2.1 Definition of DLT (Part B) 
4.1.4.2.1 Definition of DLT (Part C) 
Revision of the DLT definition for Part B 
and Part C (addition of any Grade 4 
thrombocytopenia).a  
Correction. 
5. Study population  
5.1.1 Part A 
5.1.2 Part B 
5.1.3 Part C 
Revision of the eligibility criteria such 
that participants with locally advanced 
disease must also have unresectable 
disease (definition of the study population 
in Table  5.1; Part A: inclusion criterion 
#3b; Part B and Part C: inclusion criterion 
#3a).The precision was also added 
throughout the text when relevant.a 
The sentence at the end of Section 5.1.1, 
which mentioned that inclusion criteria 
for Parts A1, B, C, D, E, F, and G will be 
defined in a protocol amendment, has 
been moved at the end of Section 5.1.3; 
reference to Parts B and C has been 
deleted. 
Clarification. 
 
 
 
 
 
 
 
Correction as 
inclusion criteria 
for Part B and 
Part C are now 
detailed in 
Sections 5.1.2 and 
5.1.3. 
5.1.2 Part B  
Inclusion of ramucirumab as an option in 
the prior treatment regimen in Part B 
(inclusion criterion #4a).a  
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2.1 Part A 
5.2.2 Part B  
5.2.3 Part C  
Revision of the eligibility criteria to 
provide a single QTc cutoff, irrespective 
of the participant’s sex (Part A: exclusion 
criterion #16b, Part B: exclusion criterion 
#20b, Part C: inclusion criterion #19b).a 
The sentence at the end of Section 5.2.1, 
which mentioned that exclusion criteria 
for Parts A1, B, C, D, E, F, and G will be 
defined in a protocol amendment, has 
been moved at the end of Section 5.2.3; 
reference to Parts B and C has been 
deleted. 
Correction. 
 
 
 
 
Correction as 
exclusion criteria 
for Part B and 
Part C are now 
detailed in 
Sections 5.2.2 and 
5.2.3. 
5.2.2 Part B  
5.2.3 Part C  
Clarification that all participants with 
known hypersensitivity to any of the study 
medications will be excluded from the 
study (exclusion criterion #2a).b 
Clarification of an 
exclusion 
criterion in Parts 
B and C. 
5.2.3 Part C  
Alignment with the UK prescribing 
information for oxaliplatin regarding the 
threshold for neutrophil count in 
exclusion criterion (exclusion criterion 
#13a).b  
Alignment with the UK prescribing 
information for calcium folinate regarding 
known or suspected pernicious anemia or 
other anemias due to vitamin B12 
deficiency (addition of exclusion criterion 
#24).b  
Update of 
exclusion criteria 
in Part C.  
6.5.3 Permitted concomitant 
treatments (medications and 
therapies) during Part C 
6.5.5 Prohibited concomitant 
treatments (medications and 
therapies) during Part B 
 
Clarification that the following should be 
avoided in Part C:a 
• 
Concomitant administration of 
medicinal product with a known 
potential to prolong the QT interval 
• 
Concurrent administration of 5-
fluorouracil and CYP2C9 substrates  
• 
Co-administration of medicinal 
products known to be nephrotoxic  
Title and text of Section 6.5.5 has been 
modified to remove the information 
pertaining only to Part C of the study. All 
the information applying to Part C has 
been copied or moved to a new section 
entitled: 6.5.6 Prohibited concomitant 
treatments (medications and therapies) 
during Part C.a 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5.7 Vaccines 
Text has been corrected as follows: 
“Administration of live (including 
attenuated) vaccines is not allowed during 
the conduct of the study and for up to 3 
months after the final dose of IMP.  
Administration of inactivated non-live 
vaccines is allowed during the study at the 
discretion of the Investigator.” 
Correction. 
6.6.2.2 UCB6114 dose modifications 
(Part B) 
6.6.3.2 UCB6114 dose modifications 
(Part C) 
Deletion of the following sentence: 
“For participants who experience a DLT, 
dose adjustments are permitted if it is 
considered in the best interest of the 
participant to continue therapy at the 
discretion of the investigator, in 
consultation with the Sponsor.”a 
Clarification. 
6.6.2.2 UCB6114 dose modifications 
(Part B) 
6.6.3.2 UCB6114 dose modifications 
(Part C) 
Addition of any Grade 4 nonhematologic 
toxicity, including diarrhea and mucositis, 
which is at least possibly related to 
UCB6114 in the list of events leading to 
treatment discontinuation.a  
Update the list of 
AEs leading to 
treatment 
discontinuation. 
6.7 Criteria for study hold or dosing 
stoppage 
Clarification that prior approval of a 
substantial amendment by the regulatory 
authorities is required for any study restart 
after defined stopping criteria have been 
met.b 
Clarification. 
9. Study assessments and procedures 
Table 9-2: Total blood volume 
collected during Cycle 1 of Parts B 
and C. 
Revision of the maximum amount of 
blood collected from each participant at 
Screening, during Cycle 1 and Cycle 2, 
and at SFU. 
Blood sample for pregnancy test has been 
moved to the footnote of the table. 
Correction/ 
clarification. 
9. Study assessments and procedures 
Schedule of Activities  
 
 
 
 
Table 1-5 Schedule of Activities for 
Part B 
Table 1-6 Schedule of Activities for 
Part C 
Update of the text to specify that liver 
specific ALP must be separated and used 
to assess the liver function instead of total 
ALP in participants with bone metastases 
and liver abnormalities considered as 
potential Hy’s low cases. 
Update of Footnote l (Tables 1-5 and 1-6). 
Update procedure 
for ALP 
assessment in 
case of liver 
abnormalities. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.5 Pharmacokinetics 
9.10 Immunogenicity 
Text pertaining to immunogenicity 
sampling was moved from the Section 
9.5 Pharmacokinetics to the 
9.10 Immunogenicity.  
Clarification. 
9.8.4 Blood samples for serum bone 
turnover markers 
 
 
 
Schedule of Activities  
Table 1-5 Schedule of Activities for 
Part B 
Table 1-6 Schedule of Activities for 
Part C 
Deletion of the following sentence: 
“Samples for analysis of circulating 
markers of bone turnover will not be 
obtained in Part B or Part C” which was 
incorrect.a 
Deletion of the related footnote in the 
Schedule of Activities’ tables (footnote 
j).a  
Correction. 
Schedule of Activities  
Table 1-5 Schedule of Activities for 
Part B 
Table 1-6 Schedule of Activities for 
Part C 
Addition of the echocardiogram 
assessments in the study procedures for 
Part B and Part C to be in line with the 
assessments planned.c 
Addition of collection time-windows for 
blood PK sampling for Part B and Part C. 
Update in the time schedule of the vital 
sign measurements on Day 1 (2h [+1h] 
and 5h+ [1h] after the end of infusion) 
Update Schedule 
of Activities for 
Part B and Part C. 
11.4 (Appendix 4) 
Update the contraceptive requirements for 
males in Parts B and C in relation to 
sperm donation and pregnant or 
breastfeeding partners (6 months 
compared to 3 months in Part A).b 
 
Addition of the recommendation to use a 
barrier contraceptive in addition to the use 
of hormonal contraceptive for woman of 
childbearing potential receiving Lonsurf® 
in the body text.b 
Clarification that effective contraceptive 
method should be utilized for at last 6 
months for participant in Parts B and C 
(compared to 3 months in Part A)b 
Alignment of the 
appendices’ text 
with the exclusion 
criteria regarding 
contraception 
requirements. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
Correction of a few typographical and 
formatting errors, deletion of footnote 
which was not applicable for a specific 
assessment (Table 1.4 [Part A], footnote n 
for “Blood collection for genetic 
analysis”), and addition of an existing 
footnote to 2 of the current procedures 
(Table 1.5 [Part B] and 1.6 [Part C] 
footnote g added to Eligibility criteria and 
Medical history as they are not to be 
assessed in Cycle 2).  
Correction. 
4.1.3 Part B - Dose escalation with 
TFD/TPI 
4.1.3.2.2 Determination of 
maximum-tolerated dose 
4.1.4 Part C - Dose escalation with 
mFOLFOX6 
4.1.4.2.2 Determination of 
maximum-tolerated dose 
Table 6-2 Study Treatments in Part B 
Table 6-3 Treatments administered in 
Part C 
10.3.1 Safety analyses 
10.7 Planned interim analysis and 
data monitoring 
10.8.1 Dose escalation module 
Clarification in the use of "cohort" and 
"dose level" for Part B and Part C.  
Clarification. 
1.2 Schema 
Figure 1.3 ONC001 Part B 
Figure 1.4 ONC001 Part C 
Clarification in the schematic 
representation of the dose escalation/DLT 
assessment period:  
• 
“Cohort” replaced by “dose level”,  
• 
Addition of the possibility of dose de-
escalation  
• 
Clarification that each dose level can 
include more than one cohort of 
participants.  
Clarification. 
Global 
The wording “Health Authorities” was 
replaced by “regulatory authorities”.  
Correction of a few typographical and 
formatting errors.  
Correction. 
aThis change has been previously implemented in protocol amendment 3.1 (US) 
bThis change has been previously implemented in protocol amendment 3.2 (UK) 
cThis change has been previously implemented in protocol amendment 3.1 (US) but the timepoints at which the 
assessment should be performed have been further updated 
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Amendment 3 (07 Jan 2021) 
Overall Rationale for the Amendment 
The overall rationale for Amendment 3 is to provide details for the conduct of Parts B and C, as 
summarized in the table below.  
Section # and Name 
Description of Change 
Brief Rationale 
Serious Adverse Event 
Reporting 
Corrected 24h Rapid Response 
Helpline phone number. 
Correction 
Global 
Added text pertaining to dose 
escalation (combination therapy) 
modules Part B and Part C 
throughout the document, including 
the synopsis, objectives and 
endpoints, schema, schedules of 
activities, background, design, 
benefit-risk assessment, dose 
selection, selection and withdrawal 
criteria, treatments administered, 
concomitant medications, dose 
modifications, and statistical 
analyses. 
Addition to provide details for 
conduct of Part B and Part C 
of the study 
Section 1.1 Synopsis, 
Rationale 
and 
Section 2.2 Background 
Clarification of available literature 
on expression data in tumors. 
Clarification 
Section 1.1 Synopsis, 
Objectives and endpoints 
and 
Section 3 Objectives and 
endpoints 
For better clarity, separated 
objectives and endpoints for Part A, 
A1, B, and C to 2 separate tables, 
one for Parts A and A1, and a second 
for Part B and C.  
Updated objectives and endpoints for 
Parts A and A1, and Parts B and C. 
Updated objectives and endpoints for 
Parts D, E, F, and G. 
Clarification 
Section 1.2 Schema 
Updated Figure 1-1 to reflect 
changes to terminology in overall 
design. 
Clarification 
Section 2.1 Study rationale 
Added text clarifying types of 
tumors selected for Part A. 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2.1 Exclusion 
Criteria Part A 
Exclusion criterion 22 renumbered 
as 22a. Text has been corrected 
from:  
“In the presence of therapeutic intent 
to anticoagulate the participant: INR 
or PT and aPTT…”  
to  
“In the presence of therapeutic intent 
to anticoagulate the participant: INR 
or PT or aPTT…” 
Correction 
Section 6.1.1 Part A, Table 
6-1 Treatments administered 
in Part A 
Updated dose formulation row to 
clarify formulation. 
Clarification 
Section 9.5 Pharmacokinetics 
and 
Section 10.3.3.1 Analysis of 
PK endpoints 
Moved text and table pertaining to 
PK analyses from Section 9.5 to 
Section 10.3.3.1. 
Correction 
Section 10.3.3.1 Analysis of 
PK endpoints 
Added text specifying which PK 
concentrations will be disclosed on 
public registries for Part A, Part B, 
and Part C. 
Addition 
Global 
Correction of spelling, grammar, or 
typographical errors. 
Correction 
Amendment 2 (12 Oct 2020) 
Overall Rationale for the Amendment 
The overall rationale for Amendment 2 is to clarify some of the study assessments and 
procedures and to add language related to the COVID-19 pandemic, as summarized in the table 
below. Minor (non-substantive) corrections to grammar and formatting are not captured in the 
table below. 
Section # and Name 
Description of Change 
Brief Rationale 
11.2. Appendix 2 Clinical 
laboratory tests 
Separated the terms “phosphorus or 
phosphate” and “albumin” 
These are separate assessments 
7. Discontinuation of study 
medication and participant 
discontinuation/withdrawal  
Section was restructured to clarify 
situations of:  
• 
participant discontinuation 
• 
treatment discontinuation 
• 
study/site discontinuation by 
sponsor 
Restructuring provides 
additional clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion criteria 
Added language to Criterion 15b 
clarifying that the presence of liver 
metastases must be recorded in the 
eCRF 
Clarification 
7.1.3 Other criteria for 
discontinuation of study 
medication 
• 
Added language allowing 
palliative bone-directed 
radiotherapy as concomitant 
treatment 
• 
Defined taking prohibited 
medications as defined 
elsewhere in the protocol as a 
criterion for discontinuation of 
study medication 
• 
Excepts palliative bone-
directed radiotherapy from 
criteria for discontinuation 
of study medication 
• 
Clarification that 
prohibited medications 
leading to discontinuation 
of study medication are 
defined in elsewhere in the 
protocol  
10.4.2.1. Antitumor activity 
endpoint definitions 
Overall survival (OS) was originally 
measured from date of study 
enrollment to date of death. Revised 
to measure OS from the date of first 
dosing to date of death. 
Alignment of start of time-to-
event analysis for OS with the 
start of the time-to-event 
analysis for progression-free 
survival (PFS) 
7.1.3 Other criteria for 
discontinuation of study 
medication 
Excepted palliative bone-directed 
radiotherapy from criteria for 
discontinuation  
 
Added Criterion No 5 
Allows participants who 
receive bone-directed 
radiotherapy to stay on 
treatment 
Adds taking prohibited 
concomitant medications to 
the criteria for discontinuation 
7.1.4 Temporary 
discontinuation of study 
medication 
Added language allowing temporary 
suspension of study medication for 
up to 3 weeks  
Allows for suspension of 
treatment with study 
medication to resolve 
toxicities 
7.2 Participant 
discontinuation/withdrawal 
from the study 
Added clarification that site will 
attempt to contact participants who 
withdraw from the study to complete 
the SFU and Final Visits. 
Clarification 
7.4. COVID-19 Pandemic 
Added a section on COVID-19 
Pandemic 
Gives guidance on how to 
adapt study processes, 
procedures, and timing to 
potential impacts of COVID-
19 
9.2 Adverse events and 
serious adverse events 
Added language regarding collection 
of AEs and SAEs related to COVID-
19 
Gives guidance on how to 
report AEs and SAEs related 
to COVID-19 
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Section # and Name 
Description of Change 
Brief Rationale 
9.2.5 Pregnancy 
Replaced “early discontinuation 
visit” with “Safety Follow-up Visit” 
when specifying follow-up for 
positive pregnancy test 
Accuracy 
10.6. Handling of dropouts or 
missing data 
Added language regarding missing 
doses due to the COVID-19 
Pandemic 
Clarification on missing doses 
due to COVID-19 Pandemic 
Appendix 11. Protocol 
amendment history 
In Amendment 1, the Summary of 
Changes table footnote “k” reference 
to Cycle 1 Day 15/16 was deleted. 
Correction of an error in the 
Summary of Changes table 
from Amendment 1. 
Table 1-3: Schedule of 
activities for Part A 
(monotherapy dose 
escalation) 
Footnote “z” was added to the 
coagulation and ECOG assessments 
on Cycle 1 Day 15/16 
Clarification that coagulation 
and ECOG in Cycle 1 is 
assessed on Day 15, not Day 
16. 
Flexibility in assessment collection 
for PK sampling and Screening 
procedures to accommodate potential 
impacts of the COVID-19 pandemic 
Allows flexibility in study 
procedures to accommodate 
potential impacts of the 
COVID-19 pandemic 
Added survival census to SFU Visit. 
Consistency with CRF 
Added language to footnote “ff” 
clarifying survival census at SFU 
Visit. 
Consistency with CRF 
Added language to Footnote “k” 
allowing collection of laboratory 
tests from local laboratories  
Allows flexibility in collection 
of laboratory test 
Added language to footnote “o” 
expanding window of PK 
assessments scheduled for Day 16 to 
Day 21 in context of COVID-19 
Allows flexibility in timing of 
PK assessments if needed in 
context of COVID-19 
5.4 Screen failures 
Language added to define screen 
failures due to impacts of the 
COVID-19 pandemic 
Pandemic guidance for screen 
failures 
5.2 Exclusion criteria 
Exclusion Criterion No 5 was 
deleted 
Removed need for Screening 
TB test of study participants  
Exclusion Criterion No 13 was 
modified to remove separate 
conditions for study participants with 
bone metastases 
Removed separation of liver-
specific AP from total AP for 
study participants with bone 
metastases 
 
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Amendment 1 (11 Jun 2020) 
Overall Rationale for the Amendment 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page 
Sponsor name has been updated. 
Belgium has recently 
adopted a new Code of 
Companies and 
Associations, resulting in a 
mandatory change of the 
name of the legal form of 
the entity “société privée à 
responsabilité limitée”, 
abbreviated “SPRL”, to 
“société à responsabilité 
limitée”, abbreviated 
“SRL”. 
Section 1.1, 
Synopsis 
Number of participants statement updated. 
For consistency with dose 
escalation text 
Timing of SFU visit updated and allowance for 
Final Visit to be conducted by phone. 
Clarification 
Section 1.2, Schema 
Footnote to the schema has been updated. 
Clarification 
Section 1.3 
Schedule of 
Activities 
Cycle 2 Day 2 column and Cycle 3 onwards 
Day 8 column deleted as all assessments on those 
days have been deleted. 
Reduction of participant 
assessment burden 
Blood collection for PK analysis row – samples 
deleted from Cycle 2 Day 2 and Final Visit. 
Reduction of participant 
assessment burden 
Blood collection immunogenicity (ADA) row – 
samples deleted from Cycle 2 Day 15, Cycle 3 
onwards Day 15, and Final Visit. 
Reduction of participant 
assessment burden 
Added new row for blood collection for ctDNA 
analysis. 
Addition 
Added new row for survival census. 
Addition 
Added new row for coagulation. 
Addition 
Footnote a was corrected to delete reference to 
Day 2 of Cycle 2. 
For consistency with 
deletion of Cycle 2 Day 2 
column 
Footnote b was deleted. 
Clarification 
Footnote c was corrected to delete reference to 
Day 8 of Cycle 3 and Cycle 4 onwards. 
For consistency with 
deletion of Cycle 3 Day 8 
column 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Footnote d has been added to the headings for 
columns Cycle 1 (Days 1 and 15), Cycle 2 (Day 
15), and Cycle 3 onwards (Days 1 and 15) to 
specify timing of predose and postdose safety 
assessments at these visits.  
Clarification 
Footnote d has been revised to include 
coagulation. 
Addition 
Footnote h has been revised to specify timing of 
ECG assessments due to reduction in number of 
assessments. 
Reduction of participant 
assessment burden 
Footnote i has been revised to clarify use of urine 
vs serum pregnancy assessments. 
Clarification 
Footnote j has been revised to correct a 
grammatical error. 
Correction of grammatical 
error 
Footnote k was added to the Cycle 1 Day 1 for the 
urinalysis, hematology, blood chemistry, and 
coagulation rows. 
Clarification 
Footnote k was revised to add coagulation, 
Clarification of timing of Day 1 predose sample 
collection was added. Clarified that laboratory 
tests may be obtained 24h prior to the scheduled 
visit. 
Clarification 
Footnote l has been revised to specify timing of 
vital sign assessments on Cycle 1 Day 1. 
Clarification 
Footnote m has been revised to specify types of 
urine abnormalities that require microscopic 
analysis. 
Clarification 
Footnote o has been revised to specify collection 
windows for end of infusion samples. 
Clarification 
Footnote q has been revised to clarify collection 
of ADA samples. 
Clarification 
Footnote r has been revised to add use of samples 
for assay verification . 
Correction 
Footnote t has been revised to clarify timing of 
tumor assessments prior to starting study 
medication and to specify exception for prior CT 
or MRI scan. 
Clarification 
Footnote z was added to specify which procedures 
are assessed Day 15 only of Cycle 1. 
Clarification 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Footnote aa was added to specify timing of 
ctDNA sampling on Cycle 3 onwards Day 1. 
Addition 
Footnote bb was added to specify that 
echocardiograms will only be assessed at even-
numbered cycles from Cycle 3 onwards. 
Clarification 
Footnote cc was added to clarify requirements for 
tumor assessments at SFU visit. 
Clarification 
Footnote dd was added to clarify when tumor 
assessment is not required at SFU Visit. 
Clarification 
Footnote ee was added to specify predose 
eligibility assessment at Cycle 1 Day 1. 
Addition 
Footnote ff was added to clarify liver laboratory 
assessments in the case of bone metastases. 
Clarification 
Footnote gg was added to specify completion of 
survival census. 
Addition 
Footnote hh was added to clarify timing of 
complete and symptom-directed physical 
examinations. 
Clarification 
Section 4.1 Overall 
design 
Table 4-1, row for Part B: colorectal carcinoma 
changed to colorectal adenocarcinoma. 
Consistency 
Sentence “Higher or lower doses may be 
considered based on emerging data.” has been 
deleted. 
For consistency with dose 
escalation text  
Pancreatic carcinoma changed to pancreatic 
adenocarcinoma. 
Consistency 
Section 4.1.1 Part A 
– Monotherapy dose 
escalation 
Specified 16-day observation for participants who 
enroll after sentinel participant experiences a 
DLT. 
Clarification 
Section 4.2 
Scientific rationale 
for study design 
Clarification of design choices with expanded 
explanatory text. 
Clarification 
Section 4.2.1 Dosing 
strategy 
Clarified SMC role in dose decisions and role in 
adding additional dose levels. Clarified that doses 
above 2000mg require an amendment. 
Clarification 
Section 5, Table 5-1 
Study population 
Row Part A: Term pancreatic carcinoma corrected 
to term pancreatic adenocarcinoma  
Rows Part B, Part D, and Part F: Term colorectal 
carcinoma corrected to colorectal 
adenocarcinoma. 
Consistency 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.1 
Inclusion criteria 
Inclusion criterion 2 has been renumbered as 2a; 
terms pancreatic carcinoma and colorectal 
carcinoma corrected pancreatic adenocarcinoma 
and colorectal adenocarcinoma, respectively. 
Consistency 
Inclusion criterion 3 has been renumbered as 3a 
and has been changed from “or” to “and”. 
Clarification 
Section 5.2 
Exclusion criteria 
Exclusion criterion 2 has been deleted. 
Clarification 
Exclusion criterion 15 has been renumbered as 
15a; and has been modified to add history of 
biliary stent. 
Clarification 
Exclusion criterion 19 has been renumbered as 
19a and has been modified to remove “or any 
other type of medical research”. 
Correction 
New criterion: Exclusion criterion 20 has been 
added to specify criterion for renal function. 
Ensure participants have 
adequate renal function 
New criterion: Exclusion criterion 21 has been 
added to exclude major surgery prior to study 
drug initiation. 
Addition 
New criterion: Exclusion criterion 22 has been 
added to specify criteria for coagulation 
parameters. 
 
Section 6.2.1 Drug 
accountability 
Drug accountability procedure changed to use of 
drug accountability logs instead of eCRF. 
Correction 
Section 6.4 
Treatment 
compliance 
Drug accountability procedure changed to use of 
drug accountability logs instead of eCRF. 
Correction 
Section 6.5.1 
Permitted 
concomitant 
treatments 
(medications and 
therapies) during 
Part A 
Term “concomitant” was deleted from last 2 
bullets (redundant with sentence preceding 
bulleted list) 
Correction 
Section 6.6.1, Table 
6-2 Dose escalation 
steps and 
justification 
Footnote c was changed to spell out PK terms 
Clarification 
List of abbreviations for table has been updated. 
Correction 
Footnote d has been deleted as any doses higher 
than 2000mg would be subject to a substantial 
protocol amendment. 
Clarification 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8 Study 
assessments and 
procedures 
Text has been added to specify the maximum 
amount of blood collected from participants 
during each part of the study. 
Clarification 
Table 8-1, coagulation added to sample types; 
number and volumes of samples updated, total 
blood volumes updated.  
Reduction of participant 
assessment burden 
Section 8.1.1 
Physical 
examination 
Clarified timing of complete and symptom-
directed physical examinations. Clarified that 
height will only be recorded at Screening. 
Clarification 
Section 8.1.5 
Coagulation added to types of laboratory 
assessments. 
 
Section 8.1.6 
Pregnancy testing 
Text has been updated to reflect use of serum or 
urine pregnancy tests. 
Clarification 
Section 8.5, Table 
8-2 Pharmacokinetic 
parameters 
AUCtau changed to AUC0-336h. 
Clarification 
Footnote a has been updated to reflect reporting. 
Clarification 
Section 8.5 
Pharmacokinetics 
Deleted PK sample collection from Final Visit. 
Reduction of participant 
assessment burden 
Section 8.5 Table 
8-3, Blood 
collection time 
points for PK 
analysis 
Cycle 1, Day 15 (samples 9 and 10), Day 16 
(sample 11), and Day 22 (sample 12) sampling 
times and predose/postdose timepoints updated. 
Correction 
Cycle 2, Day 1 (samples 13, 14, and 15) sampling 
times and predose/postdose timepoints updated. 
Correction 
First note in footnotes updated to reflect number 
of samples and blood volumes. 
Correction 
New note added to footnotes to specify predose 
sample summarization in statistical analysis. 
Clarification 
Footnote a added to specify collection of Cycle 3 
Day 1 PK sample in subjects who are not 
continuing treatment. 
Addition 
Section 8.6.1 Tumor 
assessments 
Specified exception for prior CT or MRI scan. 
Moved tumor assessments from Final Visit to 
SFU visit. 
Correction 
Section 8.8 
Pharmacodynamics 
Blood volumes updated. 
Correction 
Section 8.8.3 Blood 
samples for 
circulating tumor 
DNA analysis 
New section added. 
Addition 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.8.4 Blood 
samples for serum 
bone turnover 
markers 
Blood volume corrected. 
Correction 
Section 8.8.8 
Historical tumor 
samples 
Sentence regarding laboratory manual deleted.  
To avoid confusion at sites 
Section 8.10 
Immunogenicity 
Text updated to reflect reduction in total number 
of samples taken during Cycles 2, 3, and 4. 
Reduction of participant 
assessment burden 
Table 8-9 Blood sample timepoints for ADA 
analysis: Deletion of Day 15 samples for Cycles 
2, 3, and 4. Clarification of timing of sampling at 
SFU Visit. Comment column removed. 
Clarification. 
Section 9.1 
Definition of 
analysis sets 
Updated definitions of analysis sets, including 
deletion of FAS and addition of ADAS. 
Consistency with SAP 
Section 9.2 General 
statistical 
considerations 
Added text omitted in error from original version 
of protocol. 
Correction 
Section 9.3.1 Safety 
analyses 
Updated planned analyses. Updated vital signs 
information. 
Consistency with SAP 
Section 9.3.2 
Analysis of Baseline 
and demographic 
variables 
Clarification of study parts. 
Clarification 
9.3.3.1 Analysis of 
PK endpoints 
Updated planned analyses. 
Consistency with SAP 
9.3.3.5 Analysis of 
immunological 
endpoints 
Updated planned analyses. 
Consistency with SAP 
9.4.1 Analysis of 
primary antitumor 
activity/outcome 
endpoint 
Updated terminology. 
Consistency with SAP 
9.4.2.1 Antitumor 
activity endpoint 
definitions 
Clarification of definitions. 
Consistency with SAP 
9.4.2.2 Analysis of 
the antitumor 
activity endpoints 
Updated planned analyses. 
Consistency with SAP 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.6 handling of 
dropouts or missing 
data 
Noted that further details will be provided in SAP. 
Clarification 
Section 9.8.1 Dose 
escalation modules 
Clarified text for addition of dose level based on 
emerging data. 
Consistency with dose 
escalation scheme 
Section 10.2 
Appendix 2: Clinical 
laboratory tests 
Added coagulation parameters as a row. Deleted 
coagulation tests from other Screening tests row. 
Changed “Other Screening Tests” to “Other 
Tests). 
BUN or urea creatinine changed to BUN or urea 
Added serum creatinine. 
Clarification 
Section 10.3 
Added coagulation to abnormal laboratory test 
results bullet for events meeting the AE definition. 
Clarification 
Section 10.9, 
Appendix 9: 
RECIST v1.1 
guidelines 
Aligned text to be consistent with RECIST v1.1 
guidelines and to the eCRF mapping of terms. 
Alignment of text with 
RECIST v1.1 and eCRF 
Section 10.10 
Added aPTT, INR, and PT to list of abbreviations 
Addition 
Global 
Correction of spelling, grammar, or typographical 
errors. 
Correction 
12 
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Confidential 
Page 193 of 195 
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SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
ONC001-Protocol-amend-6-26Jun2023
Version:
1. 0
Document Number:
CLIN-000225639
Title:
ONC001 Protocol Amendment 6-26Jun2023
Approved Date:
27 Jun 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 27-Jun-2023 16:17:53 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 27-Jun-2023 16:19:43 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Jun-2023 16:21:41 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Jun-2023 17:08:50 GMT+0000
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SAP_001.pdf: 
UCB 
12 July 2023 
Statistical Analysis Plan Amendment 4 
UCB6114 
ONC001 – Part A 
Confidential 
Page 1 of 67 
STATISTICAL ANALYSIS PLAN 
PART A  
DOSE ESCALATION (MONOTHERAPY) 
Study: ONC001 
Product: UCB6114 
A PHASE 1/2 OPEN-LABEL, MULTICENTER STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND 
ANTITUMOR ACTIVITY OF UCB6114 ADMINISTERED 
INTRAVENOUSLY TO PARTICIPANTS WITH ADVANCED 
SOLID TUMORS 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
SAP/Amendment Number 
Date 
Amendment 4 Final Version 0.1 12 July 2023 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
Confidential 
Page 2 of 67 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 
Study objectives ....................................................................................................... 7 
2.1.1 
Primary objective ........................................................................................... 7 
2.1.2 
Secondary objective ....................................................................................... 7 
2.1.3 
Exploratory/Tertiary objectives ..................................................................... 8 
2.2 
Study endpoints ........................................................................................................ 8 
2.2.1 
Safety endpoints ............................................................................................. 8 
2.2.1.1 Primary safety endpoints.................................................................................... 8 
2.2.1.2 Other safety endpoints ....................................................................................... 8 
2.2.2 
Pharmacokinetic and pharmacodynamic endpoints ....................................... 8 
2.2.2.1 Secondary pharmacokinetic endpoint ................................................................ 8 
2.2.2.2 Exploratory pharmacokinetic endpoints ............................................................ 8 
2.2.2.3 Exploratory pharmacodynamic endpoints ......................................................... 9 
2.2.2.4 Exploratory immunogenicity endpoints ............................................................. 9 
2.2.3 
Efficacy endpoints ......................................................................................... 9 
2.2.3.1 Exploratory antitumor activity endpoints .......................................................... 9 
2.2.3.2 Other exploratory efficacy endpoint .................................................................. 9 
2.3 
Study design and conduct ........................................................................................ 9 
2.4 
Determination of sample size ................................................................................. 11 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 11 
3.1 
General presentation of summaries and analyses .................................................. 11 
3.2 
General study level definitions .............................................................................. 14 
3.2.1 
Relative day and time .................................................................................. 14 
3.2.2 
Study periods ............................................................................................... 14 
3.2.3 
Visits ............................................................................................................ 15 
3.3 
Definition of Baseline values ................................................................................. 15 
3.4 
Protocol deviations................................................................................................. 16 
3.5 
Analysis sets........................................................................................................... 17 
3.5.1 
Enrolled Set (ES) ......................................................................................... 17 
3.5.2 
Safety Analysis Set (SS) .............................................................................. 17 
3.5.3 
Per-protocol Set (PPS) ................................................................................. 17 
3.5.4 
Pharmacokinetic Set (PKS) ......................................................................... 17 
3.5.5 
Anti-drug Antibody Set (ADAS) ................................................................. 18 
3.5.6 
Pharmacodynamic Set (PDS) ....................................................................... 18 
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Statistical Analysis Plan Amendment 4 
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3.5.7 
DLT Evaluable Set (DES) ........................................................................... 18 
3.6 
Treatment assignment and treatment groups ......................................................... 18 
3.7 
Center pooling strategy .......................................................................................... 18 
3.8 
Coding dictionaries ................................................................................................ 19 
3.9 
Changes to protocol-defined analyses ................................................................... 19 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 19 
4.1 
Adjustments for covariates .................................................................................... 19 
4.2 
Handling of dropouts or missing data .................................................................... 19 
4.2.1 
Pharmacokinetics and pharmacodynamics .................................................. 20 
4.2.2 
Safety laboratory data .................................................................................. 20 
4.2.3 
Dates and times ............................................................................................ 20 
4.2.4 
Impact of COVID-19 ................................................................................... 22 
4.3 
Handling of repeated and unscheduled measurements .......................................... 22 
4.4 
Handling of measurements obtained for early withdrawals .................................. 23 
4.5 
Interim analyses and data monitoring .................................................................... 23 
4.6 
Multicenter studies ................................................................................................. 23 
4.7 
Multiple comparisons/multiplicity ......................................................................... 23 
4.8 
Use of an efficacy subset of participants ............................................................... 24 
4.9 
Active-control studies intended to show equivalence ............................................ 24 
4.10 
Examination of subgroups ..................................................................................... 24 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 24 
5.1 
Study participant disposition.................................................................................. 24 
5.2 
Protocol deviations................................................................................................. 26 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 26 
6.1 
Demographics ........................................................................................................ 26 
6.2 
Cancer history ........................................................................................................ 27 
6.3 
Prior anti-cancer therapy ........................................................................................ 27 
6.4 
Cancer status at Screening ..................................................................................... 28 
6.5 
Medical history and concomitant diseases ............................................................. 29 
6.6 
Prior and concomitant medications ........................................................................ 29 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 30 
8 
SAFETY ANALYSES ..................................................................................................... 30 
8.1 
Extent of exposure ................................................................................................. 30 
8.2 
Adverse events ....................................................................................................... 31 
8.2.1 
Adverse events of special interest ................................................................ 35 
8.2.2 
Infusion-related reactions ............................................................................ 35 
8.3 
Clinical laboratory evaluations .............................................................................. 35 
8.4 
Vital signs, physical findings, and other observations related to safety ................ 39 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
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8.4.1 
Vital signs .................................................................................................... 39 
8.4.2 
12-Lead Electrocardiograms ........................................................................ 40 
8.4.3 
Echocardiogram ........................................................................................... 42 
8.4.4 
ECOG performance status ........................................................................... 42 
8.4.5 
Physical examination ................................................................................... 42 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 43 
9.1 
Pharmacokinetics ................................................................................................... 43 
9.1.1 
Secondary pharmacokinetic endpoint .......................................................... 43 
9.1.2 
Exploratory pharmacokinetic endpoints ...................................................... 43 
9.2 
Pharmacodynamics ................................................................................................ 45 
9.3 
Immunogenicity ..................................................................................................... 51 
10 EFFICACY ANALYSES ................................................................................................ 55 
10.1 
Antitumor activity .................................................................................................. 55 
10.1.1 
Definitions of the antitumor activity endpoints ........................................... 55 
10.1.2 
Analysis of the antitumor activity endpoints ............................................... 58 
10.2 
ECOG performance status ..................................................................................... 60 
11 OTHER ANALYSES ...................................................................................................... 60 
12 REFERENCES ................................................................................................................ 61 
13 APPENDICES ................................................................................................................. 61 
13.1 
SMQ algorithm for identification of anaphylactic reactions ................................. 61 
13.2 
SAP Amendment 4 changes................................................................................... 65 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 67 
 
 
 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ADA 
anti-drug (UCB6114) antibody 
ADaM 
Analysis Data Model 
ALP 
alkaline phosphatase 
ALQ 
above limit of quantification 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BLQ 
below limit of quantification 
BMI 
body mass index 
BOR 
best overall response 
CA 
cancer 
CDISC 
Clinical Data Interchange Standards Consortium 
CDMS 
clinical data management system 
cGremlin-1 
circulating gremlin-1 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CPPC 
CDMS postproduction change 
CR 
complete response 
CSR 
clinical study report 
ctDNA 
circulating tumor deoxyribonucleic acid 
CTMS 
Clinical trial management system 
CV 
coefficient of variation 
DCR 
disease control rate 
DEM 
data evaluation meeting 
DES 
DLT evaluable set 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ES 
enrolled set 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAP 
fibroblast activation protein 
FDA 
Food and Drug Administration 
geoCV 
geometric coefficient of variation 
geoMean 
geometric mean 
H & E 
hematoxylin & eosin 
hh:mm 
hours:minutes 
HLT 
high level term 
ICH 
International Council for Harmonization 
IHC 
immunohistochemistry 
IM 
invasive margin 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
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iv 
intravenous 
IPD 
important protocol deviations 
LLOQ 
lower limit of quantification 
LLT 
low level term 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
number of study participants 
NCA 
noncompartmental analysis 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for AEs  
Nest 
not estimable 
ORR 
objective tumor response rate 
OS 
overall survival 
PCS 
potentially clinically significant 
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PDS 
pharmacodynamic set 
PK 
pharmacokinetic(s) 
PKS 
pharmacokinetic set 
PFS 
progression-free survival 
PPS 
per-protocol set 
PR 
partial response 
PT 
preferred term 
PTEN 
phosphatase and tensin homolog 
Q2W 
every 2 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D-M 
recommended Phase 2 dose – monotherapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SFU 
safety follow-up 
SI 
International System of Units 
SMAD4 
mothers against decapentaplegic homolog 4 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SoC 
standard of care 
SS 
safety analysis set 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
TFL 
Table, Figure and Listing 
TNM 
TNM Classification of Malignant Tumors  
TPS 
tumor proportion score 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of the dose escalation (monotherapy) module (Part A) 
of study ONC001. It also describes the summary tables, figures and listings (TFLs) to be 
generated for Part A according to: 
Protocol amendment 5, dated 14 January 2022;  
Electronic case report form (eCRF) (Clinical Data Management System [CDMS] 
postproduction change [CPPC] #14, version 23.0, dated 14 April 2023); 
UCB’s standards for TFL shells version 2023Q1; 
Part A TFL shells, final version 2.3, dated 13 March 2023; 
UCB’s Derivation of Efficacy Endpoints document, version 0.6, dated 21 January 2022. 
Unless specified in the sections below, Part A of the study will be analyzed as described in the 
most recent version of the protocol. If a future protocol amendment necessitates a substantial 
change to the analysis of the Part A study data, this SAP will be amended accordingly. In 
addition, if the methodology for the analysis of key study endpoints must be modified or updated 
prior to the final database lock for Part A of this study, a SAP amendment will be required. 
Protocol amendments that do not affect the statistical analysis will not necessitate an amendment 
to the SAP. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the clinical study report (CSR) 
together with the associated rationale.  
Note that there may be a number of data cut-offs defined prior to the final database lock for Part 
A due to the regulatory safety reporting requirements for this study.  
The content of this SAP is compatible with the International Council for Harmonization 
(ICH)/Food and Drug Administration (FDA) E9 Guidance (ICH-E9) (Phillips et al, 2003). 
UCB is the Sponsor and ICON PLC is the contract research organization (CRO) for this study. 
 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective of Part A (dose escalation module) of this study is to characterize the 
safety profile of UCB6114 administered as monotherapy in study participants with recurrent or 
metastatic advanced solid tumors. 
2.1.2 
Secondary objective 
The secondary objective of Part A of this study is to characterize the pharmacokinetics (PK) of 
UCB6114 administered as monotherapy in study participants with recurrent or metastatic 
advanced solid tumors. 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
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2.1.3 
Exploratory/Tertiary objectives 
The exploratory/tertiary objectives of Part A of this study are: 
• To document any antitumor activity observed with UCB6114 according to relevant 
Response Evaluation Criteria in Solid Tumors (RECIST) criteria; 
• To explore pharmacodynamics (PD) biomarkers of UCB6114; 
• To evaluate the incidence, emergence, and impact of anti-drug (UCB6114) antibody 
(ADA) activity. 
2.2 
Study endpoints 
2.2.1 
Safety endpoints 
2.2.1.1 Primary safety endpoints 
The primary safety endpoints for Part A of this study are the incidence and severity of treatment-
emergent adverse events (TEAEs) (including serious adverse events [SAEs]) from the first dose 
of study treatment on Day 1 of Cycle 1 to the Safety Follow-up (SFU) visit, and the incidence of 
dose limiting toxicities (DLTs) from the first dose of study treatment on Day 1 of Cycle 1 to the 
end of the DLT Observation Period (Day 28 of Cycle 1). 
2.2.1.2 Other safety endpoints 
The following other safety data will be assessed during Part A of the study to further support the 
characterization of the safety profile of UCB6114 administered as monotherapy: 
• Clinical laboratory data (hematology, serum chemistry, coagulation and urinalysis); 
• Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature); 
• 12-lead electrocardiogram (ECG); 
• Echocardiogram (left ventricular ejection fraction [LVEF]); 
• Eastern Cooperative Oncology Group (ECOG) performance status;  
• Physical examination. 
2.2.2 
Pharmacokinetic and pharmacodynamic endpoints 
2.2.2.1 Secondary pharmacokinetic endpoint 
The secondary PK endpoint in Part A is the UCB6114 concentration by scheduled assessment for 
each UCB6114 dose. 
2.2.2.2 Exploratory pharmacokinetic endpoints 
The following key and other PK parameters will be calculated, where possible: 
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Statistical Analysis Plan Amendment 4 
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ONC001 – Part A 
 
 
 
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2.2.2.3 Exploratory pharmacodynamic endpoints 
The following PD endpoints will be assessed in Part A and reported separately outside of the 
CSR: 
• Change in transcriptional and protein marker levels in blood and tumor tissue (where 
biopsies are available) by scheduled assessment and dose level; 
• Change in circulating tumor deoxyribonucleic acid (ctDNA) levels in blood by 
scheduled assessment and dose level. 
2.2.2.4 Exploratory immunogenicity endpoints 
Immunogenicity in Part A will be explored using ADA sample status and participant 
classification, and changes in titer over time. Potential relationships between ADA and PK, PD, 
anti-tumor activity and safety may also be explored but these analyses will be reported separately 
outside of the CSR. 
2.2.3 
Efficacy endpoints 
2.2.3.1 Exploratory antitumor activity endpoints 
Antitumor activity in Part A will be explored using the following endpoints: 
• Objective tumor response rate (ORR); 
• Disease control rate (DCR); 
• Duration of antitumor response (DOR); 
• Progression-free survival (PFS); 
• Overall survival (OS). 
2.2.3.2 Other exploratory efficacy endpoint 
To further explore efficacy in Part A of the study, changes from Baseline in the ECOG 
performance status scale will be assessed. 
2.3 
Study design and conduct 
Study ONC001 is a multicenter, nonrandomized, open-label, Phase 1/2 study evaluating the 
safety, PK, efficacy (as assessed by antitumor activity), PD, biomarkers, and immunogenicity 
(ADA activity) of intravenous (iv) UCB6114 as monotherapy and in combination with selected 
standard of care (SoC) regimens in study participants with advanced solid tumors. 
The study has a modular design including up to 3 dose escalation modules (Parts A, B, and C), 
1 dose adaptation module (Part A1), and up to 4 dose expansion modules (Parts D, E, F, and G). 
Depending on emerging data, not all modules may open. This SAP is focused only on the first 
dose escalation module of the study (Part A). 
Part A consists of a Screening Period (28 days), a Treatment Period (consisting of 28-day 
cycles), an SFU visit (approximately 30 days after the last dose of study treatment) and a Final 
Visit (approximately 3 months after the last dose of study treatment). The planned duration of 
study treatment is 2 cycles. Participants may remain on study for additional cycles if they are 
receiving therapeutic benefit or until they fulfill one of the criteria for study discontinuation. 
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During the Treatment Period, UCB6114 will be administered as monotherapy by iv infusion on 
Days 1 and 15 of each cycle, until the occurrence of progressive disease, unacceptable toxicity, 
or participant withdrawal. Dosing levels will be escalated (or de-escalated) stepwise in 
successive cohorts of 3 to 6 evaluable participants using a modified rolling-6 design until the 
recommended Phase 2 dose for monotherapy (RP2D-M) is determined. The rolling-6 design is 
an algorithm-based design in which a total of 6 participants can be enrolled at the same dose 
level. The modification requires that each dose level incorporates a sentinel participant. The 
enrollment of a sentinel participant in each cohort has been included as an additional risk 
mitigation measure to monitor infusion-related reactions and other early onset study treatment-
related AEs. Each sentinel participant will be assessed for at least 24 hours following the second 
treatment administration on Day 15 of Cycle 1 before further participants within the dose cohort 
can be enrolled. In the absence of a DLT observation in the sentinel participant after 16 days, the 
remaining 5 participants may be enrolled concurrently (see Figure 4-1 in the protocol). Should 
the sentinel participant experience a DLT, then participants 2 and 3 will be enrolled and observed 
for 16 days (see Figure 4-2 in the protocol).  
Part A of the study is planned to be conducted at 6 study sites in the United Kingdom (UK). 
A schematic diagram of Part A of the study is provided in Figure 2-1. 
 
Figure 2-1: Study Schematic for Part A 
 
d=days; iv=intravenous; Q2W=every 2 weeks; SMC=safety monitoring committee. 
Dose escalation to the next cohort can be performed when 3/3, 4/4, 5/5, 5/6, or 6/6 participants 
have completed the DLT observation period and have not experienced  a DLT. When a single 
DLT has been observed in a given dose level, participants will be included at the same dose 
level, up to a total of 6 participants. De-escalation will occur when 2 or more participants 
experience a DLT at a dose level and when less than 6 participants have been evaluated at the 
dose level below the level at which 2 DLTs occurred. Dose escalation requires at least 3 
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participants to be treated and observed for at least 28 days after the first dose (assuming 
UCB6114 is dosed every 2 weeks [Q2W]). If dosing is less frequent (due to missed or delayed 
doses or due to a planned change in schedule), at least 3 participants should be treated and 
observed for a minimum of 28 days (i.e. 1 cycle), before dose escalation is considered.  
The final decision for dose escalation in the next cohort will be made by a Safety Monitoring 
Committee (SMC) taking into account all the observed safety and tolerability data, and the PK 
and PD and ADA profile (where available) of the dose in that cohort and also of the doses in all 
previous cohorts, as relevant (for further details on the SMC, please refer to Section 4.5). 
Eligible participants who withdraw from the study before receiving study treatment will be 
replaced. Participants who fail to receive the second planned dose of UCB6114 within 7 days of 
the scheduled dose administration day, during the DLT observation period, for reasons not 
related to toxicity, will also be replaced for the purpose of DLT assessment. Safety data for 
replaced participants will be included in the data listings and in the summary tables, as 
applicable. 
2.4 
Determination of sample size 
No formal statistical sample size calculation has been performed for the dose escalation modules 
in study ONC001.  
The number of participants likely to be enrolled in Part A depends on how many dose levels are 
needed to define the RP2D-M. Each cohort will be conducted with a minimum of 3 treated 
participants using a modified rolling-6 design for the evaluation of DLTs. The number of 
participants assumes all (5) planned dose levels are evaluated in Part A, and that 1 dose level is 
added due to emerging data, to establish the RP2D-M. It also assumes that, on average, there will 
be an additional participant required due to drop-out/replacement and/or the modified rolling-6 
design.  
Based on these assumptions, Part A will include up to 42 eligible participants. 
 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
All TFLs will be produced by ICON PLC using SAS® Version 9.4 or higher (SAS Institute, Cary, 
North Carolina, USA). ICON PLC will also produce the analysis datasets which will adhere to 
the Clinical Data Interchange Standards Consortium (CDISC) guidance documents for Analysis 
Data Model (ADaM) and follow the UCB interpretation. General statistical and reporting 
conventions will follow the current UCB Global Conventions Document Version 1.1.  
Data will be summarized by cohort/dose level (treatment group), visit and timepoint, as 
applicable. All relevant reported and derived data will be listed and will be presented by 
treatment group, study participant and visit, as applicable. 
Categorical variables will be summarized using frequency counts and percentages. Unless 
otherwise stated, the denominator for the percentages will be based on the number of participants 
in the respective analysis set, treatment group, visit and timepoint (as applicable) with non-
missing data. 
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Statistical Analysis Plan Amendment 4 
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When reporting frequency counts and percentages, the following rules apply: 
• For categories where all participants fulfill certain criteria, the percentage value will be 
displayed as 100; 
• For categories where zero participants fulfill certain criteria, there will be no percentage 
displayed; 
• All other percentage displays will use 1 decimal place. 
Summary statistics will be presented for continuous variables including number of participants 
(n), arithmetic mean, standard deviation, median, minimum and maximum. 95% confidence 
intervals (CIs) for the arithmetic mean may also be included depending on the variable and 
where stated in the SAP. Geometric mean (geoMean), geometric coefficient of variation (geoCV) 
and 95% confidence interval (CI) for the geoMean will also be presented in the summaries of 
UCB6114 concentration data. In all relevant outputs the 95% confidence limits will be restricted 
to the possible values that the variable can take.  
 
When reporting descriptive statistics for data other than UCB6114 concentration data, the 
following rules will apply: 
• n will be an integer; 
• Mean (arithmetic and geometric), standard deviation, median and quartiles will use 1 
decimal place more, or 1 significant figure more – depending on the reporting format of 
the original data – than the original data. Original data may be data as reported directly 
onto the eCRF or summary data based on data reported onto the eCRF (e.g. mean of 
triplicates or percentage change from Baseline); 
• Confidence intervals will be presented to the same number of decimal places as the value 
around which the confidence interval is constructed; 
• Minimum and maximum will be reported using the same number of decimal places or 
significant figures as the original value; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “); 
• If no participants have data at a given timepoint, then only n=0 will be presented; 
• Percentage change from Baseline values will be calculated and displayed to 1 decimal 
place in the listings. In the summaries, where applicable, the arithmetic mean, standard 
deviation and median percentage change from Baseline values will be presented to 2 
decimal places and the minimum and maximum values presented to 1 decimal place. 
When reporting individual UCB6114 concentration data in listings and figures, and presenting 
summary statistics in tables, the following rules will apply: 
• UCB6114 concentration data should be reported in the listings to the same level of 
precision as received from the bioanalytical laboratory; 
• Missing data should be reported as ‘NV’ (no value) in the listings; 
• Concentrations below the lower limit of quantification (LLOQ) should be reported as 
BLQ (below the limit of quantification) in the listings; 
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Statistical Analysis Plan Amendment 4 
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• BLQ values prior to Cmax should be set to 0 for purposes of plotting a figure (to capture 
lag-time);  
• Actual sampling times will be used in the spaghetti plots of individual PK concentrations 
over time, and nominal sampling times will be used in the summaries of geoMean 
concentrations over time; 
• UCB6114 concentration data should be plotted on both linear and semi-logarithmic 
scales;  
• To calculate summary statistics, BLQ values should be set to half the LLOQ value and 
missing values should be excluded; 
• When the total number of BLQ and missing values exceeds one third of the total then 
only minimum and maximum should be reported for this timepoint. Other summary 
statistics should be reported as missing (“-“). The minimum should be reported as BLQ; 
• When the mean value includes one or more replaced BLQ values then a footnote should 
be included to say “contains one or more BLQ values replaced by half the LLOQ value”; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “); 
• If no participants have data at a given timepoint, then only n=0 will be presented; 
• Summary statistics for UCB6114 concentration data will be reported to the same level of 
precision as the individual data for the minimum and maximum, and to 1 additional 
decimal place or 1 additional significant figure – depending on the reporting format of the 
original data with a maximum of 3 significant figures - for the mean (arithmetic and 
geometric), median and standard deviation. The 95% CI for the geoMean will use the 
same number of decimal places or significant figures as the geoMean. It will be left blank 
if the geoCV is 0; 
• Geometric coefficient of variation will be reported as a percentage to 1 decimal place. 
The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data: 
GeoCV (%) = sqrt[(exp (SD^2) – 1)] x 100 
When reporting PK parameters in listings and figures, and presenting summary statistics in 
tables, the following rules will apply: 
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3.2 
General study level definitions 
3.2.1 
Relative day and time 
For each participant, the relative day of an event or assessment will be derived using the date of 
their first dose of study treatment as reference.  
Relative days for an event or assessment occurring before the date of first dose are calculated as 
follows: 
Relative Day = Event/Assessment Date - Date of First Dose 
The relative day for an event or assessment occurring on the date of first dose is 1. The relative 
day for an event or assessment occurring on or after the first dose to the date of the last dose of 
study treatment will be calculated as follows: 
Relative Day = (Event/Assessment Date - Date of First Dose) + 1 
For events or assessments occurring after the date of the last dose, relative day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows: 
Relative Day = Event/Assessment Date – Date of Last Dose 
There is no relative Day 0. Relative day will not be calculated in cases where dates are partial 
and should be presented as “--” in the relevant data listing. 
Relative time of TEAEs recorded on the day of infusion (Days 1 and 15 of each cycle) will be 
derived in minutes as follows using the infusion start time as reference: 
Relative Time of TEAE = Onset Time of TEAE – Start Time of Infusion 
Relative times of PK and PD sampling will be derived in hours using the end of infusion times 
on the day of dosing as reference, i.e. on Days 1 and 15 of each cycle: 
Relative Sampling Time = Sampling Time – End of Infusion Time 
3.2.2 
Study periods 
Part A of the study will consist of the following study periods: 
• Screening Period – up to 28 days; 
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• Treatment Period – Successive 28-day cycles of study treatment (Q2W dosing on Day 1 
and Day 15 of each cycle continuing until disease progression, unmanageable toxicity, or 
participant withdrawal). Within the first cycle of the Treatment Period, a 28-day DLT 
Observation Period is defined to determine safety events for dose escalation decisions. If 
a study participant is a sentinel participant in the cohort, there is an initial DLT 
Observation Period of 16 days, after which the cohort may be opened for further 
enrollment; 
• Safety Follow-up Period – up to 30 days after the last dose of study treatment. 
There will be a further extended follow-up period, up to 3 months after the last dose of study 
treatment, at which time the Final Visit will be performed.  
For each participant, the end of the Treatment Period is defined by the date of their last dose of 
study treatment.  
The end of Part A of the study is defined by the date of the Final Visit for the last participant (3 
months after the last participant’s last dose of study treatment), or the date of the SFU visit, if 
they discontinue prior to attending the Final Visit, or their last contact date if they discontinue 
early from the study without attending the SFU visit. 
3.2.3 
Visits 
Unless otherwise specified, in the TFLs, visits will be labelled as follows (as applicable): 
Screening 
Baseline 
Cycle 1, Day X 
Cycle 2, Day X  
Cycle 3, Day X 
Cycle 4, Day X 
Cycle X, Day X 
Etc. 
SFU 
Final Visit 
3.3 
Definition of Baseline values 
Baseline in Part A will be the last available value prior to the first dose of study treatment. Both 
scheduled and unscheduled values, as well as any repeated values, should be used when defining 
Baseline. 
Measurement-specific Baseline definitions are presented in Table 3-1. 
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Table 3-1: Definition of Baseline 
Measurement 
Definition of Baseline 
Echocardiogram (LVEF) 
PD biomarkers from tissue (optional tumor 
biopsies) 
Tumor assessments (antitumor activity) 
Screening value 
12-lead ECG 
Physical examination and weight 
Vital signs 
Clinical laboratory data 
ECOG performance status 
Predose value obtained on Cycle 1, Day 1, or, if 
missing, Screening value  
Serum and urinary markers of bone turnover 
Circulating Gremlin-1 (cGremlin-1) 
Immunogenicity (ADA) 
Predose sample value obtained on Cycle 1, Day 1 
ADA=anti-drug (UCB6114) antibody; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
LVEF=left ventricular ejection fraction; PD=pharmacodynamic. 
3.4 
Protocol deviations 
Per ICH definition, important protocol deviations (IPDs) are a subset of protocol deviations that 
may significantly impact the completeness, accuracy, and/or reliability of the study data or that 
may significantly affect a participant’s rights, safety, or well-being. The criteria for identifying 
potentially important protocol deviations will be defined within the IPD specifications 
document.  
 
For Part A of this study, IPDs will be categorized as follows:   
• 
Inclusion/exclusion criteria deviations  
• 
Incorrect treatment or dose administered  
• 
Procedural non-compliance  
• 
Prohibited concomitant medication use (see Section 6.5.2 of the protocol) 
• 
Withdrawal criteria deviation   
All protocol deviations will be reviewed as part of the ongoing data cleaning process and Data 
Evaluation Meetings (DEMs), and decisions made on whether they should be considered 
important or not, and whether they warrant a participant’s exclusion from an analysis set, or 
partial exclusion from an analysis due to being an IPD (e.g. prohibited concomitant medication 
use). Multiple DEMs will be scheduled prior to the final database lock for Part A, in line with 
regulatory safety reporting requirements, with the final one held after all data have been 
verified/coded/entered into the database.  
More specifically, participants who have IPDs relating to dosing of study treatment (e.g. 
interrupted, discontinued and missed infusion, incomplete/incorrect dose administered, 
additional dose received, or infusions administered outside of the defined visit window) will be 
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reviewed at the DEM for potential exclusion of UCB6114 concentration data from the by-visit 
summaries at an individual visit or from the visit at which the dosing deviation was observed 
onwards. 
Any protocol deviations that are considered related to coronavirus disease 2019 (COVID-19) 
will be reviewed on an ongoing basis in case they collectively or individually give reason to 
consider a protocol amendment (e.g. study design changes or changes to primary analysis 
methods etc.). To facilitate this ongoing review, protocol deviations will be categorized as 
‘related to COVID-19’ within the Clinical Trial Management System (CTMS). The COVID-19-
related IPDs will then be listed separately for review and discussion at the DEMs. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set (ES) 
The Enrolled Set (ES) consists of all study participants who sign the Informed Consent Form. 
This analysis set includes screening failures and will be used for the summary of disposition of 
study participants and for selected data listings (which will include all available data for the 
screening failures).  
3.5.2 
Safety Analysis Set (SS) 
The Safety Analysis Set (SS) consists of all study participants who receive at least 1 full or 
partial dose of study treatment.  
  
This analysis set will be used for the reporting of demographic, Baseline, safety and 
immunogenicity data. All summaries of the exploratory antitumor activity endpoints will be 
repeated for the SS as a sensitivity analysis.  
3.5.3 
Per-protocol Set (PPS) 
The Per-protocol Set (PPS) consists of all study participants in the SS who do not have IPDs that 
may substantially affect antitumor activity. Potential exclusions will be reviewed at the DEMs 
and a final determination of the composition of this analysis set will be made prior to the final 
database lock for Part A.  
The PPS will be the primary analysis set for the analysis of the exploratory antitumor activity 
endpoints.  
3.5.4 
Pharmacokinetic Set (PKS) 
The Pharmacokinetic Set (PKS) consists of all study participants in the SS who have at least 
1 evaluable postdose UCB6114 concentration sample (i.e. a sample which is above the lower 
limit of quantitation and for which the date and time of the sample and prior date and time of 
dosing are known). Additional participants or specific samples may be excluded from the PKS at 
the discretion of the Advanced Modeling and Simulation scientist/Quantitative Clinical 
Pharmacologist at UCB. 
Pharmacokinetic analysis will be performed for the PKS. 
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3.5.5 
Anti-drug Antibody Set (ADAS) 
The Anti-drug Antibody Set (ADAS) consists of all study participants in the SS who have at 
least 1 evaluable ADA assessment.  
Immunogenicity analyses will be performed for the ADAS. 
3.5.6 
Pharmacodynamic Set (PDS) 
The Pharmacodynamic Set (PDS) consists of all study participants in the SS who have at least 
1 evaluable PD assessment (where appropriate, the sample should be above the lower limit of 
quantitation and the date and time of the sample should be known). 
Pharmacodynamic analysis will be performed for the PDS. 
3.5.7 
DLT Evaluable Set (DES) 
The DLT Evaluable Set (DES) will include all study participants who, during the 28-day DLT 
Observation Period, receive the planned dose of UCB6114. 
The DES will be used only for evaluations by the SMC for dose-escalation decisions. 
3.6 
Treatment assignment and treatment groups 
In Part A, it is planned that study participants will be dosed Q2W at ascending dose levels in 5 
cohorts. Treatment groups will be defined by each cohort/dose level and will be presented in 
ascending order and labelled in the TFLs as illustrated in Table 3-2. 
Table 3-2: Treatment Group Labels 
Cohort/Dose Level 
Planned Treatment Group Label 
Cohort 1 (Dose Level 1) 
UCB6114 100mg  
Cohort 2 (Dose Level 2) 
UCB6114 250mg  
Cohort 3 (Dose Level 3) 
UCB6114 500mg  
Cohort 4 (Dose Level 4) 
UCB6114 1000mg  
Cohort 5 (Dose Level 5) 
UCB6114 2000mg  
Note that the actual dose levels and treatment group labels may change depending on whether 
dose escalation criteria are met. Further, additional cohorts/dose levels may be included based on 
emerging data. 
Cohort/dose level will be referred to as ‘treatment group’ from this point onwards in the SAP and 
in the TFLs. 
3.7 
Center pooling strategy 
Each study site will contribute to the summaries of data from Part A according to the number of 
evaluable participants recruited; no separate summaries for each site will be presented.   
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3.8 
Coding dictionaries 
Adverse events and medical history will be coded by UCB, using the latest available version of 
the Medical Dictionary for Regulatory Activities (MedDRA®) (Version 25.1 or higher). The 
National Cancer Institute Common Terminology Criteria for AEs (Version 5.0) (NCI CTCAE) 
dictionary will also be used by the investigator to assign CTCAE severity grades to each AE and 
will be merged with the clinical database to define a CTCAE code and term to be used in the 
summaries of TEAEs by maximum CTCAE severity grade. 
Medications (including prior anti-cancer systemic therapies) will be coded according to the 
World Health Organization Drug Dictionary (WHODD) (Version SEP/2020). Medical 
procedures will not be coded. 
The versions of the coding dictionaries used will be displayed in the relevant TFLs. 
3.9 
Changes to protocol-defined analyses 
The following changes to the protocol have been incorporated into the SAP: 
• Other safety data have not been defined as safety endpoints in the protocol, e.g. clinical 
laboratory data, vital signs, ECG, echocardiogram, ECOG performance status and 
physical examination. These have been listed in Section 2.2.1 of the SAP as ‘other safety 
endpoints’ to support the characterization of the safety profile of UCB6114 and to 
provide supporting evidence of any measurements that are deemed abnormal and 
clinically significant and reported as an AE. 
• ECOG performance status is defined as an efficacy assessment in Section 8.6.2 of the 
protocol, however, it will also be assessed from a safety perspective in Part A. The SAP 
therefore includes ECOG performance status as both a safety endpoint (Section 2.2.1) 
and an exploratory efficacy endpoint (changes from Baseline during Part A in Section 
2.2.3). 
• Section 9.4.2.1 of the protocol does not explicitly define the analysis set to be used for 
the antitumor activity endpoints but defines the denominator as the number of treated 
participants, which matches the protocol definition for the SS in Section 9.1 of the 
protocol. The SAP has been written to clarify that the PPS will be the primary analysis 
set for the analysis of the antitumor activity endpoints (Section 3.5.3) and that the SS will 
be used for the sensitivity analysis (Section 3.5.2).  
 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
There will be no imputation of missing data unless otherwise stated in the sections below. 
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4.2.1 
Pharmacokinetics and pharmacodynamics 
The reporting and handling of missing values and values that are BLQ in the TFLs is described 
in Section 3.1. Zero values will be assumed at the predose timepoint on Day 1 of Cycle 1. 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ in the safety laboratory data will be the same as those 
described for PK data in Section 3.1. Any values above the limit of quantification (ALQ) will be 
assigned as the value of upper limit of quantification. 
4.2.3 
Dates and times 
Partial dates may be imputed for the following reasons: 
• Classification of adverse events (AEs) as treatment-emergent; 
• Classification of medications recorded on the concomitant medications log as prior or 
concomitant; 
• Calculation of time since initial diagnosis, time since completion of most recent line of 
prior anti-cancer systemic therapy and time since progression/relapse on most recent line 
of prior anti-cancer systemic therapy. 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial onset/start dates: 
• If only the month and year are specified and the month and year of the first dose of study 
treatment is not the same as the month and year of the start date then the 1st of the month 
will be used, or the date of the Screening visit if this is later (if the latter imputation 
results in an end date that is earlier than the start date, then the 1st of the month will be 
used); 
• If only the month and year are specified and the month and year of the first dose of study 
treatment is the same as the month and year of the start date, then the date of the first 
dose of study treatment will be used. If this results in an imputed start date that is after 
the specified end date, then the 1st of the month will be used, or the date of Screening if 
this is later (if the latter imputation results in an end date that is earlier than the start date, 
then the 1st of the month will be used). If the imputed date is the same date as the date of 
the first dose of study treatment then, for AEs, the event will be regarded as treatment-
emergent. For medications, the medication will be classified as concomitant; 
• If only the year is specified, and the year of the first dose of study treatment is not the 
same as the year of the start date then January 01 will be used; 
• If only the year is specified, and the year of the first dose of study treatment is the same 
as the year of the start date, then the date of the first dose of study treatment will be used. 
If this results in an imputed start date that is after the specified end date, then January 01, 
or the date of the Screening visit if this is later will be used (if the latter imputation results 
in an end date that is earlier than the start date, then January 01 will be used). If the 
imputed date is the date of the first dose of study treatment then, for AEs, the event will 
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be regarded as treatment-emergent. For medications, the medication will be classified as 
concomitant. 
• If the onset/start date is completely missing then the onset/start date will be imputed to 
the date of first dose of study treatment and therefore, for AEs, the event will be regarded 
as treatment-emergent and, for medications, the medication will be classified as 
concomitant. 
The following rules will be applied to partial end/stop dates: 
• If only the month and year are specified, then the last day of the month will be used; 
• If only the year is specified, then December 31 of the known year will be used; 
• If the stop date is completely unknown, the stop date will not be imputed. 
Note that the start date or stop date of a prior medication (partial or otherwise) should not be 
imputed past the Screening date - 1.  
In addition to onset and stop dates, the onset and end times of AEs occurring on the day of 
infusion will be collected on the eCRF. Onset and end times may also be recorded for other AEs 
that do not occur on the same day as the infusion. The duration of AEs with onset and end times 
will be calculated in days and hours:minutes (hh:mm) as: 
Duration of AE = End Date and Time – Onset date and time 
In cases where only the onset and stop dates are recorded for an AE, the duration of an AE will 
be calculated in days as:  
Duration of AE = (Stop Date – Onset Date) + 1 
Note that for participants who have an AE which starts and stops on the same day, but with only 
a start time or only a stop time recorded, it will be assumed that their AE started from 00:00 (if 
no start time is recorded) and ended at 23:59 (if no stop time is recorded) on that day. 
If the date of a participant’s initial diagnosis is incomplete, it will be imputed to the most recent 
feasible date for the calculation of time since initial diagnosis as follows: 
 
• If only the day is missing, it will be imputed to the last day of the known month; 
• If the day and month are missing, it will be imputed to December 31 in the known year; 
• If the date of initial diagnosis is completely missing, then time since initial diagnosis will 
not be calculated. 
 
The above date imputation rules will be applied to partially missing stop dates of a participant’s 
last prior anti-cancer systemic therapy as well as partially and completely missing dates of 
progression/relapse on last prior anti-cancer systemic therapy. 
 
In cases where the stop date of a participant’s last prior anti-cancer systemic therapy and/or a 
participant’s date of progression on last line of prior anti-cancer systemic therapy is completely 
missing, the participant’s Screening date - 1 will be used in the calculation of the time since 
completion of most recent line of prior anti-cancer systemic therapy and the time since 
progression/relapse on most recent line of prior anti-cancer systemic therapy, respectively. 
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Note that partial dates will not be imputed as a participant’s first dose of study treatment in the 
calculation of time since initial diagnosis, time since completion of most recent line of prior anti-
cancer systemic therapy and time since progression/relapse on most recent line of prior anti-
cancer systemic therapy. 
4.2.4 
Impact of COVID-19 
The FDA and European Medicines Agency (EMA) have provided guidance (see references listed 
in Section 12) to help assure the safety of all trial participants, maintaining compliance with good 
clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic. 
At the time of writing this SAP, the impact of the pandemic is still evolving and regulators 
continue to clarify their position, and how to handle missing or delayed assessments resulting 
from the pandemic is part of the risk assessment of the impact of COVID-19 on trial integrity. 
For this purpose, the impact at a visit level will be assessed by data collected on a specific 
COVID-19 impact eCRF form and protocol deviations related to COVID-19. Due to the timing 
of the start-up of recruitment of participants into this study, the consequences for Part A are not 
expected to be significant and, as a result, no details on strategies for handling missing data are 
included in this version of the SAP. However, should the ongoing review of COVID-19-related 
protocol deviations suggest that the impact is more significant than expected, e.g. in the case of a 
second wave, the SAP may be updated to include further details of handling missing data and/or 
any sensitivity analyses required. Note that there are no guidelines regarding how much missing 
data is too much, and there is no proportion of missing data under which valid results and 
preservation of study power can be guaranteed. In accordance with the EMA guidance, an 
independent Data Monitoring Committee (DMC) may be convened to make an assessment 
regarding the scientific integrity of the study. 
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. Repeated measurements are defined as more than 1 measurement at the same 
timepoint. For example, the same laboratory parameters assessed twice using the same batch of 
blood samples due to issues with the first assessment. The following general rules will apply to 
all repeated and unscheduled measurements: 
• Unscheduled and repeated measurements prior to the first dose of study treatment will be 
used in the determination of Baseline and hence in the calculation of summary statistics 
at Baseline; 
• Unscheduled and repeated measurements performed after the first dose of study treatment 
will not be included in the calculation of change from Baseline, summary measures such 
as minimum, maximum, average and last post-Baseline value calculated for the 
summaries of laboratory data (see Section 8.3), vital signs (see Section 8.4.1) and 12-lead 
ECG (see Section 8.4.2), or summary statistics, i.e. only the scheduled measurements will 
be used and summarized. Similarly, only scheduled visits will be used in the summaries 
of shifts from Baseline to the worst post-Baseline CTCAE severity grade for laboratory 
data (see Section 8.3).  
• For the summaries of the investigator’s overall tumor response assessment, protocol-
defined windows will be applied to all post-Baseline tumor assessments (scheduled or 
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unscheduled, but excluding tumor assessments performed at the SFU visit), as detailed in 
Section 10.1.2. Those tumor assessments which fall outside of the window will be 
considered as unscheduled assessments and not included in the summaries. 
• Best overall response, DOR and PFS derivations will use data from all scheduled and 
unscheduled tumor assessments.   
• All data from unscheduled visits will, however, be included on the relevant data listings. 
4.4 
Handling of measurements obtained for early withdrawals 
Participants who withdraw early from the study for any reason will be asked to return to the 
clinic to complete the SFU visit. The SFU procedures performed at this visit are as shown in the 
Schedule of Activities in the protocol and will be summarized together with all other SFU visit 
data in the tables. 
4.5 
Interim analyses and data monitoring 
No formal interim analyses are planned during Part A of this study. 
The SMC will be established which will comprise key UCB personnel and investigators from 
participating sites. The SMC will meet after the sentinel participant in each cohort has completed 
the 16-day DLT Observation Period during Cycle 1 of study treatment. They will review 
primarily all safety data for this participant, including the individual DLTs (as applicable). Once 
the last participant in a given cohort has completed the required 28-day DLT Observation Period, 
a further SMC meeting will be convened to review all safety data (including DLTs) and any 
available PK, ADA and PD data from all participants in that cohort (and participants in previous 
cohorts, if applicable). PK, ADA and PD data reported at each SMC will always be based on the 
previous cohort due to availability and processing time required for these data. The SMC will 
then decide whether to halt dose escalation, further expand the cohort to gain additional safety 
data, or determine the next dose level to be evaluated. Further details are included in the SMC 
Charter and specifications for the data presentations will be included in a separate output 
specifications document for the SMC reviews. 
All data presented to the SMC will be cumulative in order that the members can review and 
discuss the data in its totality at the end of all completed cohorts, i.e. all safety information 
beyond Cycle 1 for all previous cohorts will be presented cumulatively for review during each 
subsequent SMC meeting. 
In addition to the planned SMC data review meetings, UCB and the SMC will have the ability to 
hold/request ad hoc meetings should they be deemed necessary (e.g. if safety concerns arise 
during Part A of the study and/or during other ongoing nonclinical and clinical studies). 
4.6 
Multicenter studies 
Part A of this study is planned to be conducted at 6 study sites in the UK. With the exception of 
participant disposition, no summaries will be presented by site. 
4.7 
Multiple comparisons/multiplicity 
Not applicable. 
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4.8 
Use of an efficacy subset of participants 
The PPS will be used as the primary analysis set for the summaries of the exploratory antitumor 
activity endpoints in Part A. 
4.9 
Active-control studies intended to show equivalence 
Not applicable. 
4.10 
Examination of subgroups 
Not applicable. 
 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Study participant disposition 
The number of study participants who were screened for Part A of this study, the number and 
percentage of screen failures and the primary reasons for screen failure will be summarized for 
the ES. A listing of participants who did not meet the eligibility criteria for Part A will also be 
presented for the ES. In addition, the disposition of study participants screened and who received 
study treatment will be summarized by site. This table will include, for each site and overall, site 
number, principal investigator name, the dates of the first participant in and the last participant 
out, the number of participants screened (ES), the number of screen failures, the number of 
participants who were treated (SS) and included in the PPS, PKS, ADAS and PDS. Disposition 
in each analysis set across all study sites will be summarized by treatment group. 
The number of study participants who received study treatment and the primary reason for 
discontinuation of study treatment during Part A will be summarized by treatment group, 
together with the number and percentage of participants who continued participation in the study 
after discontinuation of study treatment (at subsequent scheduled visits and/or SFU visit and 
Final Visit). This summary will be based on the SS. 
The number of study participants enrolled into Part A, who were screen failures as well as the 
number of eligible participants who were assigned to a study cohort but not treated will be 
presented for the ES. For those participants who did not receive study treatment, the reasons for 
early discontinuation from the study will be summarized.  
Of those participants who received study treatment, the number and percentage of participants 
who completed the study (i.e. participants who received at least 2 complete cycles of study 
treatment and attended the SFU visit), who received at least 2 complete cycles of study treatment 
but who did not attend the SFU visit and who discontinued early from Part A, together with the 
primary reasons for study discontinuation will be presented for all participants.  
The number and percentage of participants who discontinued due to AEs will be summarized 
separately for all participants, based on the SS. This will be used for European Union Drug 
Regulating Authorities Clinical Trials (EudraCT) reporting. 
Visits impacted by COVID-19 will be listed for the ES. This listing will include, visit, visit date, 
relative day, impact category (e.g. visit performed out of window, visit performed by telephone, 
visit not done, missed study drug administration/dispensation, termination of study 
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participation), relationship to COVID-19 (confirmed COVID-19 infection, suspected COVID-19 
infection, general circumstances around COVID-19 or other) and a narrative for the event. The 
number and percentage of participants with visits impacted by COVID-19 will be presented by 
treatment group and by impact category. This summary will be presented for the different  
relationships to COVID-19. The denominator for the percentage calculations will be the number 
of participants in the SS. 
In addition, the following listings will be presented: 
• Study participant disposition (ES); 
• Study treatment discontinuation (SS); 
• Study discontinuation (ES); 
• Visit dates (ES); 
• Participant analysis sets and exclusions from analysis sets (ES)*. 
* DES is not included in this listing as it is only relevant for the SMC, and not required for the 
reporting of data in the CSR. 
The listing of study participant disposition will include the date of informed consent, date and 
time of first and last dose of study treatment, date of early study discontinuation (if applicable) 
and primary reason for discontinuation. The listing of study treatment discontinuation will 
include date and time of first and last dose of study treatment, date of decision to discontinue 
study treatment and primary reason for discontinuation of study treatment, date of clinical 
progression (if applicable), number of doses of study treatment received (based on 2 doses per 
cycle), total dose of study treatment received across all cycles, number of complete cycles of 
study treatment received, and whether or not the participant had continued participation in the 
study (at subsequent visits, the SFU visit or the Final Visit). 
Note that a participant is deemed to have completed a full cycle of study treatment if they 
received a dose of study treatment on Days 1 and 15 of the cycle and a decision was not made to 
discontinue their study treatment up to and including Day 28 relative to Day 1 of the cycle. This 
will be derived based on a participant’s last dose of study treatment and whether or not the 
participant attended the visit at which they were scheduled to receive their next dose of study 
treatment. For example, if a participant received study treatment on Day 15 of Cycle 1, they 
attended the clinic on Day 1 of Cycle 2 for their next dose of study treatment then the participant 
will be counted as having completed Cycle 1. If the participant did not attend Day 1 of a 
subsequent cycle, then it is likely that a decision was made to discontinue their treatment and/or 
the study. Therefore, the date that the decision was made to discontinue study treatment will be 
used to determine whether the participant completed a cycle of study treatment. If a decision was 
made to discontinue study treatment on >Day 28 relative to Day 1 of the particular cycle then the 
participant will be counted as having completed the cycle. For any interim deliveries at a data 
cut-off, if the participant did not attend Day 1 of their next cycle and there was no decision to 
discontinue study treatment, then the latest date available for that participant should be used to 
determine whether they have completed a 28-day cycle. 
Whether or not a participant has completed the study is defined as having received at least 2 
complete cycles of study treatment and attended the SFU visit. The investigator will record a 
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study participant’s disposition status at study termination according to this definition of a  
‘completed’ participant, however, a study completion flag will also be programmatically derived 
based on the relevant data on the database and the above rules for defining completion of a full 
cycle of study treatment. 
The listing of study discontinuation will include the primary reason for early study 
discontinuation, the number of cycles of study treatment received, and the total number of days 
on study treatment. 
The total number of days on study treatment will be calculated as follows: 
𝑇𝑜𝑡𝑎𝑙 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑) + 1 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types defined in 
the IPD specification document, as per Section 3.4. 
A listing of all IPDs identified at the DEM will be presented for all study participants based on 
the SS and will include the deviation type and description. In addition, a listing of all protocol 
deviations related to COVID-19 (whether considered important or not) will be presented for the 
SS. The number and percentage of participants in the SS with IPDs will be summarized by 
treatment group and for all participants for each deviation type. The number and percentage of 
participants who were excluded from the PPS will also be presented. The denominator for the 
percentage calculations will be the number of participants in the SS. A summary will also be 
presented for all protocol deviations related to COVID-19, all IPDs related to COVID-19 and all 
IPDs related to COVID-19 leading to exclusion from the PPS. 
 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
A by-participant listing of demographics will be presented based on the ES. This will include the 
year of birth, age (as entered by investigator in the eCRF in years), sex, race, ethnicity, height (in 
cm), weight (in kg) and body mass index (BMI, in kg/m2). Height will be the measurement 
obtained at the Screening visit and weight will be the last non-missing value prior to the first 
dose of study treatment. 
The BMI will be derived in the database using the height and weight measurements recorded at 
the Screening visit and will be automatically reported to 1 decimal place on the eCRF. 
All demographic characteristics (except for date of birth) will be summarized by treatment group 
and for all study participants based on the SS. The summary of age will include descriptive 
statistics and categorical summaries, the latter based on requirements for EudraCT and 
clinicaltrials.gov reporting. 
For the EudraCT reporting, the categories will include: 
• 18 to <65 years; 
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• 65 to <85 years. 
For clinicaltrials.gov reporting, the categories will include: 
• ≤18 years; 
• 19 to <65 years; 
• ≥65 years. 
Childbearing potential and method of birth control will be listed for the ES. 
6.2 
Cancer history 
All cancer history data for Part A participants will be listed for the ES. This listing will include 
date of initial diagnosis, tumor type, TNM Classification of Malignant Tumors (TNM) 
classifications and stage, Duke’s score and Gleason score (if relevant to the tumor type), 
histological and cytological diagnosis details (as relevant), whether the participant had any 
metastases and associated anatomical location, and whether the participant had received any 
prior anti-cancer therapies (including the number of lines of any prior systemic therapies, prior 
radiation therapies and prior anti-cancer surgeries). 
Time since initial diagnosis (calculated in months using date of Screening visit and date of initial 
diagnosis and multiplying the duration in days by 12/365.25), tumor type, T, N, M classifications 
and TNM stage, Duke’s score, Gleason score, presence of metastases and anatomical location of 
metastases will be summarized by treatment group and for all study participants based on the SS. 
In the summaries of categorical variables, percentages will be calculated based on the number of 
study participants with non-missing data. Further, for the cM0(i+) M classification, Duke’s score 
and Gleason score, the denominator for the percentage calculation will be the number of study 
participants for which these assessments are applicable (since they only apply to certain tumor 
types). 
6.3 
Prior anti-cancer therapy 
Details recorded for each line of prior anti-cancer systemic therapy received by a study 
participant will be listed for the ES. This listing will include the line and type of systemic 
therapy, intent, drug name and dose, formulation, indication (current/ultimate), start and end 
dates, number of cycles received and the number of days per cycle, the participant’s best 
response and the date of that best response, reason for discontinuation and whether the 
participant had disease progression prior to the next line of systemic therapy. If there was 
progression, then the date of progression will also be listed. In addition, time from completion of 
the last prior anti-cancer systemic therapy to the start of study treatment, whether the participant 
had progression after the last line of systemic therapy and, if so, the time from progression to the 
start of study treatment will be derived and listed. 
For those participants in the ES who received prior radiotherapy, the following data will be 
listed: treatment site, type of radiotherapy, intent, settings (concurrent with other anti-cancer 
systemic therapy or stand-alone radiation therapy), and, if concurrent radiotherapy, the anti-
cancer systemic therapy line that the radiotherapy was given with and the drug name. In addition, 
the start and stop dates, total cumulative dose (if known), number of fractions (if known), the 
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participant’s best response to radiotherapy and whether the tumor at the treatment site had 
progressed since radiotherapy will be included in this listing. 
A further listing of prior anti-cancer radiotherapy with systemic therapy regimens will be 
presented for participants in the ES who had concurrent prior systemic therapy and radiotherapy 
as their prior anti-cancer therapy. This listing will include the relevant data described above 
together with the participant’s best response to that regimen. 
Date of surgery/procedure, anatomical location, description of the surgical procedure and 
whether the tumor was completely removed will be listed for those study participants in the ES 
who had prior anti-cancer surgeries or procedures. 
The following summaries of prior anti-cancer therapy regimens and surgeries will be presented 
by treatment group and for all participants for the SS: 
• Number of prior anti-cancer therapy regimens (0, 1, 2, 3, >3) (including all anti-cancer 
systemic therapy lines given alone and concurrently with radiotherapy)  
• Best response to the most recent prior anti-cancer therapy regimen 
• Number of prior anti-cancer systemic therapy + radiotherapy regimens (0, 1, 2, 3, >3) 
• Best response to the most recent anti-cancer systemic therapy + radiotherapy regimen 
• Reasons for discontinuation of the most recent line[a]   
• Time from completion of most recent line[a] to the start of study treatment (<1 month, 1-
<3 months, 3-6 months, >6 months)[b] 
• For participants that progressed after their most recent line[a], the time from progression 
to the start of study treatment (<1 month, 1-<3 months, 3-6 months, >6 months)[b] 
• Number of prior anti-cancer radiotherapies (including radiotherapies given alone and 
concurrently with anti-cancer systemic therapy) (0, 1, 2, >2) 
• Number of prior anti-cancer surgeries and procedures (0, 1, 2, >2) 
[a] Most recent line is the last prior anti-cancer therapy regimen received which may be a prior 
anti-cancer systemic therapy given alone or concurrently with radiotherapy. 
[b] 1 month = 30 days. 
Time from completion and time from progression relative to the last line of anti-cancer systemic 
therapy will also be summarized using frequency counts and percentages as well as summary 
statistics. 
The number and percentage of participants with any prior anti-cancer systemic therapy, and any 
prior anti-cancer systemic therapy given concurrently with radiotherapy will be summarized for 
the SS by treatment group and for all participants, and by WHODD Anatomical Main Group 
[Level 1 term text], Pharmacological Subgroup [Level 3 term text] and PT. 
6.4 
Cancer status at Screening 
The current cancer status of study participants at entry into Part A of this study will be assessed 
at the Screening visit and listed for the ES. This listing will include tumor type, T, N and M 
classifications and TNM stage, Duke’s score and Gleason score (if relevant to the tumor type), 
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histological and cytological diagnosis details (as relevant), whether the participant has any 
metastases and associated anatomical location, whether the tumor is recurrent and whether the 
participant had relapsed from their last line of anti-cancer therapy.  
Tumor type, TNM classifications and stage, Duke’s score, Gleason score, presence of metastases 
and anatomical location of metastases, and time since relapse on last line of therapy (calculated 
in days using the date of the Screening visit and date of relapse) will be summarized by treatment 
group and for all study participants based on the SS. In the summaries of categorical variables, 
percentages will be calculated based on the number of study participants with non-missing data. 
Further, for the cM0(i+) M classification, Duke’s score and Gleason score, the denominator for 
the percentage calculation will be the number of study participants for which these assessments 
are applicable (since they only apply to certain tumor types). 
6.5 
Medical history and concomitant diseases 
Medical history will be listed for the ES and summarized by MedDRA system organ class (SOC) 
and preferred term (PT) by treatment group and for all study participants for the SS. The reported 
term will be included in the listing. Previous medical history (any previous medical conditions 
with a stop date prior to the start of study treatment) and ongoing medical history (any ongoing 
medical conditions with a missing stop date but recorded as ongoing on the eCRF) will be 
summarized separately. These summaries will include the number and percentage of study 
participants and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the incidence in all study participants.  
Non-anti-cancer procedure history will be listed for the ES and concomitant medical procedures 
performed during the study will be listed for the SS. 
6.6 
Prior and concomitant medications 
Prior medications will include any medications that started prior to the date of the first dose of 
study treatment. This will include medications that started prior to the first dose and continued 
after. 
Concomitant medications will include medications with a start date on or after the first dose of 
study treatment and prior to the date of the last dose of study treatment + 30 days, and whose 
stop date is either missing, or on or after the date of the first dose of study treatment. Any 
medications with a start date prior to the first dose of study treatment and a stop date after, or 
continued to be ongoing during the study, will also be classified as concomitant medications. 
Medications with a start date > 30 days after the last dose of study treatment will be considered 
as post-study medications and will not be included in the summaries of concomitant medication.  
Any medication that started prior to, and stopped after the first dose of study treatment, or 
continued to be ongoing during the study, will be classified as both prior and concomitant.  
Any medications with missing start dates will be classified as both prior and concomitant 
provided that a stop date is not present or a stop date is present and it is prior to the first dose of 
UCB6114. 
Any medications with partially missing dates will be handled as described in Section 4.2.3 to 
classify them as prior or concomitant. 
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All medications (prior, concomitant and post-study) will be listed for the ES. Any prohibited 
concomitant medications, rescue medications or steroid use will be identified via a medical 
review and flagged in this listing.  
Prior and concomitant medications (per the definitions above) will be summarized for the SS by 
treatment group and by WHODD Anatomical Main Group [Level 1 term text], Pharmacological 
Subgroup [Level 3 term text] and PT. The reported term will be included in the listing. Separate 
summaries will be presented for prior medications and concomitant medications. As per the 
definitions above, prior medications which continued into the Treatment Period will also be 
classified as concomitant and will be included in both summaries. 
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in all study participants. 
A glossary of all prior and concomitant medications will be presented for the SS including the 
Anatomical Main Group (Level 1), Pharmacological Subgroup (Level 3), PT and reported term.  
 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
During Part A of this study, administration of study treatment will be performed via iv infusion 
at the study site under the supervision of the designated site personnel and in compliance with 
the Guideline for First in Human clinical studies (EMEA/CHMP/SWP/28367/07Rev. 1). 
Compliance will be monitored at the site through a review of accountability logs which will be 
used to record study treatment dispensing and return information to ensure that each study 
participant received the correct dose level. 
Any dosing deviations will be reviewed as IPDs at the DEMs and assessed for possible impact 
on the PPS. If considered important, these deviations will be included in the summary and listing 
of IPDs. 
 
8 
SAFETY ANALYSES 
All safety summaries and listings will be presented by treatment group based on the SS, unless 
otherwise stated. 
8.1 
Extent of exposure 
Details on study treatment administration on Day 1 and Day 15 of each cycle of study treatment 
will be listed. This listing will be split into two parts. The first part will include the start and stop 
dates and times of infusion, duration of infusion, infusion rate, whether the infusion was 
temporarily stopped/interrupted, whether the infusion was permanently discontinued and, if this 
was the case, whether the interruption or permanent discontinuation was due to an AE or other 
reason. The second part of this listing will include, for each visit, infusion site, total volume 
delivered, volume infused, planned total dose and total dose actually administered at infusion.  In 
addition, the percentage of planned dose received, total dose administered across all cycles, the 
number of complete cycles of study treatment received and the total number of doses of study 
treatment received will be listed. 
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The percentage of planned dose received will be calculated for each study participant at each 
dosing visit within each cycle as follows: 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑜𝑓 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑= 100 × 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒
 
 
Actual duration of infusion will be calculated in minutes only for those study participants who 
did not have any temporary interruption(s) of their infusion using the infusion start and stop 
times and included on this listing. Length of interruption(s) will be calculated for those study 
participants who had temporary interruption(s) of their infusion. 
Extent or duration of exposure will be calculated and summarized. Frequency counts and 
percentages for the number of complete cycles of study treatment received (1, 2, 3, 4, >4) and 
summary statistics for the total dose of study treatment received across all cycles, the total 
number of doses of study treatment received and the duration of exposure to study treatment will 
be presented.  
Duration of exposure will be calculated in days as follows: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒) + 30  
Note that 30 days is added to this calculation to account for a participant’s continued exposure to 
UCB6114 following their last dose of study treatment. 
Note that a participant is deemed to have completed a full cycle of study treatment if they receive 
a dose of study treatment on Day 1 and Day 15 of the cycle and a decision was not made to 
discontinue study treatment up to and including Day 28 relative to Day 1 of a cycle.  
8.2 
Adverse events 
The primary safety endpoints for Part A of this study are the incidence and severity of TEAEs 
(including SAEs) from the first dose of study treatment on Day 1 of Cycle 1 until the end of the 
SFU Period (up to 30 days following the last dose of study treatment), and the incidence of DLTs 
from the first dose of study treatment on Day 1 of Cycle 1 until the end of the DLT Observation 
Period (Day 28 of Cycle 1). 
All AEs in Part A of the study will be coded using MedDRA® and classified as pre-treatment and 
treatment-emergent relative to the first dose of study treatment. Adverse events with a start date 
prior to the first dose of study treatment will be defined as pre-treatment AEs. A TEAE is 
defined as any AE with a start date on or after the first dose of study treatment up until the last 
dose of study treatment + 30 days. A pre-treatment AE which increases in severity on or after the 
first dose of study treatment will also be counted as a TEAE. Note that in this case, the pre-
existing AE will have a stop date and an outcome of ‘worsened’ and a new AE (with the same 
verbatim) will be entered with the same start date and the increased severity recorded on the 
eCRF. Any AE (including SAEs) with an onset date later than the last dose of study treatment + 
30 days will not be considered as treatment-emergent and therefore will not be included in the 
tabulations of TEAEs. These AEs will be considered as post-study AEs and will be listed only. 
Where onset dates are missing or partially missing, AEs will be assumed to be treatment-
emergent, unless there is clear evidence to suggest that the AE started prior to the first dose of 
study treatment and it has not increased in severity. Missing or partially missing dates for AEs 
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will be handled as described in Section 4.2.3. All AEs for a participant will be recorded in the 
eCRF from the time of informed consent until completion or early discontinuation of Part A of 
this study. Serious adverse events are to be reported up to 30 days after the Final Visit (i.e. up to 
150 days after the last dose of study treatment). 
Adverse events will be assigned an NCI CTCAE severity grade (Grade 1/Grade 2/Grade 3/Grade 
4/Grade 5), where possible. If a CTCAE toxicity grading is not possible, then the intensity of the 
AE (mild/moderate/severe) will be recorded on the eCRF. If the AE is not gradable, is serious, 
and is considered as life threatening, then the intensity for this AE will be missing and one of the 
reasons for seriousness will be recorded as life threatening.  
Adverse events will also be categorized according to their relationship to study treatment 
(related/not related), and whether the event is a DLT, as judged by the investigator. A DLT is 
defined as a TEAE related to study treatment that occurs during Cycle 1 and fulfills any of the 
criteria listed in Section 4.1.1.4 of the protocol. The investigator is expected to record whether an 
AE is a DLT on the eCRF. 
An overview of the number and percentage of participants who experience TEAEs will be 
presented. This summary will include the number and percentage of participants with any 
TEAEs, serious TEAEs, related TEAEs, discontinuations from study treatment due to TEAE(s), 
discontinuations from the study due to TEAE(s), CTCAE Grade ≥ 3 TEAEs, CTCAE Grade ≥3 
related TEAEs, DLTs, AEs leading to death and TEAEs leading to death; event counts will also 
be included against each of these categories. 
In addition, the following summaries will be presented by SOC, high level term (HLT) and PT: 
• Incidence of TEAEs; 
• Incidence of serious TEAEs; 
• Incidence of non-serious TEAEs; 
• Incidence of TEAEs leading to a temporary interruption and/or reduction in dose of study 
treatment; 
• Incidence of TEAEs leading to discontinuation of study treatment; 
• Incidence of TEAEs leading to discontinuation of study; 
• Incidence of DLTs; 
• Incidence of adverse events of special interest (AESIs) (Hy’s Law – see Section 8.2.1 
below); 
• Incidence of infusion-related reactions (defined as hypersensitivity reactions, 
anaphylactic reactions and cytokine release syndrome – See Section 8.2.2); 
• Incidence of TEAEs by maximum CTCAE severity grade; 
• Incidence of TEAEs by maximum relationship; 
• Incidence of TEAEs by relationship; 
• Incidence of serious TEAEs by relationship; 
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• Incidence of non-serious TEAEs by relationship; 
• Incidence of fatal TEAEs by relationship; 
• Incidence and event rate of TEAEs by treatment-emergent ADA positivity. 
The following summaries will be presented by SOC and PT for EudraCT reporting: 
• Incidence of non-serious TEAEs above the threshold of 5% of participants in any 
treatment group; 
• Incidence of non-serious TEAEs above the threshold of 5% of participants in any 
treatment group by relationship. 
The above summaries of TEAEs will be ordered alphabetically by SOC, alphabetically by HLT 
within SOC and decreasing incidence of PT events within SOC/HLT in all study participants. 
For tables including only the number and percentage of participants, summaries will be ordered 
alphabetically by SOC, alphabetically by HLT within SOC and decreasing incidence of 
participants with each PT within SOC/HLT in all study participants. 
The incidence of TEAEs by maximum CTCAE severity grade will be presented by CTCAE 
term. CTCAE term will be obtained from the NCI CTCAE Version 5.0 via a mapping of 
MedDRA lower level terms. This summary will be ordered by decreasing incidence of 
participants with each CTCAE term in all study participants. 
Summary tables will contain frequency counts and percentages, and the number of events, where 
applicable. A study participant who experiences the same event multiple times will be counted 
only once in the frequency counts for the PT, but all events will be included. 
In the summaries of TEAEs by relationship, participants will be counted in “Not related” and 
“Related” categories (or “Missing” in the case where an event has a missing relationship). A 
study participant who experiences the same event multiple times will be included in the most 
related category for the summaries by maximum relationship.  
In the overview summary of TEAEs, participants will be counted as having at least one TEAE 
with CTCAE severity grade ≥3, and in the summary of TEAEs by maximum CTCAE severity 
grade, participants will be counted as having at least one TEAE in the following categories: 
‘Grade 1’, ‘Grade 2’, ‘Grade 3’, ‘Grade 4’, ‘Grade 3 or 4’, ‘Grade 5’, ‘Grade ≥3’. Events for 
which no CTCAE severity grade is recorded by the investigator but an intensity is recorded 
instead, the intensity of this event will be assigned to a CTCAE severity grade for the purpose of 
these summaries, i.e. ‘Mild’ will be included as ‘Grade 1’, ‘Moderate’ will be included as ‘Grade 
2’, ‘Severe’ will be included as ‘Grade 3’, ‘Life Threatening’ will be included as ‘Grade 4’ and, 
if the participant dies due to the event, it will be included as ‘Grade 5’. The determination of 
whether the event is life threatening or results in death will be based on the reason for 
seriousness recorded as life-threatening or death on the eCRF, or on the event having a fatal 
outcome. Otherwise, if both the CTCAE severity grade and intensity is missing then the CTCAE 
severity grade in these summaries will be missing. A study participant who experiences the same 
event multiple times will be included in the highest severity grade category in the summary of 
TEAEs by maximum CTCAE severity grade.  
A glossary of all AEs will be presented including the MedDRA SOC, HLT, PT, reported term 
and low level term (LLT).  
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A listing of all AEs will be presented by study participant for the ES. The listing will include the 
onset date and stop date of the event (including relative days) and also the onset times and stop 
times of events where available. Period of onset of AEs will also be presented on this listing. 
Period of onset of AEs will be defined as follows for the purpose of the listing: 
 
• 
If the AE has an onset date prior to the date of the Screening visit, then Period=Pre-study; 
 
• 
If the AE has an onset date on or after the date of the Screening visit and has an onset 
date and time prior to the start time of study treatment (i.e. prior to the start time of the 
infusion on Day 1 of Cycle 1) then Period=Screening; 
 
• If the AE has an onset date and time on or after the start time of study treatment (i.e. on or 
after the start time of the infusion on Day 1 of Cycle 1) and up to the date and time of the 
start of Cycle 2 (i.e. prior to the start time of the infusion on Day 1 of Cycle 2) then 
Period=Cycle 1; 
 
• If the AE has an onset date and time on or after the start time of study treatment (i.e. on or 
after the start time of the infusion on Day 1 of Cycle 2) and up to the date and time of the 
start of Cycle 3 (i.e. prior to the start time of the infusion on Day 1 of Cycle 3) then 
Period=Cycle 2; 
 
• Same as above for subsequent cycles (Cycle 3 etc.); 
 
• If the AE has an onset date after the last dose of study treatment up to and including 30 
days after the last dose of study treatment, then Period=SFU; 
 
• 
If the event has an onset date after the 30-day period following the last dose of study 
treatment, then Period=Post-study. 
The listing of all AEs will also include the AE duration (derived in days, hh:mm for AEs with 
onset and stop times recorded and derived in days for all other AEs with only onset dates and 
times recorded, days/time since infusion (time if an onset time is recorded, days otherwise), 
seriousness and reason for seriousness, CTCAE severity grade, intensity (where a CTCAE 
severity grade is not recorded), pattern of event, relationship to study treatment and action taken 
with study treatment (including other action taken), whether an autopsy was performed and cause 
of death. In addition, the listing will flag AEs that led to discontinuation from the study, TEAEs, 
AESIs, SAEs, infusion-related reactions, and DLTs. Whether an AE is related to a concomitant 
medication (which will include the COVID-19 vaccination), the names of any co-suspect 
medications and the outcome (sequelae, date and time) of the AE will also be listed. 
Separate listings of all SAEs, TEAEs leading to discontinuation of study treatment and TEAEs 
leading to discontinuation of the study will also be presented.  
All deaths that occur on study (defined as during study treatment or within 30 days of study 
treatment discontinuation) will be listed separately. This listing will include the primary cause of 
death and the number of days between the date of the last dose of study treatment and death. 
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8.2.1 
Adverse events of special interest  
An AESI is any AE that a regulatory authority has mandated be reported on an expedited basis, 
regardless of the seriousness, expectedness, or relatedness of the AE to the administration of a 
UCB product/compound.  
For ONC001, potential Hy’s Law is used to identify AESIs and is defined using the laboratory 
data and the following potential drug-induced liver injury (PDILI) criteria: 
• ≥3x upper limit of normal (ULN) alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of 
≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the biochemical 
abnormality; 
• Study participants who have evidence of liver metastases may be considered to have an 
alternate etiology for the described laboratory abnormalities. 
All AESIs will be flagged on the listing of AEs. 
8.2.2 
Infusion-related reactions  
Infusion-related reactions are defined as hypersensitivity reactions, anaphylactic reactions and 
cytokine release syndrome with onset within 24 hours after the start of the UCB6114 infusion.   
All potential infusion-related reactions will be identified programmatically and will then undergo 
medical review for confirmation based on participant characteristics and other signs and 
symptoms. The final assessment from the medical review will be used in the programming to 
ensure that all infusion-related reactions are flagged correctly in the listings and included in the 
relevant summaries. 
Hypersensitivity reactions will be programmatically identified as any TEAE with a PT from both 
a narrow and broad scope search of category A terms of the ‘Hypersensitivity’ Standardized 
MedDRA Query (SMQ). 
Anaphylactic reactions will be programmatically identified using an algorithmic approach based 
on the ‘Anaphylactic Reaction’ SMQ. Further details on this algorithm are given in Section 13.1. 
Note that if the MedDRA version is increased from 25.1 during the study, any changes to the 
terms included in the ‘Anaphylactic Reaction’ SMQ should be applied. 
Cytokine release syndrome will be programmatically identified as any TEAE with a PT of 
‘Cytokine release syndrome’ from the broad scope search of category A terms of the 
‘Hypersensitivity’ SMQ. Since this disorder is characterized by fever, headache, tachycardia, 
hypotension, rash, tachypnoea and/or hypoxia, a further medical review of participants with 
these events occurring within 24 hours after infusion of study treatment will be performed to 
confirm any further infusion-related reactions. 
Note that any other AEs (i.e. not identified as infusion-related reactions using the rules above) 
which result in a temporary interruption or permanent discontinuation of an infusion will not be 
considered as an infusion-related reaction. 
8.3 
Clinical laboratory evaluations 
The use of multiple local laboratories (1 per site in the UK) in Part A of this study has meant that 
results have been recorded in different units and with reference to different normal ranges, and 
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further, for some laboratory tests, different normal ranges have been applied to males and 
females and age groups. As a first step to ensure comparability of laboratory results, results and 
normal ranges will be converted to the same International System of Units (SI) units using 
UCB’s standard conversion factors. This will be programmed at the Study Data Tabulation 
Model (SDTM) level. Note though that the simple conversion to SI units does not represent a full 
homogenization of results from different local laboratories using different methods. To ensure 
full comparability, the observed laboratory results will be normalized to a unique set of standard 
reference ranges using the location-scale normalization formula (Chuang-Stein, 1992) which 
normalizes all results in relation to a standard set of reference ranges (for hematology, clinical 
chemistry and coagulation parameters): 
𝑠= 𝐿𝑆+ (𝑥− 𝐿𝑋) (𝑈𝑆−𝐿𝑆)
(𝑈𝑋− 𝐿𝑋) 
where: 
s = normalized observed value 
x = original observed value in SI units 
LS = Lower Limit of the reference range chosen to be the standard reference range 
US = Upper Limit of the reference range chosen to be the standard reference range 
LX = Lower Limit of the reference range associated with the original observed value in SI 
units (local laboratory reference range) 
UX = Upper Limit of the reference range associated with the original observed value in SI 
units (local laboratory reference range) 
 
This transformation preserves the distance of the original laboratory result from the lower limit 
of normal as a multiple of the specified standard reference range. 
 
Note that the choice of the standard reference range is arbitrary, however, the most recent 
reference ranges used by ICON Central Laboratories (including the age and gender specific 
reference ranges for parameters, where available) will be used to normalize the results in this 
study. 
 
Normalization of the laboratory results will be performed in the ADaM programming by ICON. 
All laboratory data (hematology, serum chemistry and coagulation) and changes from Baseline 
for numeric variables will be listed for participants who have at least one value outside of the 
reference range. All urinalysis data will be listed for all participants. Data will be listed by study 
participant, laboratory panel, laboratory parameter and visit within each treatment group. Any 
laboratory measurements that are BLQ or ALQ will be handled as described in Section 4.2.2. For 
the relevant numeric laboratory parameters, the reference ranges supplied by the local analytical 
laboratory will be used to flag values outside the reference range as low or high in this listing. 
For the parameters for which the local laboratory cannot supply the reference ranges, the 
reference ranges provided by ICON Central Laboratories will be used instead. A listing of all 
laboratory results outside of the reference range will also be presented. The reference ranges will 
also be reported in the listings. 
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In addition, for the relevant laboratory tests, CTCAE severity grades (Grade 1, Grade 2, Grade 3, 
Grade 4) will be applied (where possible) in the ADaM programming according to NCI CTCAE 
Version 5.0, and these grades will also be listed for the relevant laboratory parameters. Note that 
Grade 0 will be applied in cases where a result is normal for the relevant laboratory test and 
Grade 5 is not applicable in the grading of laboratory data. 
Observed values and changes from Baseline in the hematology, serum chemistry and coagulation 
parameters presented below in Table 8-1 will be summarized at each visit. In addition, for each 
of these parameters, the Baseline value, the minimum, maximum, average and last post-Baseline 
value for each participant will be summarized by cycle using descriptive statistics. These post-
Baseline summary measures will be calculated based on all available scheduled postdose values 
within each cycle, i.e. from Day 8 of the current cycle up to Day 1 (predose) of the subsequent 
cycle. The last value in a cycle will be the predose value of the subsequent cycle where a 
subsequent cycle occurs, otherwise it will be the value at the last scheduled assessment. If only 1 
value is available then the average will not be calculated and presented but this value will be 
used for the minimum, maximum and last post-Baseline summary measures. These summary 
measures for each cycle will also be listed.  
For those laboratory parameters with a CTCAE toxicity assigned, shift tables for the change 
from Baseline in CTCAE severity grade at each visit and to the worst post-Baseline CTCAE 
severity grade during the Treatment Period will be presented.  
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Table 8-1: Clinical Laboratory Assessments 
Laboratory Assessment 
Laboratory Parameters 
Hematology 
Platelet Count, RBC Count, Hemoglobin, Hematocrit, RBC 
Indices (MCV, MCH, MCHC), WBC Count with Differential 
(Absolute Neutrophils, Absolute Lymphocytes, Absolute 
Monocytes, Absolute Eosinophils, Absolute Basophils) 
Clinical Chemistry 
ALT, AST, ALP (including liver-specific ALP for use in 
assessing participants with bone metastases at Screening), 
Bicarbonate, Sodium, Potassium, Magnesium, Chloride, 
Calcium, Total Bilirubin, BUN or Urea, Serum Creatinine, 
Glucose (non-fasted), Phosphorus or Phosphate, Albumin, 
Total Protein, Uric Acid, Amylase, GGT, Cholesterol, 
Creatine Kinase, CRP, LDH, Lipase, Triglycerides 
Coagulation 
aPTT and either PT or INR  
Routine Urinalysis 
Specific Gravity, pH, Glucose, Protein, Blood, Ketones, 
Bilirubin, Urobilinogen, Nitrite, Leukocyte Esterase by 
Dipstick 
Microscopic Examination (if blood or protein is abnormal, 
including crystals) 
Screening Tests 
Pregnancy tests: FSH and estradiol (for women of 
non-childbearing potential only); serum or urine hCG 
pregnancy test (for women of childbearing potential)  
Bone turnover markers: blood BAP, blood CTx, urinary NTx 
and urinary CTxII  
Tumor markers: PSA, CA125, CA19-9 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPPT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; BAP=bone alkaline phosphatase; BUN=blood urea nitrogen; CA=cancer antigen; CRP=C-reactive protein; 
CTx=C-terminal telopeptide; FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; hCG=human chorionic 
gonadotropin; INR=international normalized ratio; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; NTx=N-terminal telopeptide; 
PSA=prostate specific antigen; PT=prothrombin time; RBC=red blood cell; WBC=white blood cell. 
The screening laboratory tests included above in Table 8-1 will be listed only. 
Liver function abnormalities will be defined using the following criteria: 
• ALT or AST ≥2xULN 
• ALT or AST ≥3xULN 
• Total bilirubin ≥2xULN 
• Total bilirubin ≥3xULN 
• ALT or AST ≥5xULN 
• ALT or AST ≥8xULN 
• ALT or AST ≥3xULN AND total bilirubin ≥2xULN (>35% direct bilirubin) 
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For the subgroups of participants with liver metastases and without liver metastases at Baseline, 
the number and percentage of participants in each liver function abnormality category will be 
summarized at each visit. 
In addition, participants with potential drug induced liver injury (PDILI) criteria are those that 
fulfill the following laboratory data (based on liver function tests) criteria at a visit: 
• AST or ALT and total bilirubin within the normal range at Baseline and AST or ALT 
≥3xULN concurrent with total bilirubin ≥2xULN; 
• AST, ALT or total bilirubin above ULN at Baseline and AST or ALT ≥2 times Baseline 
values AND AST or ALT ≥3xULN (participants without liver metastases at 
Baseline)/AST or ALT ≥8xULN (participants with liver metastases at Baseline) 
concurrent with total bilirubin above ULN at Baseline and total bilirubin ≥2 times 
Baseline value or ≥3xULN (whichever is lower). 
All relevant laboratory data collected for participants with a PDILI event (i.e. liver function tests) 
will be listed at the visits at which at least one of the above criteria was fulfilled.  
The number and percentage of participants meeting different combinations of the ALT, AST and 
total bilirubin criteria defined above will be summarized by treatment group. This summary will 
be presented for all participants as well as for the subgroups of participants who had liver 
metastases at Baseline and participants without liver metastases at Baseline. 
A separate listing will also be produced containing DILI-relevant family medical history, 
lifestyle data (alcohol consumption or drug abuse in the previous 6 months), hepatic event 
supplemental medical history and any hepato-toxic medications taken for participants in the SS 
with a PDILI event. 
8.4 
Vital signs, physical findings, and other observations related to 
safety 
8.4.1 
Vital signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include:  
• Systolic and diastolic blood pressure; 
• Pulse rate; 
• Oral body temperature; 
• Respiratory rate. 
On dosing visits (Days 1 and 15 of each cycle), vital signs on treatment days (i.e. on Days 1 and 
15 of each cycle) will be assessed at multiple timepoints: predose, 10 minutes (±5 minutes) and 
30 minutes (±10 minutes) after the start of the infusion, at the end of the infusion (+15 minutes); 
and at 1 hour (+15 minutes) after the end of the infusion. In addition, on Cycle 1 Day 1, vital 
signs will also be assessed at 2 hours (+1 hour) and 8 hours (+2 hours) after the end of the 
infusion, to correspond with PK sampling timepoints; vital signs measurements will be 
performed prior to the collection of PK samples. 
At Screening and on non-treatment days (Days 2, 8, 16 and 22 of Cycle 1 and Day 8 of Cycle 2 
and the SFU visit), vital signs will be measured once prior to collection of PK samples. 
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Observed vital sign measurements and changes from Baseline will be listed by visit and 
timepoint and summarized using descriptive statistics. In addition, for each of the vital signs, the 
Baseline value, the minimum, maximum, average and last post-Baseline value for each 
participant will be calculated based on all available scheduled postdose values during each cycle 
up to the predose value on Day 1 of the subsequent cycle and will be summarized by cycle using 
descriptive statistics. The last value in a cycle will be the predose value of the subsequent cycle 
where a subsequent cycle occurs, otherwise it will be the value at the last scheduled assessment. 
If only 1 value is available then the average will not be calculated and presented but this value 
will be used for the minimum, maximum and last post-Baseline summary measures. These 
summary measures for each cycle will also be listed.  
For the multiple vital signs measurements on treatment days (i.e. on Days 1 and 15 of each 
cycle), changes from the predose value will be calculated at each postdose timepoint and 
summarized using descriptive statistics.  
For each vital signs parameter, the mean (±standard deviation) change from Baseline value will 
be plotted over scheduled visit and timepoint with treatment group overlaid on the same plot. 
The incidence of treatment-emergent markedly abnormal (TEMA)/potentially clinically 
significant (PCS) vital signs based on blood pressure and pulse rate measurements will be 
summarized by visit and timepoint using frequency counts and percentages. The criteria for 
identifying a TEMA/PCS are included in Table 8-2. 
Table 8-2: TEMA/PCS Criteria for Vital Signs 
Variable (unit) 
Lowa 
Higha 
Systolic Blood Pressure (mmHg)  
 
Value <90 and ≥20 decrease 
from Baseline 
Value >140 and ≥20 increase from 
Baseline 
Diastolic Blood Pressure 
(mmHg)  
Value <50 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
Pulse Rate (bpm) 
Value <45 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
bpm=beats per minute; PCS=potentially clinically significant; mmHg=millimeter of mercury; TEMA=treatment-emergent  
markedly abnormal. 
a Both conditions must be satisfied for a measurement to be considered PCS. 
8.4.2 
12-Lead Electrocardiograms  
Electrocardiograms will be performed at each visit and timepoint in triplicate with the participant 
in a supine position after a minimum of 5 minutes rest.  
On Days 1 and 15 of Cycle 1, ECGs will be performed in triplicate at multiple timepoints 
relative to the dose of study treatment (predose, end of infusion, and 8 hours after the end of 
infusion prior to PK sampling). On all other treatment days (Days 1 and 15 of all subsequent 
cycles of study treatment), ECGs will be performed in triplicate predose. At Screening and on 
non-treatment days, ECGs will be performed once in triplicate prior to PK sampling. 
All ECGs will be evaluated for any clinically relevant changes by the investigator.  
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Electrocardiograms will also be collected for central reading, the data from which will be 
analyzed separately.  
All summaries and listings of ECG data will be based on the local (site) 12-lead ECG 
measurements. 
The following ECG parameters will be reported: 
• PR interval;  
• QT interval; 
• QRS interval; 
• QTcF interval (QT corrected for heart rate using Fridericia’s formula [QTcF]); 
• Heart rate.  
Observed values and changes from Baseline in these ECG parameters will be listed and 
summarized by visit using descriptive statistics. The mean of the triplicate measurements taken 
for each parameter will be used in the summary at each visit and timepoint. If less than 3 of the 
triplicate measurements are taken then the mean of the available measurements will be used (if 
only 1 of the 3 triplicate measurements is available then this value will be used in the 
summaries). The Baseline value will be the mean of the last scheduled or unscheduled triplicate 
measurements taken prior to first dose of study treatment on Day 1 of Cycle 1. If no predose 
triplicate measurements are taken then the mean of the triplicate measurements taken at 
Screening will be used. The mean of only the scheduled triplicate measurements at each Post-
Baseline visit and timepoint will be included in the summary. In addition, for each of the ECG 
parameters, the  minimum, maximum, average and last post-Baseline value for each participant 
will be calculated based on the mean of the triplicate of all available scheduled postdose 
measurements during each cycle up to the predose value on Day 1 of the subsequent cycle, and 
will be summarized by cycle using descriptive statistics. The last value in a cycle will be the 
predose mean triplicate value of the subsequent cycle where a subsequent cycle occurs, 
otherwise it will be the mean triplicate value at the last scheduled assessment. If only 1 mean 
triplicate value is available then the average will not be calculated and presented but this value 
will be used for the minimum, maximum and last post-Baseline value summary measures. These 
summary measures for each cycle will also be listed.  
For the multiple ECGs performed on Days 1 and 15 of Cycle 1, changes from the predose value 
will be calculated at each postdose timepoint and summarized using descriptive statistics.  
Mean (±standard deviation) change from Baseline in QTcF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot. Individual observed values of QTcF will be 
presented over actual time in a spaghetti plot. 
The following cut-points in QTcF will be applied for observed data and changes from Baseline:  
For observed QTcF data: 
• <450 msec; 
• ≥450 to <480 msec; 
• ≥480 to <500 msec; 
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• ≥500 msec. 
For changes from Baseline in QTcF: 
• <30 msec; 
• ≥30 to <60 msec; 
• ≥60 msec. 
The incidence of participants in each of these categories will be summarized using frequency 
counts and percentages by visit. 
A listing of 12-lead ECG abnormal findings will be presented. 
Electrocardiograms will also be collected for central reading; however, these data will be 
reported in an addendum to the CSR. 
8.4.3 
Echocardiogram 
Echocardiograms will be performed at the Screening visit, on Day 1 of Cycles 2 and 3, and then 
on Day 1 of even cycles from Cycle 3 onwards.  
All details on the echocardiogram assessments performed at each visit will be listed including the 
observed LVEF measurements and changes from Baseline, as well as information on whether the 
result was normal, abnormal NCS or abnormal CS. 
Observed values and changes from Baseline in LVEF will be summarized by visit using 
descriptive statistics. In addition, shift tables for the change from Baseline in normal, abnormal 
NCS, abnormal CS LVEF results will be summarized by visit. 
Mean (±standard deviation) change from Baseline in LVEF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot. Individual observed LVEF results will be 
presented over actual time in a spaghetti plot. 
8.4.4 
ECOG performance status 
ECOG performance status will be listed by participant and visit and will be summarized using 
frequency counts and percentages. A shift table summarizing the changes from Baseline to each 
post-Baseline visit will also be presented. Further detail on the ECOG performance scale, the 
listings and summaries are included in Section 10.2. 
8.4.5 
Physical examination 
Physical examination abnormalities from the complete physical examination performed at 
Screening and predose on Day 1 of Cycle 1, and from the symptom-directed physical 
examinations performed at other visits (predose on dosing visits), will be listed. 
 
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9 
PHARMACOKINETICS AND PHARMACODYNAMICS  
9.1 
Pharmacokinetics 
9.1.1 
Secondary pharmacokinetic endpoint 
The secondary PK endpoint for Part A of the study is the UCB6114 concentration in blood by 
time and dose.  
UCB6114 concentrations will be listed for the SS and summarized using descriptive statistics by 
dose level (treatment group) and nominal (scheduled) sampling timepoints for the PKS (n, 
arithmetic mean, standard deviation, median, minimum, maximum, geoMean, geoCV and 95% 
CI for the geoMean [assuming lognormally distributed data]).  
Listings of the UCB6114 concentration data will include the actual and nominal (scheduled) 
sampling times and any deviations between them. Deviations will be calculated relative to the 
start of the iv infusion. Any samples that are obtained outside the tolerance window permitted at 
the specified timepoint will be discussed at the DEM and any possible exclusion from the 
summaries will be documented accordingly. 
Individual study participant UCB6114 concentration-time profiles and spaghetti plots of the 
individual concentration-time profiles for UCB6114 will be displayed graphically on the linear 
and semi-logarithmic scale. Geometric mean profiles of UCB6114 concentrations over nominal 
(scheduled) time will be presented with treatment group overlaid on the same plot, on both the 
linear and semi-logarithmic scale. The 95% CIs for the geoMean will be displayed on the linear 
scale plot only and the LLOQ will be included on all semi-logarithmic scale plots of UCB6114 
concentrations. 
Depending on the data, the UCB6114 concentration-time data may be subject to a population PK 
analysis using non-linear mixed effects modelling to characterize the disposition characteristics 
of UCB6114 in the current study. The influence of important variables such as body weight and 
ADA status on the population PK parameter estimates may be evaluated. These analyses will be 
described in a separate data analysis plan and reported separately. 
9.1.2 
Exploratory pharmacokinetic endpoints 
Where possible, key and other PK parameters will be derived by ICON PLC using 
noncompartmental analysis (NCA) performed using Phoenix WinNonlin® v8.0.0.3716 or higher 
(Certara L.P., Princeton, NJ, USA) and according to UCB’s Guideline on Performing NCA 
Analysis version 1.0 dated 15 Nov 2017. An assessment of dose-proportionality will also be 
performed.  
Key and other derived PK parameters are defined in Table 9-1. 
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Table 9-1: 
Pharmacokinetic Parameters 
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9.2 
Pharmacodynamics 
The following exploratory PD and biomarker endpoints will be obtained from blood and urine 
samples which will be analyzed at a number of external laboratory vendors: 
• Serum markers of bone turnover;  
• Urinary markers of bone turnover;  
• cGremlin-1; 
• Serum protein/proteomic analysis; 
• Transcriptomic analysis; 
• Genetic analysis; 
• CtDNA. 
The impact of UCB6114 on bone turnover will be explored using the serum and urinary markers 
provided by the analytical laboratory. These markers will be listed for the SS and summarized 
descriptively over time for the PDS by dose level (treatment group), as described for the clinical 
laboratory parameters in Section 8.3. For each marker of bone turnover, the mean (±standard 
deviation) value and the mean (±standard deviation) change from Baseline value will be plotted 
over scheduled visit with treatment group overlaid on the same plot. 
cGremlin-1 will be reported as concentration in blood by nominal (scheduled) assessment and 
dose level. Concentrations of cGremlin-1 will be listed for the SS and summarized for the PDS 
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using descriptive statistics by dose level (treatment group) and nominal (scheduled) sampling 
timepoints (n, arithmetic mean, standard deviation, median, minimum, maximum, geoMean, 
geoCV and 95% CI for the geoMean [assuming lognormally distributed data]). Changes from 
Baseline will also be summarized. Individual study participant cGremlin-1 concentration-time 
profiles will be displayed graphically in spaghetti plots and geoMean cGremlin-1 concentration 
and 95% CI will be plotted at each nominal (scheduled) timepoint with treatment group overlaid 
on the same plot. 
Serum protein/proteomic analysis, transcriptomic analysis, genetic analysis and the analysis of 
the test results from the blood samples taken for ctDNA will be performed and reported 
separately outside of the CSR. 
Hematoxylin and eosin (H & E) staining and immunohistochemistry (IHC) will be used to 
analyze any available historical tissue biopsy samples obtained prior to a participant’s entry into 
the study (e.g. at the time of diagnosis).  
Test results from the H & E staining and for target genes, phosphatase and tensin homolog 
(PTEN), Ki67 (cellular marker for proliferation in tumors), Gremlin-1, mothers against 
decapentaplegic homolog 4 (SMAD4) and fibroblast activation protein (FAP) will be listed by 
variable and sample analyzed (multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant) for the SS. No summaries of these data will be generated due to the 
expected small numbers of historical biopsy samples analyzed for each dose level (treatment 
group).   
The following key/component variables will be derived based on H & E staining, PTEN, Ki67, 
Gremlin-1 and FAP test results. No derived variables will be generated for SMAD4; only raw 
test results will be listed. Note that multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant and therefore multiple test results will be presented in the listings. 
H & E: Tissue Integrity (Percentage of Necrosis in Tumor Area) 
In order to assess tissue integrity, percentage of necrosis in the tumor area will be categorized as 
‘<20%’ and ‘>=20%’. If percentage of necrosis data are missing but other H & E staining and 
IHC data are available for a participant (i.e. the participant had historical tumor biopsy sample(s) 
analyzed), then the result will be categorized as ‘Not Done’.  
This categorical variable will be listed together with all other H & E test results. 
PTEN: Tissue Sample Quality Control 
The presence of staining of intrinsic control elements on the slides together with the level of 
staining intensity will be used to determine the tissue sample quality control. 
If staining of intrinsic control elements on stained slides=’YES’ and staining intensity of intrinsic 
control elements on stained slides is 1, 2 or 3 then the tissue sample quality control is ‘Good’, 
otherwise if the staining intensity of intrinsic control elements=0 then the tissue sample quality 
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control is ‘Questionable’. If staining of intrinsic control elements on stained slides=’NOT 
PRESENT’ then the tissue sample quality control is ‘No staining present’.  If both variables are 
missing but other IHC results are available (i.e. the participant had historical tumor biopsy 
sample(s) analyzed), then the result will be categorized as ‘Not done’.   
This categorical variable will be listed together with the presence/absence of staining of intrinsic 
control elements on the slides, the level of staining intensity, staining pattern, staining artifacts 
and any assay-specific comments. Since the percent of tumor cells with staining intensity 0/1/2/3 
and the H-score (test results for which will be provided by the laboratory) are less relevant to 
assessing the quality control of the tissue sample, these raw test results will not be listed. 
Ki67 – Proliferative Activity of the Tumor  
In order to assess the proliferative activity of the tumor mass, cellular proliferation reflected by 
the number of Ki67-positive cell objects in the tumor region divided by the total number of cell 
objects in the tumor region will be categorized as ‘<=10%’ or ‘>10%’ with the latter category 
indicating an actively/moderately proliferating tumor. If the test result is ‘NOT EVALUABLE’ 
or missing but IHC results are available (i.e. the participant had historical tumor biopsy 
sample(s) analyzed), then the result will be categorized as ‘Not done’.  
This categorical variable will be listed together with all other Ki67 raw test results. 
Gremlin-1: Cytoplasmic Histoscore 
The cytoplasmic histoscore will be calculated as a weighted score based on the percentage of 
tumor cells with Gremlin-1 cytoplasmic staining intensity 1, 2 or 3 as follows: 
(1 x percent tumor cells with Gremlin-1 cytoplasmic staining intensity 1) + (2 x percent tumor 
cells with Gremlin-1 cytoplasmic staining intensity 2) + (3 x percent tumor cells with Gremlin-1 
cytoplasmic staining intensity 3). 
The cytoplasmic histoscore will be missing if the participant had a historical biopsy tumor 
sample analyzed but there are no test results for percent tumor cells with Gremlin-1 cytoplasmic 
staining intensity 1, 2 or 3. 
The cytoplasmic histoscore will be listed together with all other Gremlin-1 raw test results. 
FAP 
From the image analysis of FAP-stained slides, the tumor will be classified into 2 regions: the 
cancer (CN) tumor region and the invasive margin (IM) region using a pre-established digital 
automated algorithm.  The IM region is usually a small proportion of the whole tumor and, per 
standard procedures at the analytical laboratory, will be identified first. As a result, there is a risk 
that some parts of the CN tumor region may be inaccurately classified as part of the IM region, 
particularly in cases when the tumor is small. Therefore, instead of using the results for the 
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percentage of high, medium and low intensity FAP provided by the laboratory, a decision was 
made to back-calculate the areas of the CN tumor region and the IM region and add these 
together in order to re-calculate the percentage of high, medium and low intensity FAP in the 
whole tumor. 
These back-calculated results and derived variables based on FAP test results are defined in 
Table 9-2. 
Table 9-2: 
FAP Derived Variables 
Variable No. FAP Derived Variable 
Description and Calculation 
1[a] 
Total Analyzed Tumor 
Area (um2) 
This is the total tumor area (um2) across the CN tumor region 
and the IM region and will be calculated as the sum of the 
areas of the CN tumor region (um2) and the IM region (um2) 
where a non-missing numeric test result is available for both 
the area of the CN tumor region and the area of the IM 
region. Note that, in cases where no IM region is defined, the 
area of the IM region will be recorded as 0 or ‘NOT 
APPLICABLE’, or may be missing.  If the area of the IM 
region is recorded as ‘NOT APPLICABLE’ or is missing, 
then 0 will be assumed in this calculation and the total 
analyzed tumor area will be equal to the area of the CN tumor 
region. 
This variable will be missing if both the areas of the CN 
tumor region and IM region are missing, or if one or both are 
‘NOT EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
2  
Measured Area of 
Weakly Stained FAP in 
the CN Tumor Region 
(um2)  
This is the back-calculated area of weakly stained FAP in the 
CN tumor region (weak positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of weakly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
weakly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
3  
Measured Area of 
Moderately Stained FAP 
in the CN Tumor Region 
(um2)  
This is the back-calculated area of moderately stained FAP in 
the CN tumor region (moderate positive) and will be 
calculated by multiplying the area of the CN tumor region 
(um2) and the relative area of moderately stained FAP in the 
CN tumor region (%) where a non-missing numeric test 
result is available for both the area of the CN tumor region 
and the relative area of moderately stained FAP in the CN 
tumor region. 
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Variable No. FAP Derived Variable 
Description and Calculation 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
4  
Measured Area of 
Strongly Stained FAP in 
the CN Tumor Region 
(um2)  
This is the back-calculated area of strongly stained FAP in 
the CN tumor region (strong positive) and will be calculated 
by multiplying the area of the CN tumor region (um2) and the 
relative area of strongly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
strongly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
5  
Measured Area of 
Weakly Stained FAP in 
the IM Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
IM region (weak FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative 
area of weakly stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area 
of the IM region and the relative area of weakly stained FAP 
in the IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
6  
Measured Area of 
Moderately Stained FAP 
in the IM Region (um2)  
This is the back-calculated area of moderately stained FAP in 
the IM region (moderate FAP-positive) and will be calculated 
by multiplying the area of the IM region (um2) and the 
relative area of moderately stained FAP in the IM region (%) 
where a non-missing numeric test result is available for both 
the area of the IM region and the relative area of moderately 
stained FAP in the IM region. 
This variable will be set to 0 if one or both are ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
7[a]  
Measured Area of 
Strongly Stained FAP in 
the IM Region (um2)  
This is the back-calculated area of strongly stained FAP in 
the IM region (strong FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative 
area of strongly stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area 
of the IM region and the relative area of strongly stained FAP 
in the IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
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Variable No. FAP Derived Variable 
Description and Calculation 
8[a] 
Total FAP-Positive 
Tumor Area (um2) 
This is the total FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be 
calculated as the sum of component derived variables 2-7. 
If all 6 component variables are 0 then this derived variable 
will be missing. 
9[a] 
Total Measured Area of 
Weakly Stained FAP 
(um2) 
This is the total weak FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 2 
and 5. 
10[a] 
Total Measured Area of 
Moderately Stained FAP 
(um2) 
This is the total moderate FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 3 
and 6. 
11[a] 
Total Measured Area of 
Strongly Stained FAP 
(um2) 
This is the total strong FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 4 
and 7. 
12[a] 
Total Relative Area of 
Weakly Stained FAP (%) 
This is the percentage of weak FAP expression across the CN 
tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 9 as   
(Total Measured Area Of Weakly Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
13[a] 
Total Relative Area of 
Moderately Stained FAP 
(%) 
This is the percentage of moderate FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 10 
as   
(Total Measured Area Of Moderately Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
14[a] 
Total Relative Area of 
Strongly Stained FAP 
(%) 
This is the percentage of strong FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 11 
as   
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Variable No. FAP Derived Variable 
Description and Calculation 
(Total Measured Area Of Strongly Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
15[a] 
Total Relative FAP-
Positive Tumor Area 
(TPS) (%) 
This is the total proportion score which is the percentage of 
FAP-positive area across the CN tumor region and the IM 
region (whole tumor) and will be calculated using component 
derived variables 1 and 8 as  
(Total FAP-Positive Tumor Area / Total Analyzed Tumor 
Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
16[a] 
Total FAP Histoscore 
This is a histoscore for the combined CN tumor region and 
IM region (whole tumor) and will be calculated as a weighted 
score based on component derived variables 12, 13 and 14 as  
(1 x Total Relative Area of Weakly Stained FAP) + (2 x 
Total Relative Area of Moderately Stained FAP) + (3 x Total 
Relative Area of Strongly Stained FAP) 
CN=cancer; FAP=fibroblast activation protein, IM=invasive margin, TPS=total proportion score. 
[a] Included in the listing of FAP test results. 
The derived variables containing the [a] flag in Table 9-2 above will be listed together with 
information on staining artifacts and any assay-specific comments provided by the laboratory. 
 
Further informal analyses may be performed to explore the relationship between the PD and 
biomarker endpoints with antitumor activity, ADA status, and also with key PK parameters. The 
PK-PD effects of UCB6114 may be assessed using a population analysis approach. These 
analyses will also be performed separately outside of the CSR and the details of analysis 
methods will be included in a separate analysis plan. 
The incidence of available historical tumor biopsies will be summarized by treatment group.  
The incidence of PD samples taken from blood and urine will be summarized by cycle and 
treatment group.  
9.3 
Immunogenicity 
Anti-drug (UCB6114) antibody status and classification, changes from Baseline in titer over time 
and the incidence of treatment-emergent ADA positivity are exploratory immunogenicity 
endpoints in Part A of this study. Potential relationships between ADA and PK, PD, antitumor 
activity and safety will also be explored but this will be reported separately outside of the CSR. 
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Serum samples will be collected from all study participants for the measurement of ADA and the 
evaluation of immunogenicity according to the Schedule of Activities in the protocol.  
All listings of ADA will be presented for the SS and summaries of the ADA data will be 
presented by treatment group for the ADAS. 
Anti-drug (UCB6114) antibodies will be measured using a three-tiered assay approach: 
Screening assay, confirmatory assay and titration assay.  
Samples will first be evaluated in the Screening assay using a false positivity rate of 5% 
(reported as ‘negative screen’ or ‘positive screen’), followed by analysis of screened positive 
samples in the confirmatory assay (which is a drug depletion assay) to confirm the positivity of 
the samples (reported as ‘negative immunodepletion’ or ‘positive immunodepletion’). Samples 
that are confirmed as positive in the confirmatory assay will be evaluated in a titration assay to 
assess the ADA level and this will be reported as titer (reciprocal dilution factor including 
minimum required dilution). 
Anti-drug (UCB6114) antibody sample status will be determined as follows from the pre-
treatment sample taken on Day 1 of Cycle 1 (Baseline) and all post-treatment (post-Baseline) 
samples.  
• Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
• Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
Anti-drug (UCB6114) antibody sample status will be listed for each participant at each visit by 
treatment group. This listing will include sampling dates and times, the Screening assay result, 
the confirmatory assay result and the derived ADA sample status. In addition, the titer from the 
titration assay (if applicable) will be listed together with the change from Baseline in titer. The 
number and percentage of participants with a positive or negative sample at each visit will be 
summarized by treatment group. Percentages will be calculated based on the number of 
participants with a non-missing/sufficient sample at the visit. 
Based on the ADA status of the samples, study participants will be categorized according to the 
following 6 ADA classifications in Table 9-3: 
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Table 9-3: 
ADA Classifications 
Classification Classification Label 
Definition 
1 
Pre-ADA negative – treatment 
induced ADA negative 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA negative status at all sampling 
timepoints post-Baseline (including SFU). 
Participants with missing post-Baseline samples are 
included as long as the missing samples do not 
result in an unmonitored period greater than 16 
weeks. 
2 
Pre-ADA negative – treatment 
induced ADA positive 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA positive status at any sampling 
timepoint post-Baseline (including SFU).  
3 
Pre-ADA positive – treatment 
reduced ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA negative status at all 
sampling timepoints post-Baseline (including SFU)  
4 
Pre-ADA positive – treatment 
unaffected ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with titer values of the same magnitude as Baseline 
(≤1.80-fold difference from the Baseline value) or 
with decreased titer values compared to Baseline 
(>1.80-fold decrease from the Baseline value). 
5 
Pre-ADA positive – treatment 
boosted ADA positive 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with increased titer values compared to Baseline 
(>1.80-fold increase from the Baseline value. 
6 
Inconclusive 
Includes participants who do not satisfy the criteria 
for classifications 1-5 
ADA=anti-drug (UCB6114) antibody; SFU=Safety Follow-up. 
Note: The terminology ‘treatment unaffected’ is ambiguous as the criteria refers to ADA responses that are not increased upon 
dosing compared to Baseline level whereas titers may reduce. 
A study participant will be classified as having treatment-emergent ADA positivity if they 
satisfy one of the following criteria: 
• The Baseline result is ADA negative and at least one post-Baseline result is ADA 
positive (pre-ADA negative – treatment induced ADA positive) – ADA classification 2 in 
Table 9-3; 
• The Baseline result is ADA positive and at least one post-Baseline result shows a pre-
defined fold increase in titer from the Baseline value (the fold increase from Baseline 
required to meet this criterion will be defined with the development of the assay and will 
be included in the TFLs) (pre-ADA positive – treatment boosted ADA positive) – ADA 
classification 5 in Table 9-3. 
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Total anti-drug (UCB6114) antibody incidence will be determined by the number and 
percentage of participants with treatment-emergent ADA positivity (as defined above). The 
denominator for the percentage calculation will be the number of participants with at least one 
available/reported post-Baseline result. 
Total prevalence of pre-anti-drug (UCB6114) antibody will be determined by the number and 
percentage of participants who are pre-ADA positive (i.e. participants who have a positive ADA 
status at Baseline). The denominator for the percentage calculation will be the number of 
participants with an available/reported Baseline sample result. 
Total anti-drug (UCB6114) antibody prevalence will be determined by the number and 
percentage of participants with ADA classifications 2, 4 and 5 in Table 9-3 (i.e. an ADA positive 
status at any post-Baseline sampling timepoint. The denominator for the percentage calculation 
will be the number of participants with at least one available/reported sample result (either at 
Baseline and/or post-Baseline). 
The ADA classification for each participant will be listed by treatment group. This listing will 
also include whether or not the participant achieved treatment-emergent ADA positivity (ADA 
incidence), whether the participant was pre-ADA positive (pre-ADA prevalence) and whether 
the participant had an ADA positive status at any post-Baseline sampling timepoint (ADA 
prevalence). In addition, the visit at which the participant first achieved treatment-emergent 
ADA positivity will be included.  
The number and percentage of participants in each of the 6 ADA classifications defined above in 
Table 9-3 will be presented by treatment group. Also, in this tabulation, ADA incidence and 
prevalence (as defined above) will be summarized. 
The first occurrence of treatment-emergent ADA positivity (based on the criteria above) will be 
summarized using frequency counts and percentages at each post-Baseline visit by treatment 
group. This tabulation will include a count of the number of participants at each post-Baseline 
visit who fulfill at least one of the above defined criteria for treatment-emergent ADA positivity; 
participants will be counted in the numerator based on the earliest visit at which one of these 
criteria is fulfilled. At other visits, participants will be counted in the denominator (assuming an 
assessment of treatment-emergent positivity is available) and this will be used in the percentage 
calculations. 
Individual study participant ADA titer profiles over actual time will be presented graphically on 
the linear and the semi-logarithmic scale. The linear scale plots will be repeated for the subset of 
participants who achieve treatment-emergent ADA positivity during Part A.  
Mean (±standard deviation) Cmin will be plotted by ADA sample status over scheduled time with 
treatment groups overlaid on the same plot. 
 
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10 
EFFICACY ANALYSES 
10.1 
Antitumor activity 
The analysis of antitumor activity is exploratory in Part A of this study. 
10.1.1 
Definitions of the antitumor activity endpoints 
The following endpoints are defined based on RECIST (Version 1.1) which standardizes solid 
tumor measurements and provides guidelines for the objective assessment of changes in tumor 
size during anti-cancer treatment.  
Appendix 9 (Section 11.9) of the protocol contains the RECIST 1.1 guidelines to be used in this 
study, adapted from Eisenhauer (2009), and includes the definitions of target and non-target 
lesions, the definitions of target and non-target lesion responses at each tumor assessment, the 
criteria for determining overall tumor response at each tumor assessment based on target lesion 
response, non-target lesion response and the presence/absence of new lesions, and a participant’s 
best overall response (BOR).   
At each post-Baseline tumor assessment, the investigator will record responses for target lesions 
and non-target lesions, whether or not there has been an appearance of any new lesions, and the 
participant’s overall tumor response based on their target lesion response, non-target lesion 
response and the presence/absence of new lesions. Note that target lesion response and non-
target lesion response assessments will be based on the changes in the pre-existing lesions at 
Baseline and the appearance of new lesions will only factor in the determination of an overall 
tumor response of PD at that tumor assessment visit (i.e. per Tables A and B in Section 11.9.2 of 
Appendix 9 of the protocol). 
Objective response rate (ORR) is defined as the percentage of participants with a BOR of 
complete response (CR) or partial response (PR) during Part A.  
Disease Control Rate (DCR) is defined as the percentage of participants with a BOR of CR, 
PR, or stable disease (SD) during Part A.  
Best overall response (BOR) is defined for each study participant as the best overall tumor 
response from each tumor assessment (scheduled and unscheduled assessments performed 
between Days 21 and 28 of every even cycle of study treatment) according to the RECIST 
criteria for changes in target and non-target lesions and the appearance of new lesions. Best 
overall response is determined from the start of study treatment until documented objective 
disease progression or the date of subsequent anti-cancer therapy (systemic therapy, surgery or 
radiotherapy for cancer), whichever occurs first. If anti-cancer therapy is started on the same day 
as a tumor assessment, then the overall response from that assessment will be used in the 
derivation of BOR. For a BOR of SD, a participant’s tumor measurements must have met the SD 
criteria at least once after the start of study treatment at a minimum interval of no less than 6–8 
weeks (42-56 days).  
For Part A of this study, BOR determination requires confirmation of CR or PR responses at a 
subsequent assessment ≥4 weeks (28 days) after the criteria for CR or PR responses are first met. 
In addition, Table C in Appendix 10.9 of the protocol provides the derivation of BOR when 
confirmation of CR and PR responses are required. Confirmed BOR and unconfirmed BOR will 
be derived programmatically based on the overall tumor assessment data recorded on the eCRF 
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by the investigator and using the detailed guidance included in the Derivation of Efficacy 
Endpoints document Version 0.6 (dated 21 January 2022). 
Duration of response (DOR) will be calculated for participants with a confirmed BOR of CR or 
PR as the time in days from the start date of the confirmed CR or PR to the first date that 
recurrent or progressive disease is objectively documented (i.e. according to the RECIST 
guidelines). This will be referred to as the duration of confirmed response and the following 
calculation will be performed: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
Duration of response will also be calculated for participants with an unconfirmed BOR of CR or 
PR (which may either be confirmed at a later tumor assessment or unconfirmed) as the time in 
days from the start date of the CR or PR to the date of the first documented objective disease 
progression (i.e. according to the RECIST guidelines). The following calculation will be 
performed: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For the purpose of a sensitivity analysis of both duration of confirmed response and duration of 
unconfirmed response, the above calculations will take into consideration the occurrence of both 
objective disease progression (per RECIST 1.1) and clinical disease progression (as described in 
Appendix 11.9 of the protocol and as determined by the investigator and recorded as a reason for 
study treatment discontinuation on the eCRF), whichever occurs first.  If clinical disease 
progression occurs on the same date that a participant’s objective disease progression is 
determined, then the participant will be included in the sensitivity analyses as having objective 
disease progression. 
The following calculations will therefore be performed for the sensitivity analyses: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For participants who die without objective disease progression, duration of confirmed response 
and duration of unconfirmed response will be censored on the date of death, regardless of cause. 
For a participant who discontinues early from Part A of the study with no objective disease 
progression, duration of confirmed response and duration of unconfirmed response will be 
censored on the date of their last available (scheduled or unscheduled) tumor assessment at 
which a lack of objective disease progression was determined. Participants who discontinue 
study treatment but who do not have documented objective disease progression (i.e. according to 
the RECIST guidelines), duration of confirmed response and duration of unconfirmed response 
will be censored at the date of their last available (scheduled or unscheduled) tumor assessment 
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at which a lack of objective disease progression was determined. Such participants might include 
those that are ongoing in Part A at the time of any defined data cut-off.  
In the sensitivity analyses of duration of confirmed response and duration of unconfirmed 
response, the same censoring rules will apply except that the date of last contact will be used for 
the censoring of participants who discontinue early from Part A, complete Part A of the study or 
are ongoing in the study at a data cut-off for Part A without objective disease progression, 
clinical disease progression or death.  
Date of last contact will be the latest of the dates of premature study termination and of last 
contact recorded on Study Termination eCRF page, the date of death, the date of last dose of 
study treatment, the dates of all visits, AE start and end dates (with partial dates imputed as 
earliest possible) and the date of contact recorded on the Survival Safety Follow-up and Survival 
Final Follow-up eCRF forms. 
Further details on the derivation of duration of confirmed response and duration of unconfirmed 
response are included in the Derivation of Efficacy Endpoints document Version 0.6 (dated 21 
January 2022). 
Progression-free survival (PFS) will be calculated as the time in days from the first dose of 
study treatment to the date of the first documented objective disease progression (i.e. according 
to the RECIST guidelines), or death due to any cause, whichever occurs first. The following 
calculation will be performed: 
𝑃𝐹𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒/𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒) + 1  
Participants who die due to any cause without a documented objective disease progression will 
be considered to have progressed on the date of their death. Participants who do not have any 
post-Baseline tumor assessments will be censored on the date of their first dose of study 
treatment. Participants who discontinue early from Part A or discontinue study treatment without 
documented objective disease progression or death, will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who start anti-cancer therapy during Part A without a 
prior documented objective disease progression will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment prior to the initiation of the subsequent 
anti-cancer therapy. If anti-cancer therapy starts on the same date as the participant’s tumor 
assessment and determination of objective disease progression, or the participant’s death (due to 
any cause), then the participant will not be censored and the participant will be included as 
having an uncensored event on this date. This censoring rule will also be applied to participants 
who are ongoing at any data cut-off for an analysis of Part A data who have no documented 
objective disease progression. The use of anti-cancer therapy during Part A will be identified via 
ongoing medical review of the concomitant medications together with the start dates of further 
anti-cancer therapy information recorded on the survival follow-up pages of the eCRF. 
As a sensitivity analysis, PFS will also be  calculated as the time in days from the first dose of 
study treatment to the date of the first documented objective disease progression (per RECIST 
1.1), the date of clinical disease progression, as determined by the investigator, or the date of 
death due to any cause, whichever occurs first. Last contact date (as defined above for DOR) will 
be used for the censoring of participants still alive with no reported disease progression 
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(objective or clinical). The same rules described above for the censoring of participants who start 
anti-cancer therapy will be applied in this sensitivity analysis. 
Further details on the derivation of PFS are included in the Derivation of Efficacy Endpoints 
document Version 0.6 (dated 21 January 2022). 
Overall survival (OS) will be calculated as the time in days from the date of first dose of study 
treatment to the date of death from any cause. Participants will be followed up to ascertain their 
survival status at the SFU visit (within 30 days after their last dose of study treatment) and at the 
Final Visit (3 months after their last dose of study treatment); they will not be followed up 
beyond this timepoint. 
The following calculation will be performed: 
𝑂𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝑆𝑡𝑢𝑑𝑦 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡) + 1 
For participants who discontinue early from Part A of the study or who discontinue study 
treatment due to disease progression but continue in the study, who complete the Part A, or who 
are ongoing in the study at a data cut-off for Part A, but are not known to have died, OS will be 
censored on the date of their last contact.  
10.1.2 
Analysis of the antitumor activity endpoints 
The analyses of the antitumor activity endpoints in Part A will be performed for the PPS. As a 
sensitivity analysis, all analyses will be repeated for the SS. All listings will be presented for the 
SS. Summaries and listings will be presented by treatment group. 
All lesion assessment data recorded at Baseline and during the Treatment Period (during every 
even cycle of study treatment) will be listed separately for target lesions, non-target lesions and 
new lesions. These listings will include lesion number and lesion type (nodal/non-nodal), 
location, method of assessment, dimension (or an indication that the lesion is too small to 
measure, for target lesions only) and lesion response evaluation (for non-target lesions at post-
Baseline assessments). The listing for target lesions will also include the derived eCRF 
component data used for the determination of the overall target lesion response at each post-
Baseline assessment (e.g. sum of all dimensions across target lesions and percentage change 
from Baseline in the sum). In addition, the overall response assessment for target lesions and 
non-target lesions, as determined by the investigator, will be listed together with the presence of 
new lesions and the investigator’s overall tumor response assessment.  
The investigator’s overall tumor response assessment will be summarized using frequency 
counts and percentages by visit (tumor assessment). For the purpose of this summary, post-
Baseline tumor assessments (scheduled or unscheduled but excluding tumor assessments 
performed at the SFU visit) will be assigned to the targeted Day 22 visit of each even cycle of 
study treatment using the protocol-defined window of Day 21 to 28 (±2 days).  For participants 
who receive 2 or more cycles of study treatment, post-Baseline tumor assessments that were 
performed on Day 19 to Day 30 relative to Day 1 of each even cycle will be included as Cycle 
2/4/6/8 etc. Day 22 assessments. For participants who discontinue study treatment prior to the 
start of Cycle 2, post-Baseline tumor assessments that were performed on Day 47 to 58 relative 
to Day 1 of Cycle 1 will be included as a Cycle 2 Day 22 assessment.  Otherwise, the tumor 
assessment will be classified as an unscheduled assessment and not included in the summary of 
overall tumor response. 
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Bar charts will also be produced for overall tumor response rate by treatment group for each 
visit. In addition, waterfall plots of participants’ percentage change from Baseline in the sum of 
dimensions for all target lesions will be presented by treatment group and visit. The individual 
participants’ bars will be colored by overall tumor response at the visit. 
Confirmed BOR and unconfirmed BOR for each participant will be derived programmatically 
using the investigator’s overall tumor response assessments (scheduled and unscheduled) 
performed between Days 21 and 28 of Cycle 2 and each subsequent even cycle of study 
treatment and the RECIST criteria. Whether a BOR of CR or PR is confirmed or unconfirmed 
will be indicated on this listing. Using a participant’s confirmed BOR and unconfirmed BOR, 
whether the participant achieves an objective tumor response (i.e. a BOR of CR or PR) and/or 
disease control (i.e. a BOR of CR, PR or SD) during study treatment will be determined based on 
both confirmed BOR and unconfirmed BOR. These derived data will be listed for the SS. 
Confirmed BOR and unconfirmed BOR will be summarized using frequency counts and 
percentages. Bar charts will also be produced for confirmed BOR and unconfirmed BOR by 
treatment group.  
The number and percentage of participants achieving objective tumor response and disease 
control (ORR and DCR) based on confirmed BOR and unconfirmed BOR will be presented and, 
if data allow, exact 95% confidence intervals for binomial proportions will be calculated using 
the Clopper-Pearson method and presented for the response rates. In the calculation of ORR and 
DCR, the denominator will include all participants in the analysis set. Objective response rate 
and DCR (based on confirmed BOR and unconfirmed BOR) will also be summarized in bar 
charts by treatment group overall and by tumor type and ECOG performance status at Baseline. 
In addition, waterfall plots of each participant’s best percentage change from Baseline in the sum 
of the dimensions for all target lesions will be presented by treatment group overall and by tumor 
type and ECOG performance status at Baseline with the individual participants’ bars colored by 
confirmed BOR and unconfirmed BOR. 
 
The summaries and analyses of DOR, PFS and OS will be carried out as described below, if the 
data allow. 
Duration of confirmed response, duration of unconfirmed response and PFS will be listed and 
summarized descriptively using Kaplan-Meier estimation. These summaries will be repeated for 
the sensitivity analyses of these endpoints (defined in Section 10.1.1 above) and will include the 
number and percentage of participants with the event, the number and percentage of participants 
censored, minimum and maximum values and Kaplan-Meier estimates of the 25th percentile, 
median, 75th percentile and corresponding 95% CIs calculated using Greenwood’s formula. In 
addition, DOR and PFS rates at specific timepoints (3 months, 6 months, 9 months) will be 
derived from the Kaplan-Meier estimation and presented together with associated 95% CIs. 
Kaplan-Meier curves will be presented for duration of confirmed response, duration of 
unconfirmed response and PFS, and for the associated sensitivity analyses. Treatment groups 
will be overlaid on each plot.  
Survival status collected on the eCRF at the SFU visit and at the Final Visit will be listed for 
each participant by treatment group. This listing will include the participant’s survival status, 
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date and cause of death, whether an autopsy was performed and date of autopsy, whether the 
participant had received any further antitumor treatment after the last dose of study treatment and 
the type of treatment, and whether the participant’s disease had been assessed since the end of 
study treatment including method of assessment and the overall response.  
Overall survival times will be listed and summarized descriptively using Kaplan-Meier 
estimation. Note that since participants are only followed up for survival until the Final Visit in 
Part A of the study, a summary of OS may not be meaningful (i.e. if no participants die then OS 
cannot be assessed).  
Additional exploratory analyses of selected antitumor activity endpoints may be performed based 
on subgroups of participants in the SS.  
Additionally, the relationship of the antitumor activity variables with key PK parameters may be 
explored but this will be reported separately. 
10.2 
ECOG performance status 
ECOG performance status is an additional efficacy assessment performed in Part A of this study 
and is defined in Table 10-1. 
Table 10-1: ECOG Performance Status Scale 
Grade 
ECOG performance status scale 
0 
Fully active, able to carry on all pre-disease performance 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 for more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group. 
ECOG performance status will be listed by treatment group at each visit together with changes 
from Baseline for the SS. 
ECOG performance status will be summarized as an ordinal categorical variable using frequency 
counts and percentages. Shift tables for the change from Baseline in each grade will be 
summarized by visit. 
 
11 
OTHER ANALYSES  
Not applicable. 
 
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12 
REFERENCES 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-center 
clinical trials. Drug Information Journal. Vol 26, 77-84, 1992. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
European Medicines Agency, Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronavirus) Pandemic, accessed 29-March-2020.  
(https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf) 
International Council for Harmonization/Food and Drug Administration E9 Guidance (ICH-E9) 
(Phillips et al, 2003). 
US Food and Drug Administration FDA Guidance on Conduct of Clinical Trials of Medical 
Products During COVID-19 Public Health Emergency Guidance for Industry, Investigators and 
Institutional Review Boards, accessed 29-March-2020. 
(https://www.fda.gov/media/136238/download) 
 
13 
APPENDICES 
13.1 
SMQ algorithm for identification of anaphylactic reactions 
Based on MedDRA Version 25.1, the SMQ=‘Anaphylactic reaction’ consists of 3 parts: 
1) A narrow search containing PTs that represent core anaphylactic reaction terms:  
Category A 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Circulatory collapse 
Dialysis membrane reaction 
Kounis syndrome 
Procedural shock 
Shock 
Shock symptom 
Type I hypersensitivity 
2) A broad search:  
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Category B 
Acute respiratory failure 
Asthma 
Bronchial oedema 
Bronchospasm 
Cardio-respiratory distress 
Chest discomfort 
Choking 
Choking sensation 
Circumoral oedema 
Cough 
Cough variant asthma 
Cyanosis 
Dyspnoea 
Hyperventilation 
Irregular breathing 
Laryngeal dyspnoea 
Laryngeal oedema 
Laryngospasm 
Laryngotracheal oedema  
Mouth swelling 
Nasal obstruction 
Oedema mouth 
Oropharyngeal oedema 
Oropharyngeal spasm 
Oropharyngeal swelling 
Pharyngeal oedema 
Pharyngeal swelling 
Respiratory arrest 
Respiratory distress 
Respiratory failure 
Reversible airways obstruction 
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Sensation of foreign body 
Sneezing 
Stridor 
Swollen tongue 
Tachypnoea 
Throat tightness 
Tongue oedema  
Tracheal obstruction 
Tracheal oedema 
Upper airway obstruction 
Vaccine associated enhanced respiratory disease 
Wheezing 
Category C 
Allergic oedema 
Angioedema 
Circumoral swelling 
Erythema 
Eye oedema 
Eye pruritis 
Eye swelling 
Eyelid oedema 
Face oedema 
Flushing 
Injection site urticaria 
Lip oedema 
Lip swelling 
Nodular rash 
Ocular hyperaemia 
Oedema 
Oedema blister 
Periorbital oedema 
Periorbital swelling 
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Pruritis 
Pruritis allergic 
Rash 
Rash erythematous 
Rash pruritic 
Skin swelling 
Swelling 
Swelling face 
Swelling of eyelid 
Urticaria 
Urticaria papular 
Category D 
Blood pressure decreased 
Blood pressure diastolic decreased  
Blood pressure systolic decreased 
Cardiac arrest 
Cardio-respiratory arrest 
Cardiovascular insufficiency 
Diastolic hypotension 
Hypotension 
Hypotensive crisis 
Post procedural hypotension 
 
Note that if the MedDRA version is increased from 25.1 during the study, any changes to the 
terms in the above categories should be applied. 
 
The following algorithmic approach will be applied: A or (B and C) or [D and (B or C)], i.e.  
If a participant has a TEAE which codes to a PT included in Category A, then the event will be 
flagged as an anaphylactic reaction. Note that participants with a TEAE coded to a PT=’Type 1 
hypersensitivity’ will also be flagged as having a hypersensitivity reaction as this PT is also 
included in the Category A narrow search for the ‘Hypersensitivity’ SMQ. 
OR 
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If a participant has a TEAE which codes to a PT included in Category B AND has a TEAE 
which codes to a PT included in Category C, and both TEAEs have the same start date, then 
both events will be flagged as anaphylactic reactions. 
OR 
If a participant has a TEAE which codes to a PT included in Category D AND has (either a 
TEAE which codes to a PT included in Category B OR a TEAE which codes to a PT included in 
Category C), and both TEAEs have the same start date, then both events will be flagged as 
anaphylactic reactions. 
13.2 
SAP Amendment 4 changes 
The main rationale for SAP Amendment 4 is to include details on the additional key derived and 
component exploratory variables required based on the results from the analyses of historical 
tumor biopsy samples in Part A. It was decided that these additional variables were needed to 
improve the interpretability of the test results received from the laboratory. Note that there have 
not been any tumor biopsies performed at Screening or at Cycle 1 Day 22 in Part A. Per protocol, 
these tumor biopsies are optional in Part A and only samples available from historical tumor 
biopsies have been sent to the laboratory and analyzed to date. This SAP amendment also 
provides some clarifications relating to the handling of data for the purpose of summarizing 
safety and exploratory anti-tumor activity endpoints. 
The key changes are summarized in the table below (note that additional minor corrections and 
clarifications were also applied in this amendment but are not included in this table). 
 
Section  
Description of Change 
1 
The versions and dates of supporting study documentation were 
updated. 
3.5.7 
The definition of the DLT Evaluable Set (DES) was included in 
this section consistent with the latest version of the protocol. 
5.1 
An update was made to the example illustrating the definition of a 
complete cycle of UCB6114. 
8.1 
The additional summary of the total number of doses of study 
treatment received was included. 
8.2 
Rules for handling missing relationship to study treatment for an 
adverse event were updated. 
8.4.2 
Clarification on the handling of triplicate ECG measurements was 
included. 
9.2 
Details on the analysis of the historical tumor biopsy samples was 
included together with rules for defining key and component 
derived variables based on the test results received from the 
laboratory. These variables were considered important for clearer 
interpretation of these results from data listings. 
9.3 
A predefined fold-increase of 1.80 was included. 
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Section  
Description of Change 
10.1.2 
Rules for applying the protocol-defined window around the post-
Baseline tumor assessments (scheduled and unscheduled) for the 
purpose of summarizing the investigator’s overall tumor response 
assessment were included. 
General 
MedDRA® version number was updated to the latest version (25.1) 
throughout the document. 
 
 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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STATISTICAL ANALYSIS PLAN 
PART A1  
DOSE OPTIMIZATION (MONOTHERAPY) 
Study: ONC001 
Product: UCB6114 
A PHASE 1/2 OPEN-LABEL, MULTICENTER STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND 
ANTITUMOR ACTIVITY OF UCB6114 ADMINISTERED 
INTRAVENOUSLY TO PARTICIPANTS WITH ADVANCED 
SOLID TUMORS 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
SAP/Amendment Number Date 
Amendment 1 
25 July 2023 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 9 
2 
PROTOCOL SUMMARY ................................................................................................. 9 
2.1 
Study objectives ....................................................................................................... 9 
2.1.1 
Primary objective ........................................................................................... 9 
2.1.2 
Secondary objective ..................................................................................... 10 
2.1.3 
Exploratory/Tertiary objectives ................................................................... 10 
2.2 
Study endpoints ...................................................................................................... 10 
2.2.1 
Safety endpoints ........................................................................................... 10 
2.2.1.1  
Primary safety endpoints .................................................................... 10 
2.2.1.2  
Other safety endpoints ....................................................................... 10 
2.2.2 
Pharmacokinetic and pharmacodynamic endpoints ..................................... 10 
2.2.2.1  
Secondary pharmacokinetic endpoint ................................................ 10 
2.2.2.2  
Exploratory pharmacokinetic endpoints ............................................ 10 
2.2.2.3  
Exploratory pharmacodynamic endpoints ......................................... 11 
2.2.2.4  
Exploratory immunogenicity endpoints ............................................. 11 
2.2.3 
Efficacy endpoints ....................................................................................... 11 
2.2.3.1  
Exploratory antitumor activity endpoints .......................................... 11 
2.2.3.2  
Other exploratory efficacy endpoint .................................................. 11 
2.3 
Study design and conduct ...................................................................................... 11 
2.4 
Determination of sample size ................................................................................. 13 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 14 
3.1 
General presentation of summaries and analyses .................................................. 14 
3.2 
General study level definitions .............................................................................. 16 
3.2.1 
Relative day and time .................................................................................. 16 
3.2.2 
Study periods ............................................................................................... 17 
3.2.3 
Visits ............................................................................................................ 17 
3.3 
Definition of Baseline values ................................................................................. 18 
3.4 
Protocol deviations................................................................................................. 18 
3.5 
Analysis sets........................................................................................................... 19 
3.5.1 
Enrolled Set (ES) ......................................................................................... 19 
3.5.2 
Safety Analysis Set (SS) .............................................................................. 19 
3.5.3 
Per-protocol Set (PPS) ................................................................................. 19 
3.5.4 
Pharmacokinetic Set (PKS) ......................................................................... 19 
3.5.5 
Anti-drug Antibody Set (ADAS) ................................................................. 20 
3.5.6 
Pharmacodynamic Set (PDS) ....................................................................... 20 
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3.5.7 
DLT Evaluable Set (DES) ........................................................................... 20 
3.6 
Treatment assignment and treatment groups ......................................................... 20 
3.7 
Center pooling strategy .......................................................................................... 21 
3.8 
Coding dictionaries ................................................................................................ 21 
3.9 
Changes to protocol-defined analyses ................................................................... 21 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 21 
4.1 
Adjustments for covariates .................................................................................... 21 
4.2 
Handling of dropouts or missing data .................................................................... 21 
4.3 
Pharmacokinetics and pharmacodynamics ............................................................ 21 
4.4 
Safety laboratory data ............................................................................................ 22 
4.4.1 
Dates and times ............................................................................................ 22 
4.4.2 
Impact of COVID-19 ................................................................................... 24 
4.5 
Handling of repeated and unscheduled measurements .......................................... 24 
4.6 
Handling of measurements obtained for early withdrawals .................................. 25 
4.7 
Interim analyses and data monitoring .................................................................... 25 
4.8 
Multicenter studies ................................................................................................. 25 
4.9 
Multiple comparisons/multiplicity ......................................................................... 25 
4.10 
Use of an efficacy subset of participants ............................................................... 25 
4.11 
Active-control studies intended to show equivalence ............................................ 25 
4.12 
Examination of subgroups ..................................................................................... 26 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 26 
5.1 
Study participant disposition.................................................................................. 26 
5.2 
Protocol deviations................................................................................................. 28 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 28 
6.1 
Demographics ........................................................................................................ 28 
6.2 
Cancer history ........................................................................................................ 29 
6.3 
Prior anti-cancer therapy ........................................................................................ 29 
6.4 
Cancer status at Screening ..................................................................................... 31 
6.5 
Medical history and concomitant diseases ............................................................. 31 
6.6 
Prior and concomitant medications ........................................................................ 32 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 33 
8 
SAFETY ANALYSES ..................................................................................................... 33 
8.1 
Extent of exposure ................................................................................................. 33 
8.2 
Adverse events ....................................................................................................... 34 
8.2.1 
Adverse events of special interest ................................................................ 37 
8.2.2 
Infusion-related reactions ............................................................................ 38 
8.3 
Clinical laboratory evaluations .............................................................................. 38 
8.4 
Vital signs, physical findings, and other observations related to safety ................ 41 
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8.4.1 
Vital signs .................................................................................................... 41 
8.4.2 
12-Lead Electrocardiograms ........................................................................ 42 
8.4.3 
Echocardiogram ........................................................................................... 44 
8.4.4 
ECOG performance status ........................................................................... 44 
8.4.5 
Physical examination ................................................................................... 44 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 45 
9.1 
Pharmacokinetics ................................................................................................... 45 
9.1.1 
Secondary pharmacokinetic endpoint .......................................................... 45 
9.1.2 
Exploratory pharmacokinetic endpoints ...................................................... 45 
9.2 
Pharmacodynamics ................................................................................................ 46 
9.3 
Immunogenicity ..................................................................................................... 54 
10 EFFICACY ANALYSES ................................................................................................ 56 
10.1 
Antitumor activity .................................................................................................. 56 
10.1.1 
Definitions of the antitumor activity endpoints ........................................... 57 
10.1.2 
Analysis of the antitumor activity endpoints ............................................... 60 
10.2 
ECOG performance status ..................................................................................... 63 
11 OTHER ANALYSES ...................................................................................................... 63 
12 REFERENCES ................................................................................................................ 63 
13 APPENDICES ................................................................................................................. 64 
13.1 
SMQ algorithm for identification of anaphylactic reactions ................................. 64 
13.2 
SAP Amendment 1 changes................................................................................... 66 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 68 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ADA 
anti-drug (UCB6114) antibody 
ADaM 
Analysis Data Model 
ADAS 
anti-drug antibody set 
ALP 
alkaline phosphatase 
ALQ 
above limit of quantification 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BLQ 
below limit of quantification 
BMI 
body mass index 
BOR 
best overall response 
CA 
cancer 
CDISC 
Clinical Data Interchange Standards Consortium 
CDMS 
clinical data management system 
cGremlin-1 
circulating gremlin-1 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019   
CPPC 
CDMS postproduction change 
CR 
complete response 
CS 
clinically significant 
CRC 
colorectal adenocarcinoma  
CRO 
contract research organization 
CSR 
clinical study report 
ctDNA 
circulating tumor deoxyribonucleic acid 
CTMS 
clinical trial management system 
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DCR 
disease control rate 
DEM 
data evaluation meeting 
DES 
DLT evaluable set 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ES 
enrolled set 
EudraCT 
FAP 
European Union Drug Regulating Authorities Clinical Trials 
fibroblast activation protein 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEJ  
gastroesophageal junction 
geoCV 
geometric coefficient of variation 
geoMean 
geometric mean 
H & E 
hematoxylin and eosin 
hh:mm 
hours:minutes 
HLT 
high level term 
ICH 
International Council for Harmonization 
IHC 
immunohistochemistry 
IM 
invasive margin 
iv 
intravenous 
IPD 
important protocol deviations 
LLOQ 
lower limit of quantification 
LLT 
lowest level term 
LoT 
list of TFLs 
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LVEF 
left ventricular ejection fraction 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRD 
minimum required dilution 
n 
number of study participants 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for AEs  
NC 
not calculable 
NCS 
not clinically significant  
NEst 
not estimable 
NV 
no value 
ORR 
objective tumor response rate 
OS 
overall survival 
PCS 
potentially clinically significant 
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PDS 
pharmacodynamic set 
PK 
pharmacokinetic(s) 
PKS 
pharmacokinetic set 
PFS 
progression-free survival 
PPS 
pSMAD1/5/8 
per-protocol set 
phosphorylated mothers against decapentaplegic homolog 1/5/8 
PR 
partial response 
PT 
PTEN 
preferred term 
phosphatase and tensin homolog 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
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SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SDTM 
Study Data Tabulation Model 
SFU 
safety follow-up 
SI 
SMAD4 
International System of Units 
mothers against decapentaplegic homolog 4 
SMC 
Safety Monitoring Committee 
SoC 
standard of care 
SOC 
system organ class 
SS 
safety analysis set 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
TFL 
Table, Figure and Listing 
TNM 
TNM Classification of Malignant Tumors  
TPS 
tumor proportion score 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 
 
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1 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of the dose optimization module (Part A1) of study 
ONC001. Separate SAPs are available for the other parts of the study. This SAP also describes 
the summary tables, figures and listings (TFLs) to be generated for Part A1 according to  
Protocol amendment 6, dated 26 JUN 2023,  
Electronic case report form (eCRF) (Clinical Data Management System [CDMS] 
postproduction change [CPPC] #14, Version 23.0, dated 14 APR 2023),  
UCB’s standards for TFL shells Version 2023Q1, 
Part A TFL shells Final Version 2.4, dated 4 JUL 2023,  
Part A1 TFL shells Final Version 2.0, dated 25 JUL 2023, 
Part A, A1, B, C List of TFLs (LoT) Draft Version 1.1, dated 13 MAR 2023, 
ONC001 Derivation of Efficacy Endpoints Version 0.6, dated 21 JAN 2022. 
Unless specified in the sections below, Part A1 of the study will be analyzed as described in the 
most recent version of the protocol. If a future protocol amendment necessitates a substantial 
change to the analysis of the Part A1 study data, this SAP will be amended accordingly. In 
addition, if the methodology for the analysis of key study endpoints must be modified or updated 
prior to the final database lock for Part A1 of this study, a SAP amendment will be required. 
Protocol amendments that do not affect the statistical analysis will not necessitate an amendment 
to the SAP. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the clinical study report (CSR) 
together with the associated rationale.  
Note that there may be a number of data cut-offs defined prior to the final database lock for Part 
A1 due to the regulatory safety reporting requirements for this study.  
The content of this SAP is compatible with the International Council for Harmonization 
(ICH)/Food and Drug Administration (FDA) E9 Guidance. 
UCB is the Sponsor and ICON PLC is the contract research organization (CRO) for this study. 
 
2 PROTOCOL SUMMARY 
2.1 Study objectives 
2.1.1 
Primary objective 
The primary objective of Part A1 (dose optimization module) of this study is to characterize the 
safety profile of UCB6114 administered as monotherapy in study participants with unresectable 
locally advanced or metastatic colorectal adenocarcinoma, gastric adenocarcinoma, 
adenocarcinoma of the gastroesophageal junction, or pancreatic adenocarcinoma. 
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2.1.2 
 Secondary objective 
The secondary objective of Part A1 of this study is to characterize the pharmacokinetics (PK) of 
UCB6114 administered as monotherapy in study participants with unresectable locally advanced 
or metastatic colorectal adenocarcinoma, gastric adenocarcinoma, adenocarcinoma of the 
gastroesophageal junction, or pancreatic adenocarcinoma. 
2.1.3 
Exploratory/Tertiary objectives 
The exploratory/tertiary objectives of Part A1 of this study are: 
• To document any antitumor activity observed with UCB6114 administered according to 
relevant Response Evaluation Criteria in Solid Tumors (RECIST) criteria; 
• To explore pharmacodynamics (PD) biomarkers of UCB6114; 
• To evaluate the incidence, emergence, and impact of anti-drug (UCB6114) antibody 
(ADA) activity. 
2.2 Study endpoints 
2.2.1 
Safety endpoints 
2.2.1.1  
Primary safety endpoints 
The primary endpoints for Part A1 of this study are for safety, specifically the incidence and 
severity of treatment-emergent adverse events (TEAEs) (including serious adverse events 
[SAEs]) from the first dose of UCB6114 on Day 1 of Cycle 1 to the Safety Follow-up (SFU) 
visit, and the incidence of dose limiting toxicities (DLTs) from the first dose of UCB6114 on 
Day 1 of Cycle 1 to the end of the 28-day DLT Observation Period for all cohorts. 
2.2.1.2  
Other safety endpoints 
The following other safety data will be assessed during Part A1 of the study to further support 
the characterization of the safety profile of UCB6114 administered as monotherapy: 
• Clinical laboratory data (hematology, serum chemistry, coagulation and urinalysis); 
• Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature); 
• 12-lead electrocardiogram (ECG); 
• Echocardiogram (left ventricular ejection fraction [LVEF]); 
• Eastern Cooperative Oncology Group (ECOG) performance status;  
• Physical examination. 
2.2.2 
Pharmacokinetic and pharmacodynamic endpoints 
2.2.2.1  
Secondary pharmacokinetic endpoint 
The secondary endpoint in Part A1 of this study is for PK, specifically UCB6114 concentration 
by scheduled assessment for each UCB6114 dose schedule cohort. 
2.2.2.2  
Exploratory pharmacokinetic endpoints 
 will be exploratory PK endpoints in Part A1.  
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2.2.2.3  
Exploratory pharmacodynamic endpoints 
The following exploratory PD endpoints will be assessed in Part A1 and reported separately 
outside of the CSR: 
• Change in transcriptional and protein marker levels in blood and tumor tissue by 
scheduled assessment/timepoint and for each UCB6114 dose schedule cohort. 
• Change in circulating tumor deoxyribonucleic acid (ctDNA) levels in blood by 
scheduled assessment and for each UCB6114 dose schedule cohort. 
2.2.2.4  
Exploratory immunogenicity endpoints 
Immunogenicity in Part A1 will be explored using ADA sample status and participant 
classification, and changes in titer over time. Potential relationships between ADA and PK, PD, 
anti-tumor activity and safety may also be explored but these analyses will be reported separately 
outside of the CSR. 
2.2.3 
Efficacy endpoints 
2.2.3.1  
Exploratory antitumor activity endpoints 
Antitumor activity in Part A1 will be explored using the following endpoints: 
• Objective tumor response rate (ORR); 
• Disease control rate (DCR); 
• Duration of antitumor response (DOR); 
• Progression-free survival (PFS); 
• Overall survival (OS). 
2.2.3.2  
Other exploratory efficacy endpoint 
To further explore efficacy in Part A1 of the study, changes from Baseline in the ECOG 
performance status scale will be assessed. 
2.3 
Study design and conduct 
Study ONC001 is a multicenter, nonrandomized, open-label, Phase 1/2 study evaluating the 
safety, PK, efficacy (as assessed by antitumor activity), PD, biomarkers, and immunogenicity 
(ADA activity) of intravenous (iv) UCB6114 as monotherapy and in combination with selected 
standard of care (SoC) regimens in study participants with advanced solid tumors. 
The study has a modular design including up to 3 dose escalation modules (Parts A, B, and C), 
1 dose optimization module (Part A1), and up to 4 dose expansion modules (Parts D, E, F, and 
G). Depending on emerging data, not all modules may open. This SAP is focused only on the 
dose optimization module of the study to evaluate alternative dosing schedules for UCB6114 
administered as monotherapy in participants with unresectable locally advanced or metastatic 
colorectal adenocarcinoma, gastric adenocarcinoma, adenocarcinoma of the gastroesophageal 
junction, or pancreatic adenocarcinoma. 
Part A1 consists of a Screening Period, Treatment Period (consisting of 28-day cycles for 
Cohorts 1, 2, and 4, and of 21-day cycles for Cohort 3), a SFU visit and a Final Visit. During the 
Treatment Period, UCB6114 will be administered as iv infusion as per the defined dosing 
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schedules in Table 6-6 of the protocol until the occurrence of progressive disease, unacceptable 
toxicity, or withdrawal of consent.  
Part A1 will be initiated after Cohort 5 of Part A (2000mg every 2 weeks [Q2W]) has been 
determined to be safe (i.e. DLT incidence <33%, see Section 4.1.2.4 of the protocol). Eligible 
participants with unresectable locally advanced or metastatic colorectal adenocarcinoma, gastric 
adenocarcinoma, adenocarcinoma of the gastroesophageal junction, or pancreatic 
adenocarcinoma will receive iv infusion of UCB6114 as monotherapy. 
The planned dose optimization scheme for Part A1 will assess the safety and tolerability of the 
new drug formulation and will explore shortening of the infusion time and less frequent dosing 
as follows:  
• Cohort 1: 2000mg Q2W (60-minute iv infusion), 28-day treatment cycle 
• Cohort 2: 2000mg Q2W (30-minute iv infusion), 28-day treatment cycle 
• Cohort 3: 3000mg every 3 weeks (Q3W) (90-minute iv infusion), 21-day treatment cycle 
• Cohort 4: 4000mg every 4 weeks (Q4W) (120-minute iv infusion), 28-day treatment 
cycle  
Up to 32 participants will be allocated 1:1:1:1 to one of the 4 cohorts, with each cohort enrolling 
up to 8 study participants including 1 sentinel participant with an observation period of 48 hours. 
The enrollment of a sentinel participant in each cohort has been included as an additional risk 
mitigation measure to monitor infusion related reactions and other early onset treatment-related 
AEs.  
The planned duration of study treatment is 2 cycles. Participants may, however, remain in the 
study for additional cycles if they are receiving therapeutic benefit (stable disease [SD], partial 
response [PR], or complete response [CR]) or until they fulfill one of the criteria for study 
treatment discontinuation. Participants will continue study treatment until disease progression, 
unmanageable toxicity, or withdrawal of consent. Upon discontinuation from study treatment, 
participants will be referred to appropriate follow-up care per the investigator’s judgment.  
A schematic diagram of Part A1 of the study is provided in Figure 2-1. 
 
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Figure 2-1: Study Schematic for Part A1 
 
A Safety Monitoring Committee (SMC) will convene after each sentinel participant is assessed 
for at least 48 hours following the first administration of UCB6114 in the first cycle of a cohort 
to determine whether further participants within the cohort can be enrolled. The SMC will also 
convene after 25%, 50% and 100% of study participants in Part A1 have completed the required 
28-day DLT Observation Period. If deemed necessary, an additional SMC meeting can convene 
after 75% of the participants have completed the required 28-day DLT Observation Period. If 1 
or more DLTs are reported for a cohort then an ad hoc SMC will convene to determine if the 
dosing schedule and study module can continue as planned.  
After consultation, the SMC will provide recommendations which could include an expansion of 
enrollment in a particular cohort to gain additional safety data, continuation of Part A1 with 
modifications or a temporary suspension of enrollment in a particular cohort. Details are 
described in the Part A1 SMC Charter. 
2.4 Determination of sample size 
In Part A1, up to 32 eligible participants will be enrolled across 4 alternative dosing schedules; 8 
participants per cohort is considered sufficient to protect against an unacceptable level of 
toxicity. The probability of declaring a dose schedule (cohort) too toxic, given a toxicity rate 
greater than the maximum tolerable toxicity rate (33%) is approximately 90%. However, the 
probability is reduced to 80% when the dose optimization module is considered independent of 
Part A. An administrative decision to stop enrolling into Part A1 may be made by the Sponsor at 
any time.  
 
 
 
Pre-treatment 
period 
Up to 28 days 
Baseline 
Assessments 
Sent.inel 
a.ss~ment 
period 
48 hours 
Sentinel 
assessment 
period 
48 hours 
Sentinel 
assessment 
period 
48 hours 
Sentinel 
assessment 
period 
48 hours 
Treatment Period 
C cle 1 * 
Cohort 1: n=1+7 
UCB6114 Iv 2000mg, 60-mlnute Infusion 
01 + 015 
Cohort 2: n=1+7 
UCB6114 Iv 2000mg 30-mlnute Infusion 
01 + 015 
Cohort 3: n=l+7 
UCB6114 Iv 3000mg, 90-mlnute Infusion 
01 
Cohort 4: n=1+7 
UCB6114 Iv 4000mg, , 120-mlnute Infusion 
01 
Subse , uent C cles • 
Cohort 1: 
UCB6114 Iv 2000mg 
Q2W In 28 Day Cycles 
Cohort 2: 
UCB6114 Iv 2000mg 
Q2W In 28 Day Cycles 
Cohort 3: 
UCB6114 Iv 3000mg 
Q3W In 21 Day Cycles 
Cohort 4: 
UCB6114 Iv 4000mg 
Q4W In 28 Day Cycles 
• Cohorts 1, 2, and 4: 28-day treatment cycles; Cohort 3: 21-day treatment cycles 
D=day: iv=intravenous: Q2W=cvcry 2 weeks: QJ W=c,•cry J weeks: Q4W=cvery 4 weeks 
Up to 30 days 
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3 DATA ANALYSIS CONSIDERATIONS 
3.1 General presentation of summaries and analyses 
All TFLs will be produced by ICON PLC using SAS® Version 9.4 or higher (SAS Institute, Cary, 
North Carolina, USA). ICON PLC will also produce the analysis datasets which will adhere to 
the Clinical Data Interchange Standards Consortium (CDISC) guidance documents for Analysis 
Data Model (ADaM) and follow UCB's interpretation. General statistical and reporting 
conventions will follow the current UCB Global Conventions Document Version 1.1.  
Data will be summarized by UCB6114 dose schedule cohort (treatment group), visit and 
timepoint, as applicable. All relevant reported and derived data will be listed and will be 
presented by treatment group, study participant and visit, as applicable. 
Categorical variables will be summarized using frequency counts and percentages. Unless 
otherwise stated, the denominator for the percentages will be based on the number of participants 
in the respective analysis set, treatment group, visit and timepoint (as applicable) with non-
missing data. 
When reporting frequency counts and percentages, the following rules apply: 
• For categories where all participants fulfill certain criteria, the percentage value will be 
displayed as 100; 
• For categories where zero participants fulfill certain criteria, there will be no percentage 
displayed; 
• All other percentage displays will use 1 decimal place. 
Summary statistics will be presented for continuous variables including number of participants 
(n), arithmetic mean, standard deviation, median, minimum and maximum. 95% confidence 
intervals (CIs) for the arithmetic mean may also be included depending on the variable and 
where stated in the SAP. Geometric mean (geoMean), geometric coefficient of variation (geoCV) 
and 95% CI for the geoMean will also be presented in the summaries of UCB6114 concentration 
data. In all relevant outputs the 95% confidence limits will be restricted to the possible values 
that the variable can take.  
 
When reporting descriptive statistics for data other than UCB6114 concentration data, the 
following rules will apply: 
• n will be an integer; 
• Mean (arithmetic and geometric), standard deviation, median and quartiles will use 1 
decimal place more, or 1 significant figure more – depending on the reporting format of 
the original data – than the original data. Original data may be data as reported directly 
onto the eCRF or summary data based on data reported onto the eCRF (e.g. mean of 
triplicates or percentage change from Baseline); 
• Confidence intervals will be presented to the same number of decimal places as the value 
around which the CI is constructed; 
• Minimum and maximum will be reported using the same number of decimal places or 
significant figures as the original value; 
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• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “); if no participants have data at a given 
timepoint, then only n=0 will be presented; 
• Percentage change from Baseline values will be calculated and displayed to 1 decimal 
place in the listings. In the summaries, where applicable, the mean, standard deviation 
and median percentage change from Baseline values will be presented to 2 decimal places 
and the minimum and maximum values presented to 1 decimal place. 
When reporting individual UCB6114 concentration data in listings and figures, and presenting 
summary statistics in tables, the following rules will apply: 
• UCB6114 concentration data should be reported in the listings to the same level of 
precision as received from the bioanalytical laboratory; 
• Missing data should be reported as ‘NV’ (no value) in the listings; 
• Concentrations below the lower limit of quantification (LLOQ) should be reported as 
BLQ (below the limit of quantification) in the listings; 
• BLQ values prior to Cmax should be set to 0 for purposes of plotting a figure (to capture 
lag-time);  
• Actual sampling times will be used in the spaghetti plots of individual PK concentrations 
over time, and nominal sampling times will be used in the summaries of geoMean 
concentrations over time; 
• UCB6114 concentration data should be plotted on both linear and semi-logarithmic 
scales;  
• To calculate summary statistics, BLQ values should be set to half the LLOQ value and 
missing values should be excluded; 
• When the total number of BLQ and missing values exceeds one third of the total then 
only minimum and maximum should be reported for this timepoint. Other summary 
statistics should be reported as missing (“-“). The minimum should be reported as BLQ; 
• When the mean value includes one or more replaced BLQ values then a footnote should 
be included to say “contains one or more BLQ values replaced by half the LLOQ value”; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “); if no participants have data at a given 
timepoint, then only n=0 will be presented; 
• Summary statistics for UCB6114 concentration data will be reported to the same level of 
precision as the individual data for the minimum and maximum, and to 1 additional 
decimal place or 1 additional significant figure – depending on the reporting format of the 
original data with a maximum of 3 significant figures - for the mean (arithmetic and 
geometric), median and standard deviation. The 95% CI for the geoMean will use the 
same number of decimal places or significant figures as the geoMean. It will be left blank 
if the geoCV is 0; 
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• Geometric coefficient of variation will be reported as a percentage to 1 decimal place. 
The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data: 
𝐺𝑒𝑜𝐶𝑉(%) = √exp 𝑆𝐷2 −1 × 100 
 
When reporting PK parameters in listings and figures, and presenting summary statistics in 
tables, the following rules will apply: 
3.2 General study level definitions 
3.2.1 
Relative day and time 
For each participant, the relative day of an event or assessment will be derived using the earliest 
date of their first dose of UCB6114 as reference.  
Relative days for an event or assessment occurring before the date of the first dose are calculated 
as follows: 
Relative Day = Event/Assessment Date - Date of First Dose of UCB6114 
The relative day for an event or assessment occurring on the date of first dose is 1. The relative 
day for an event or assessment occurring on or after the first dose to the date of the last dose of 
UCB6114 will be calculated as follows: 
Relative Day = (Event/Assessment Date - Date of First Dose of UCB6114) + 1 
For events or assessments occurring after the date of the last dose of UCB6114, relative day will 
be prefixed with ‘+’ in the data listings and will be calculated as follows: 
Relative Day = Event/Assessment Date – Date of Last Dose of UCB6114 
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There is no relative Day 0. Relative day will not be calculated in cases where dates are partial 
and should be presented as “--” in the relevant data listing. 
Relative time of TEAEs recorded on, but not limited to, the day of UCB6114 infusion, will be 
derived in minutes as follows using the infusion start time as reference: 
Relative Time of TEAE = Onset Time of TEAE – Start Time of UCB6114 Infusion 
Relative times of PK and PD sampling will be derived in hours using the end of infusion times 
on the day of UCB6114 dosing as reference: 
Relative Sampling Time = Sampling Time – End Time of UCB6114 Infusion 
3.2.2 
Study periods 
Part A1 of the study will consist of the following study periods: 
• Screening Period – up to 28 days; 
• Treatment Period – Successive 28-day cycles for Cohorts 1, 2, and 4, and 21-day cycles 
for Cohort 3. UCB6114 is administered as iv infusion as per defined dosing schedules 
until the occurrence of progressive disease, unacceptable toxicity, or withdrawal of 
consent;    
• Safety Follow-up Period – up to 30 days after the last dose of UCB6114. 
There will be a further extended follow-up period, up to 3 months after the last dose of 
UCB6114, at which time the Final Visit will be performed.   
For each participant, the end of the Treatment Period is defined by the date of their last dose of 
UCB6114.   
The end of Part A1 of the study is defined by the date of the Final Visit for the last participant (3 
months after the last participant’s last dose of UCB6114), or the date of the SFU visit, if they 
discontinue prior to attending the Final Visit, or their last contact date if they discontinue early 
from the study without attending the SFU visit. 
3.2.3 
Visits 
Unless otherwise specified, in the TFLs, visits will be labelled as follows (as applicable) using 
timepoints as recorded in the database: 
Screening 
Baseline 
Cycle 1, Day X 
Cycle 2, Day X  
Cycle 3, Day X 
Cycle 4, Day X 
Cycle X, Day X 
Etc. 
SFU 
Final Visit 
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3.3 Definition of Baseline values 
Baseline in Part A1 will be the last available value prior to the first dose of UCB6114. Both 
scheduled and unscheduled values, as well as any repeated values, should be used when defining 
Baseline.  
Measurement-specific Baseline definitions are presented in Table 3-1 below. 
Table 3-1: 
Definition of Baseline 
Measurement 
Definition of Baseline 
Echocardiogram (LVEF) 
Tumor assessments (antitumor activity) 
Tumor biopsy (Ki67, SMAD4, FAP, 
pSMAD1/5/8) 
Screening value 
12-lead ECG 
Physical examination and weight 
Vital signs 
Clinical laboratory data 
ECOG performance status 
Predose value obtained on Cycle 1, Day 1, or, if 
missing, Screening value  
Circulating gremlin-1 (cGremlin-1) 
Immunogenicity (ADA) 
Predose sample value obtained on Cycle 1, Day 1 
ADA=anti-drug (UCB6114) antibody; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
LVEF=left ventricular ejection fraction. 
3.4 Protocol deviations 
Per ICH definition, important protocol deviations (IPDs) are a subset of protocol deviations that 
may significantly impact the completeness, accuracy, and/or reliability of the study data or that 
may significantly affect a participant’s rights, safety, or well-being. The criteria for identifying 
potentially important protocol deviations will be defined within the IPD specifications 
document.  
 
For Part A1 of this study, IPDs will be categorized as follows:   
• 
Inclusion/exclusion criteria deviations;  
• 
Incorrect treatment or dose administered;  
• 
Procedural non-compliance;  
• 
Prohibited concomitant medication use (see Section 6.5.6 of the protocol); 
• 
Withdrawal criteria deviation.   
All protocol deviations will be reviewed as part of the ongoing data cleaning process and Data 
Evaluation Meetings (DEMs), and decisions made on whether they should be considered 
important or not, and whether they warrant a participant’s exclusion from an analysis set, or 
partial exclusion from an analysis due to being an IPD (e.g. prohibited concomitant medication 
use). Multiple DEMs will be scheduled prior to the final database lock for Part A1, in line with 
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regulatory safety reporting requirements, with the final one held after all data have been 
verified/coded/entered into the database.  
More specifically, participants who have IPDs relating to dosing of UCB6114 (e.g. interrupted, 
discontinued and missed infusion, incomplete/incorrect dose administered, additional dose 
received, or infusions administered outside of the defined visit window) will be reviewed at the 
DEM for potential exclusion of UCB6114 concentration data from the by-visit summaries at an 
individual visit or from the visit at which the dosing deviation was observed onwards. 
Any protocol deviations that are considered related to coronavirus disease 2019 (COVID-19) 
will be reviewed on an ongoing basis in case they collectively or individually give reason to 
consider a protocol amendment (e.g. study design changes or changes to primary analysis 
methods etc.). To facilitate this ongoing review, protocol deviations will be categorized as 
‘related to COVID-19’ within the Clinical Trial Management System (CTMS) (ICOTrial).  The 
COVID-19-related IPDs will then be listed separately for review and discussion at the DEMs. 
3.5 Analysis sets 
Study participants will be analyzed according to the dose, frequency of dosing and duration of 
infusion they actually received regardless of which treatment group they were assigned to. 
3.5.1 
Enrolled Set (ES) 
The Enrolled Set (ES) consists of all study participants who sign the Informed Consent Form. 
This analysis set includes screening failures and will be used for the summary of disposition of 
study participants and for selected data listings (which will include all available data for the 
screening failures).  
3.5.2 
Safety Analysis Set (SS) 
The Safety Analysis Set (SS) consists of all study participants who receive at least 1 full or 
partial dose of UCB6114. 
This analysis set will be used for the reporting of demographic, baseline characteristics, safety 
and immunogenicity data. All summaries of the exploratory antitumor activity endpoints will be 
repeated for the SS as a sensitivity analysis.    
3.5.3 
Per-protocol Set (PPS) 
The Per-protocol Set (PPS) consists of all study participants in the SS who do not have IPDs that 
may substantially affect antitumor activity. Potential exclusions will be reviewed at the DEMs 
and a final determination of the composition of this analysis set will be made prior to the final 
database lock for Part A1.  
The PPS will be the primary analysis set for the analysis of the exploratory antitumor activity 
endpoints.  
3.5.4 
Pharmacokinetic Set (PKS) 
The Pharmacokinetic Set (PKS) consists of all study participants in the SS who have at least 
1 evaluable postdose UCB6114 concentration sample (i.e. a sample which is above the lower 
limit of quantitation and for which the date and time of the sample and prior date and time of 
dosing are known). Additional participants or specific samples may be excluded from the PKS at 
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the discretion of the Advanced Modeling and Simulation scientist/Quantitative Clinical 
Pharmacologist at UCB. 
Pharmacokinetic analysis will be performed for the PKS. 
3.5.5 
Anti-drug Antibody Set (ADAS) 
The Anti-drug Antibody Set (ADAS) consists of all study participants in the SS who have at 
least 1 evaluable ADA assessment (i.e. a sample that has a reported result [is not missing or 
inconclusive]).  
Immunogenicity analyses will be performed for the ADAS. 
3.5.6 
Pharmacodynamic Set (PDS) 
The Pharmacodynamic Set (PDS) consists of all study participants in the SS who have at least 
1 evaluable PD assessment (where appropriate, the sample should be above the lower limit of 
quantitation and the date and time of the sample should be known). 
Pharmacodynamic analyses will be performed for the PDS. 
3.5.7 
DLT Evaluable Set (DES) 
The DLT Evaluable Set (DES) will include all study participants who, during the 28-day DLT 
Observation Period, receive the planned dose of UCB6114. 
The DES will be used only for evaluations by the SMC to determine if a dosing schedule and 
Part A1 can continue as planned.  
3.6 Treatment assignment and treatment groups 
In Part A1, it is planned that study participants will be dosed with UCB6114 to evaluate a new 
dose formulation, different frequencies of dosing (e.g. Q3W, Q4W), and different durations of 
infusion. Treatment groups will be defined by each UCB6114 dose schedule cohort and will be 
presented in ascending cohort number order and labelled in the TFLs as illustrated in Table 3-2. 
Table 3-2: Treatment Group Labels 
UCB6114 Dose Schedule Cohort 
Planned Treatment Group Label 
Cohort 1 
UCB6114 2000mg Q2W (60-min), 28D  
Cohort 2 
UCB6114 2000mg Q2W (30-min), 28D  
Cohort 3  
UCB6114 3000mg Q3W (90-min), 21D  
Cohort 4  
UCB6114 4000mg Q4W (120-min), 28D  
min=minutes; Q2W=every 2 weeks; Q3W=every 3 weeks; Q4W=every 4 weeks; 21D=21-day cycle; 28D=28-day 
cycle. 
UCB6114 dose schedule cohort will be referred to as ‘treatment group’ from this point onwards 
in the SAP and in the TFLs. 
 
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3.7 Center pooling strategy 
Each study site will contribute to the summaries of data from Part A1 according to the number of 
evaluable participants recruited; no separate summaries for each site will be presented.   
3.8 Coding dictionaries 
Adverse events (AEs) and medical history will be coded by UCB, using the latest available 
version of the Medical Dictionary for Regulatory Activities (MedDRA®) (Version 25.1 or 
higher). The National Cancer Institute Common Terminology Criteria for AEs (Version 5.0) 
(NCI CTCAE) dictionary will also be used by the investigator to assign CTCAE severity grades 
to each adverse event (AE) and will be merged with the clinical database to define a CTCAE 
code and term to be used in the summaries of TEAEs by maximum CTCAE severity grade. 
Medications (including prior anti-cancer systemic therapies) will be coded according to the 
World Health Organization Drug Dictionary (WHODD) (Version SEP/2020). Medical 
procedures will not be coded. 
The versions of the coding dictionaries used will be displayed in the relevant TFLs. 
3.9 Changes to protocol-defined analyses 
The following changes to the protocol have been incorporated into the SAP: 
• Other safety data have not been defined as safety endpoints in the protocol, e.g. clinical 
laboratory data, vital signs, ECG, echocardiogram, ECOG performance status and 
physical examination. These have been listed in Section 2.2.1 of the SAP as ‘other safety 
endpoints’ to support the characterization of the safety profile of UCB6114 and to 
provide supporting evidence of any measurements that are deemed abnormal and 
clinically significant and reported as an AE. 
• ECOG performance status is defined as an efficacy assessment in Section 9.6.2 of the 
protocol, however, it will also be assessed from a safety perspective in Part A1. The SAP 
therefore includes ECOG performance status as both a safety endpoint (Section 2.2.1) 
and an exploratory efficacy endpoint (changes from Baseline during Part A1 in Section 
2.2.3). 
 
4 STATISTICAL/ANALYTICAL ISSUES 
4.1 Adjustments for covariates 
Not applicable. 
4.2 Handling of dropouts or missing data 
There will be no imputation of missing data unless otherwise stated in the sections below. 
4.3 Pharmacokinetics and pharmacodynamics 
The reporting and handling of missing values and values that are BLQ in the TFLs is described 
in Section 3.1. Zero values will be assumed at the predose timepoint on Day 1 of Cycle 1. 
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4.4 Safety laboratory data 
The rules for handling values that are BLQ in the safety laboratory data will be the same as those 
described for PK data in Section 3.1. Any values above the limit of quantification (ALQ) will be 
assigned as the value of upper limit of quantification. 
4.4.1 
Dates and times 
Partial dates may be imputed for the following reasons: 
• Classification of AEs as treatment-emergent; 
• Classification of medications recorded on the concomitant medications log as prior or 
concomitant; 
• Calculation of time since initial diagnosis, time since completion of most recent line of 
prior anti-cancer systemic therapy and time since progression/relapse on most recent line 
of prior anti-cancer systemic therapy. 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial onset/start dates: 
• If only the month and year are specified and the month and year of the first dose of 
UCB6114 is not the same as the month and year of the start date then the 1st of the month 
will be used, or the date of the Screening visit if this is later (if the latter imputation 
results in an end date that is earlier than the start date, then the 1st of the month will be 
used); 
• If only the month and year are specified and the month and year of the first dose of 
UCB6114 is the same as the month and year of the start date, then the date of the first 
dose of UCB6114 will be used. If this results in an imputed start date that is after the 
specified end date, then the 1st of the month will be used, or the date of the Screening 
visit if this is later (if the latter imputation results in an end date that is earlier than the 
start date, then the 1st of the month will be used). If the imputed date is the same date as 
the date of the first dose of UCB6114 then, for AEs, the event will be regarded as 
treatment-emergent. For medications, the medication will be classified as concomitant; 
• If only the year is specified, and the year of the first dose of UCB6114 is not the same as 
the year of the start date then January 01 will be used; 
• If only the year is specified, and the year of the first dose of UCB6114 is the same as the 
year of the start date, then the date of the first dose of UCB6114 will be used. If this 
results in an imputed start date that is after the specified end date, then January 01, or the 
date of the Screening visit if this is later will be used (if the latter imputation results in an 
end date that is earlier than the start date, then January 01 will be used). If the imputed 
date is the date of the first dose of UCB6114 then, for AEs, the event will be regarded as 
treatment-emergent. For medications, the medication will be classified as concomitant. 
• If the onset/start date is completely missing then the onset/start date will be imputed to 
the date of first dose of UCB6114 and therefore, for AEs, the event will be regarded as 
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treatment-emergent and, for medications, the medication will be classified as 
concomitant. 
The following rules will be applied to partial end/stop dates: 
• If only the month and year are specified, then the last day of the month will be used; 
• If only the year is specified, then December 31 of the known year will be used; 
• If the stop date is completely unknown, the stop date will not be imputed. 
Note that the start date or stop date of a prior medication (partial or otherwise) should not be 
imputed past the Screening visit date - 1.  
In addition to onset and stop dates, the onset and end times of AEs occurring on the day of 
UCB6114 infusion will be collected on the eCRF. Onset and end times may also be recorded for 
other AEs that do not occur on the same day as the UCB6114 infusion. The duration of AEs with 
onset and end times will be calculated in days and hours:minutes (hh:mm) as: 
Duration of AE = End Date and Time – Onset Date and Time 
In cases where only the onset and stop dates are recorded for an AE, the duration of an AE will 
be calculated in days as:  
Duration of AE = (Stop Date – Onset Date) + 1 
Note that for participants who have an AE which starts and stops on the same day, but with only 
a start time or only a stop time recorded, it will be assumed that their AE started from 00:00 (if 
no start time is recorded) and ended at 23:59 (if no stop time is recorded) on that day. 
If the date of a participant’s initial diagnosis is incomplete, it will be imputed to the most recent 
feasible date for the calculation of time since initial diagnosis as follows: 
• If only the day is missing, it will be imputed to the last day of the known month; 
• If the day and month are missing, it will be imputed to December 31 in the known year; 
• If the date of initial diagnosis is completely missing, then time since initial diagnosis will 
not be calculated. 
The above date imputation rules will be applied to partially missing stop dates of a participant’s 
last prior anti-cancer systemic therapy as well as partially and completely missing dates of 
progression/relapse on last prior anti-cancer systemic therapy. 
In cases where the stop date of a participant’s last prior anti-cancer systemic therapy and/or a 
participant's date of progression on last line of prior anti-cancer systemic therapy is completely 
missing, the participant’s Screening date -1 will be used in the calculation of the time since 
completion of most recent line of prior anti-cancer systemic therapy and the time since 
progression/relapse on most recent line of prior anti-cancer systemic therapy, respectively. 
 
Note that partial dates will not be imputed as a participant’s first dose of UCB6114 in the 
calculation of time since initial diagnosis, time since completion of most recent line of prior anti-
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cancer systemic therapy and time since progression/relapse on most recent line of prior anti-
cancer systemic therapy. 
4.4.2 
Impact of COVID-19 
The FDA and European Medicines Agency (EMA) have provided guidance (see references listed 
in Section 12) to help assure the safety of all trial participants, maintaining compliance with good 
clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic. 
At the time of writing this SAP, the impact of the pandemic is still evolving, and regulators 
continue to clarify their position, and how to handle missing or delayed assessments resulting 
from the pandemic is part of the risk assessment of the impact of COVID-19 on trial integrity.  
For this purpose, the impact at a visit level will be assessed by data collected on a specific 
COVID-19 impact eCRF form and protocol deviations related to COVID-19. Due to the timing 
of the start-up of recruitment of participants into this study, the consequences for Part A1 are not 
expected to be significant and, as a result, no details on strategies for handling missing data are 
included in this version of the SAP. However, should the ongoing review of COVID-19-related 
protocol deviations suggest that the impact is more significant than expected, e.g. in the case of a 
new wave, the SAP may be updated to include further details of handling missing data and/or 
any sensitivity analyses required. Note that there are no guidelines regarding how much missing 
data is too much, and there is no proportion of missing data under which valid results and 
preservation of study power can be guaranteed. 
4.5 Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. Repeated measurements are defined as more than 1 measurement at the same 
timepoint. For example, the same laboratory parameters assessed twice using the same batch of 
blood samples due to issues with the first assessment. The following general rules will apply to 
all repeated and unscheduled measurements: 
• Unscheduled and repeated measurements prior to the first dose of UCB6114 will be used 
in the determination of Baseline and hence in the calculation of summary statistics at 
Baseline. 
• Unscheduled and repeated measurements performed after the first dose of UCB6114 will 
not be included in the calculation of change from Baseline or summary statistics, i.e. only 
the scheduled measurements will be used and summarized. Similarly, only scheduled 
visits will be used in the summaries of shifts from Baseline to the worst post-Baseline 
CTCAE severity grade for laboratory data (see Section 8.3).  
• For the summaries of the investigator’s overall tumor response assessment, protocol-
defined windows will be applied to all post-Baseline tumor assessments (scheduled or 
unscheduled, but excluding tumor assessments performed at the SFU visit), as detailed in 
Section 10.1.2. Those tumor assessments which fall outside of the window will be 
considered as unscheduled assessments and not included in the summaries. 
• Best overall response, DOR and PFS derivations will use all scheduled and unscheduled 
tumor assessments.   
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• Blood samples for PK and/or cGremlin-1 analysis collected on the day of the On-
Treatment biopsy when these blood samples are not scheduled will be documented on 
unscheduled eCRF pages; these data will be included in the summaries. 
• All data from unscheduled visits will, however, be included on the relevant data listings. 
4.6 Handling of measurements obtained for early withdrawals 
Participants who withdraw early from the study for any reason will be asked to return to the 
clinic to complete the SFU visit. The SFU procedures performed at this visit are as shown in the 
Schedule of Activities in the protocol and will be summarized together with all other SFU visit 
data in the tables. 
4.7 Interim analyses and data monitoring 
No formal interim analyses are planned during Part A1 of this study. 
In Part A1, the SMC will review all the safety and tolerability data for the sentinel participant in 
each UCB6114 dose schedule cohort (48 hours following first UCB6114 administration). The 
SMC will also review available safety, tolerability, and PK data as well as any available 
biomarker and ADA data once 25%, 50% and 100% study participants in Part A1 have 
completed the required 28-day DLT Observation Period. If deemed necessary, an additional 
SMC meeting can convene after 75% of the participants have completed the required 28-Day 
DLT Observation Period. If 1 or more DLTs (refer to Protocol Section 4.1.2.4 for the definition 
of DLTs) are reported for a cohort then, an ad hoc SMC will convene to determine if the dosing 
schedule and Part A1 can continue as planned. 
The SMC established for Part A is comprised of key Sponsor personnel and investigators from 
participating sites. Investigators joined the SMC from new sites added in Parts B and C. The 
SMC for Part A1 will include the cumulative members, who are still actively enrolling study 
participants into the study. 
In addition to the planned SMC data review meetings, the Sponsor and the SMC will have the 
ability to hold/request ad hoc meetings should they be deemed necessary (e.g. if safety concerns 
arise during Part A1 of the study and/or during other ongoing nonclinical and clinical studies). 
4.8 Multicenter studies 
Part A1 of this study is planned to be conducted at study sites in the UK and US. With the 
exception of participant disposition, no summaries will be presented by site or country. 
4.9 Multiple comparisons/multiplicity 
Not applicable. 
4.10 Use of an efficacy subset of participants 
The PPS will be used as the primary analysis set for the summaries of the exploratory antitumor 
activity endpoints in Part A1. 
4.11 Active-control studies intended to show equivalence 
Not applicable. 
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4.12 Examination of subgroups 
Not applicable. 
 
5 STUDY POPULATION CHARACTERISTICS 
5.1 Study participant disposition 
The number of study participants who were screened for Part A1 of this study, the number and 
percentage of screen failures and the primary reasons for screen failure will be summarized for 
the ES. A listing of participants who did not meet the eligibility criteria for Part A1 will also be 
presented for the ES. In addition, the disposition of study participants screened and who received 
study treatment will be summarized by country and site. This table will include, for each site in 
the UK and US and overall, site number, principal investigator name, the dates of the first 
participant in and the last participant out, the number of participants screened (ES), the number 
of screen failures, the number of participants who were treated (SS) and included in the PPS, 
PKS, ADAS and PDS. Disposition in each analysis set across all study sites will be summarized 
by treatment group.  
The number of study participants who received study treatment and the primary reason for 
discontinuation of study treatment during Part A1 will be summarized by treatment group, 
together with the number and percentage of participants who continued participation in the study 
after discontinuation of study treatment (at subsequent scheduled visits and/or SFU visit and 
Final Visit). This summary will be based on the SS. 
The number of study participants enrolled into Part A1, who were screen failures as well as the 
number of eligible participants who were assigned to a study cohort but not treated will be 
presented for the ES. For those participants who did not receive study treatment, the reasons for 
early discontinuation from the study will be summarized.   
Of those participants who received study treatment, the number and percentage of participants 
who completed the study (i.e. participants who received at least 2 complete cycles of UCB6114 
and attended the SFU visit), who received at least 2 complete cycles of study treatment but who 
did not attend the SFU visit and who discontinued early from Part A1, together with the primary 
reasons for study discontinuation will be presented for all participants.  
The number and percentage of participants who discontinued due to AEs will be summarized 
separately for all participants, based on the SS. This will be used for European Union Drug 
Regulating Authorities Clinical Trials (EudraCT) reporting.  
The following study disposition tables will also be presented by tumor type (colorectal 
adenocarcinoma [CRC], gastric adenocarcinoma and adenocarcinoma of the gastroesophageal 
junction combined [Gastric/GEJ-Cancer] and Pancreatic Adenocarcinoma), depending on the 
number of participants with specific tumor types. 
• Disposition and Reasons for Discontinuation of Study Treatment 
• Disposition and Reasons for Discontinuation of Study 
• Discontinuation of the Study Due to AEs 
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Visits impacted by COVID-19 will be listed for the ES. This listing will include, visit, visit date, 
relative day, impact category (e.g. visit performed out of window, visit performed by telephone, 
visit not done, missed study drug administration/dispensation, termination of study 
participation), relationship to COVID-19 (confirmed COVID-19 infection, suspected COVID-19 
infection, general circumstances around COVID-19 or other) and a narrative for the event. The 
number and percentage of participants with visits impacted by COVID-19 will be presented by 
treatment group and by impact category. This summary will be presented for the different 
relationships to COVID-19. The denominator for the percentage calculations will be the number 
of participants in the SS. 
In addition, the following listings will be presented: 
• Study participant disposition (ES); 
• Study treatment discontinuation (SS); 
• Study discontinuation (ES); 
• Visit dates (ES); 
• Participant analysis sets and exclusions from analysis sets (ES)*. 
*DES is not included in this listing as it is only relevant for the SMC, and not required for the 
CSR. 
The listing of study participant disposition will include the date of informed consent, date and 
time of first and last dose of UCB6114, date of early study discontinuation (if applicable) and 
primary reason for discontinuation.   
The listing of study treatment discontinuation will include date and time of first and last dose of 
UCB6114, date of decision to discontinue UCB6114 and primary reason for discontinuation of 
UCB6114, date of clinical progression (if applicable), number of doses of UCB6114 received 
(based on doses per cycle), total dose of UCB6114 received across all cycles, number of 
complete cycles of UCB6114 received, and whether or not the participant had continued 
participation in the study (at subsequent visits, the SFU visit or the Final Visit). 
A participant in Cohort 1 or 2 is deemed to have completed a full cycle of UCB6114 if they 
receive a dose of UCB6114 on Day 1 and Day 15 of the cycle and a decision was not made to 
discontinue study treatment up to and including Day 28 relative to Day 1 of the cycle.  
 
A participant in Cohort 3 is deemed to have completed a full cycle of UCB6114 if they receive a 
dose of UCB6114 on Day 1 of the cycle and a decision was not made to discontinue study 
treatment up to and including Day 21 relative to Day 1 of the cycle. 
 
A participant in Cohort 4 is deemed to have completed a full cycle of UCB6114 if they receive a 
dose of UCB6114 on Day 1 of the cycle and a decision was not made to discontinue study 
treatment up to and including Day 28 relative to Day 1 of the cycle. 
Whether or not a participant has completed a full cycle of UCB6114 will be derived based on the 
participant’s last dose of UCB6114 and whether or not the participant attended the visit at which 
they were scheduled to receive their next dose of UCB6114. For example, in Cohorts 1 and 2, if 
a participant received UCB6114 on Day 1 and Day 15 of Cycle 1 and attended the clinic for their 
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UCB6114 infusion on Day 1 of Cycle 2 then the participant will be counted as having completed 
Cycle 1. If the participant in Cohort 1 or 2 did not attend Day 1 of a subsequent cycle, then it is 
likely that a decision was made to discontinue their UCB6114 treatment and/or the study. 
Therefore, the date that the decision was made to discontinue UCB6114 will be used to 
determine whether the participant completed a cycle of study treatment. If a decision was made 
to discontinue UCB6114 on >Day 28 relative to Day 1 of the particular cycle then the participant 
will be counted as having completed the cycle. Similar derivations will be programmed for 
Cohort 3 based on a 21-day cycle, and for both Cohorts 3 and 4 based on Day 1 dosing only. 
For any interim deliveries at a data cut-off, if a participant did not attend Day 1 of their next 
cycle and there was no decision to discontinue UCB6114, then the latest date available for that 
participant should be used to determine whether they have completed a full cycle of UCB6114. 
Whether or not a participant has completed the study is defined as having received at least 2 
complete cycles of study treatment and attended the SFU visit. The investigator will record a 
study participant’s disposition status at study termination according to this definition of a 
‘completed’ participant, however, a study completion flag will also be programmatically derived 
based on the relevant data on the database and the above rules for defining completion of a full 
cycle of study treatment. 
The listing of study discontinuation will include the primary reason for early study 
discontinuation, the number of cycles of study treatments received, and the total number of days 
on study treatment. 
5.2 Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types defined in 
the IPD specification document, as per Section 3.4. 
A listing of all IPDs identified at the DEM will be presented for all study participants based on 
the SS and will include the deviation type and description. In addition, a listing of all protocol 
deviations related to COVID-19 (whether considered important or not) will be presented for the 
SS. The number and percentage of participants in the SS with IPDs will be summarized by 
treatment group and for all participants for each deviation type. The number and percentage of 
participants who were excluded from the PPS will also be presented. The denominator for the 
percentage calculations will be the number of participants in the SS. A summary will also be 
presented for all protocol deviations related to COVID-19, all IPDs related to COVID-19 and all 
IPDs-related to COVID-19 leading to exclusion from the PPS. 
 
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
6.1 Demographics 
A by-participant listing of demographics will be presented based on the ES. This will include the 
year of birth, age (as entered by investigator in the eCRF in years), sex, race, ethnicity, height (in 
cm), weight (in kg) and body mass index (BMI, in kg/m2). Height will be the measurement 
obtained at the Screening visit and weight will be the last non-missing value prior to the first 
dose of study treatment. 
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The BMI will be derived in the database using the height and weight measurements recorded at 
the Screening visit and will be automatically reported to 1 decimal place on the eCRF. 
All demographic characteristics (except for date of birth) will be summarized by treatment group 
and for all study participants based on the SS. The summary of age will include descriptive 
statistics and categorical summaries, the latter based on requirements for EudraCT and 
clinicaltrials.gov reporting. In addition, summaries will be programmed by tumor type (CRC, 
Gastric/GEJ-Cancer and Pancreatic Adenocarcinoma) depending on the number of participants 
with specific tumor types and may be presented in the CSR. 
For the EudraCT reporting, the categories will include: 
• 18 to <65 years; 
• 65 to <85 years. 
For clinicaltrials.gov reporting, the categories will include: 
• ≤18 years; 
• 19 to <65 years; 
• ≥65 years. 
Childbearing potential and method of birth control will be listed for the ES. 
6.2 Cancer history 
All cancer history data for Part A1 participants will be listed for the ES. This listing will include 
date of initial diagnosis, tumor type, TNM Classification of Malignant Tumors (TNM) 
classifications and stage, Duke’s score (participants with CRC only), histological and cytological 
diagnosis details (as relevant), whether the participant had any metastases and associated 
anatomical location, and whether the participant had received any prior anti-cancer systemic 
therapies (including the number of lines of any prior anti-cancer systemic therapies, prior 
radiation therapies and prior anti-cancer surgeries). 
Time since initial diagnosis (calculated in months using date of Screening visit and date of initial 
diagnosis and multiplying the duration in days by 12/365.25), tumor type, T, N, and M 
classifications and TNM stage, Duke’s score (participants with CRC only), presence of 
metastases and anatomical location of metastases will be summarized by treatment group and for 
all study participants based on the SS. In the summaries of categorical variables, percentages will 
be calculated based on the number of study participants with non-missing data. Further, for the 
Duke’s score, the denominator for the percentage calculation will be the number of participants 
with CRC. 
Cancer history will be programmed by tumor type (CRC, Gastric/GEJ-Cancer and Pancreatic 
Adenocarcinoma) depending on the number of participants with specific tumor types and may be 
presented in the CSR. 
6.3 Prior anti-cancer therapy 
Details recorded for each line of prior anti-cancer systemic therapy received by a study 
participant will be listed for the ES. This listing will include the line and type of systemic 
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therapy, intent, drug name and dose, formulation, indication (current/ultimate), start and end 
dates, number of cycles received and the number of days per cycle, the participant’s best 
response and the date of that best response, reason for discontinuation and whether the 
participant had disease progression prior to the next line of systemic therapy. If there was 
progression, then the date of progression will also be listed. In addition, time from completion of 
the last prior anti-cancer systemic therapy to the start of UCB6114, whether the participant had 
progression after the last line of anti-cancer systemic therapy and, if so, the time from 
progression to the start of UCB6114 will be derived and listed. 
For those participants in the ES who received prior radiotherapy, the following data will be 
listed: treatment site, type of radiotherapy, intent, settings (concurrent with other anti-cancer 
systemic therapy or stand-alone radiation therapy), and, if concurrent radiotherapy, the anti-
cancer systemic therapy line that the radiotherapy was given with and the drug name. In addition, 
the start and stop dates, total cumulative dose (if known), number of fractions (if known), the 
participant’s best response to radiotherapy and whether the tumor at the treatment site had 
progressed since radiotherapy will be included in this listing. 
A further listing of prior anti-cancer radiotherapy with systemic therapy regimens will be 
presented for participants in the ES who had concurrent prior anti-cancer systemic therapy and 
radiotherapy as their prior anti-cancer therapy. This listing will include radiotherapy treatment 
site, start and stop dates of radiotherapy and systemic therapy together with the participant’s best 
response to that regimen. 
Date of surgery/procedure, anatomical location, description of the surgical procedure and 
whether the tumor was completely removed will be listed for those study participants in the ES 
who had prior anti-cancer surgeries or procedures. 
The following summaries of prior anti-cancer therapy regimens and surgeries will be presented 
by treatment group and for all participants for the SS: 
• Number of prior anti-cancer therapy regimens (0, 1, 2, 3, >3) (including all anti-cancer 
systemic therapy lines given alone and concurrently with radiotherapy)  
• Best response to the most recent prior anti-cancer therapy regimen 
• Number of prior anti-cancer systemic therapy + radiotherapy regimens (0, 1, 2, 3, >3) 
• Best response to the most recent anti-cancer systemic therapy + radiotherapy regimen 
• Reasons for discontinuation of the most recent line[a]   
• Time from completion of most recent line[a] to the start of UCB6114 (<1 month, 1-<3 
months, 3-6 months, >6 months)[b] 
• For participants that progressed after their most recent line[a], the time from progression 
to the start of UCB6114 (<1 month, 1-<3 months, 3-6 months, >6 months)[b] 
• Number of prior anti-cancer radiotherapies (including radiotherapies given alone and 
concurrently with anti-cancer systemic therapy) (0, 1, 2, >2) 
• Number of prior anti-cancer surgeries and procedures (0, 1, 2, >2) 
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[a] Most recent line is the last prior anti-cancer therapy regimen received which may be a prior 
anti-cancer systemic therapy given alone or concurrently with radiotherapy. 
[b] 1 month = 30 days. 
Time from completion and time from progression relative to the last line of anti-cancer systemic 
therapy will also be summarized using frequency counts and percentages as well as summary 
statistics. 
The number and percentage of participants with any prior anti-cancer systemic therapy, and any 
prior anti-cancer systemic therapy given concurrently with radiotherapy will be summarized for 
the SS by treatment group and for all participants, and by WHODD Anatomical Main Group 
[Level 1 term text], Pharmacological Subgroup [Level 3 term text] and PT. 
Prior anti-cancer therapy summaries will be programmed by tumor type (CRC, Gastric/GEJ-
Cancer and Pancreatic Adenocarcinoma) depending on the number of participants with specific 
tumor types and may be presented in the CSR. 
6.4 Cancer status at Screening 
The current cancer status of study participants at entry into Part A1 of this study will be assessed 
at the Screening visit and listed for the ES. This listing will include tumor type, T, N and M 
classifications and TNM stage, Duke’s score (participants with CRC only), histological and 
cytological diagnosis details (as relevant), whether the participant has any metastases and 
associated anatomical location, whether the tumor is recurrent and whether the participant had 
relapsed from their last line of anti-cancer systemic therapy.  
Tumor type, T, N, and M classifications and TMN stage, Duke’s score (participants with CRC 
only), presence of metastases and anatomical location of metastases, and time since relapse on 
last line of therapy (calculated in days using the date of the Screening visit and date of relapse) 
will be summarized by treatment group and for all study participants based on the SS. In the 
summaries of categorical variables, percentages will be calculated based on the number of study 
participants with non-missing data. Further, for the Duke’s score, the denominator for the 
percentage calculation will be the number of study participants with CRC. 
Cancer status will be programmed by tumor type (CRC, Gastric/GEJ-Cancer and Pancreatic 
Adenocarcinoma) depending on the number of participants with specific tumor types and may be 
presented in the CSR. 
6.5 Medical history and concomitant diseases 
Medical history will be listed for the ES and summarized by MedDRA® system organ class 
(SOC) and preferred term (PT) by treatment group and for all study participants for the SS. The 
reported term will be included in the listing. Previous medical history (any previous medical 
conditions with a stop date prior to the start of UCB6114) and ongoing medical history (any 
ongoing medical conditions with a missing stop date but recorded as ongoing on the eCRF) will 
be summarized separately. These summaries will include the number and percentage of study 
participants and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the incidence in all study participants.  
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Non-anti-cancer procedure history will be listed for the ES and concomitant medical procedures 
performed during the study will be listed for the SS. 
Medical history and concomitant disease may be presented by tumor type (CRC, Gastric/GEJ-
Cancer and Pancreatic Adenocarcinoma) depending on the number of participants with specific 
tumor types. 
6.6 Prior and concomitant medications 
Prior medications will include any medications that started prior to the date of the first dose of 
UCB6114. This will include medications that started prior to the first dose of UCB6114 and 
continued after. 
Concomitant medications will include medications with a start date on or after the first dose of 
UCB6114 and prior to the date of the last dose of UCB6114 + 30 days, and whose stop date is 
either missing, or on or after the date of the first dose of UCB6114. Any medications with a start 
date prior to the first dose of UCB6114 and a stop date after, or continued to be ongoing during 
the study, will also be classified as concomitant medications. Medications with a start date > 30 
days after the last dose of UCB6114 will be considered as post-study medications and will not be 
included in the summaries of concomitant medication.  
Any medication that started prior to and stopped after the first dose of UCB6114 or continued to 
be ongoing during the study, will be classified as both prior and concomitant.  
Any medications with completely missing start dates will be classified as both prior and 
concomitant provided that a stop date is not present or a stop date is present but is prior to the 
first dose of UCB6114.  
Any medications with partially missing dates will be handled as described in Section 4.4.1 to 
classify them as prior or concomitant. 
All medications (prior, concomitant and post-study) will be listed for the ES. Any prohibited 
concomitant medications, rescue medications or steroid use will be identified via a medical 
review and flagged in this listing.   
Prior and concomitant medications (per the definitions above) will be summarized for the SS by 
treatment group and by WHODD Anatomical Main Group [Level 1 term text], Pharmacological 
Subgroup [Level 3 term text] and PT. The reported term will be included in the listing. Separate 
summaries will be presented for prior medications and concomitant medications.  
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in all study participants. 
A glossary of all prior and concomitant medications will be presented for the SS including the 
Anatomical Main Group (Level 1), Pharmacological Subgroup (Level 3), PT and reported term.  
Prior and concomitant medications will be programmed by tumor type (CRC, Gastric/GEJ-
Cancer and Pancreatic Adenocarcinoma) depending on the number of participants with specific 
tumor types and may be presented in the CSR. 
 
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7 MEASUREMENTS OF TREATMENT COMPLIANCE 
During Part A1 of this study, administration of study treatment will be performed via iv infusion 
at the study site under the supervision of the designated site personnel and in compliance with 
the Guideline for First in Human clinical studies (EMEA/CHMP/SWP/28367/07Rev. 1). 
Compliance will be monitored at the site through a review of accountability logs which will be 
used to record study treatment dispensing and return information to ensure that each study 
participant received the correct dose level and frequencies of dosing (e.g. Q3W, Q4W). 
Any dosing deviations will be reviewed as IPDs at the DEMs and assessed for possible impact 
on the PPS and PKS. If considered important, these deviations will be included in the summary 
and listing of IPDs. 
 
 
8 SAFETY ANALYSES 
All safety summaries and listings will be presented by treatment group based on the SS, unless 
otherwise stated. 
All safety summaries will be programmed by tumor type (CRC, Gastric/GEJ-Cancer and 
Pancreatic Adenocarcinoma) depending on the number of participants with specific tumor types 
and may be presented in the CSR. 
8.1 Extent of exposure 
Details on UCB6114 administration on Day 1 (all cohorts) and Day 15 (Cohort 1 and 2 only) of 
each cycle will be listed. This listing will be split into two parts. The first part will include the 
start and stop dates and times of infusion, duration of infusion, infusion rate, whether the 
infusion was temporarily stopped/interrupted, whether the infusion was permanently 
discontinued and, if this was the case, whether the interruption or permanent discontinuation was 
due to an AE or other reason. The second part of this listing will include, for each visit, infusion 
site, total volume delivered, volume infused, planned total dose and total dose actually 
administered at infusion. In addition, the percentage of planned dose received, total dose 
administered across all cycles, the number of complete cycles of UCB6114 received and the total 
number of doses of UCB6114 received will be listed. 
The percentage of planned dose received will be calculated for UCB6114 for each study 
participant at each dosing visit within each cycle as follows: 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑜𝑓 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑= 100 × 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒
 
Actual duration of infusion will be calculated in minutes only for those study participants who 
did not have any temporary interruption(s) of their infusion using the infusion start and stop 
times and included on this listing. Length of interruption(s) will be calculated in minutes for 
those study participants who had temporary interruption(s) of their infusion. 
Extent or duration of exposure will be calculated and summarized. Frequency counts and 
percentages for the number of complete cycles of UCB6114 received (0, 1, 2, 3, 4, >4) and 
summary statistics for the total dose of UCB6114 received across all cycles, the total number of 
doses of UCB6114 received and the duration of exposure to UCB6114 will be presented.  
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Total duration of exposure will be calculated in days as follows: 
𝑇𝑜𝑡𝑎𝑙 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒) + 30  
Note that 30 days is added to this calculation to account for a participant’s continued exposure to 
UCB6114 following their last dose of study treatment. 
Note that the definition of a participant deemed to have completed a full cycle of UCB6114 is 
given in Section 5.1. 
8.2 Adverse events 
The primary safety endpoints for Part A1 of this study are the incidence and severity of TEAEs 
(including SAEs) from the first dose of UCB6114 treatment on Day 1 of Cycle 1 until the end of 
the SFU Period (up to 30 days following the last dose of UCB6114), and the incidence of DLTs 
from the first dose of UCB6114 on Day 1 of Cycle 1 until the end of the DLT Observation 
Period (Day 28 of Cycle 1). 
All AEs for a participant will be recorded in the eCRF from the time of informed consent until 
completion or early discontinuation of Part A1 of this study. Serious adverse events are to be 
reported up to 30 days after the Final Visit (i.e. up to 150 days after the last dose of UCB6114). 
All AEs in Part A1 of the study will be coded using MedDRA® and classified as pre-treatment 
and treatment-emergent relative to the first infusion of UCB6114.   
Adverse events with a start date prior to the first dose of UCB6114 will be defined as pre-
treatment AEs. A TEAE is defined as any AE with a start date on or after the first dose of 
UCB6114 up until the last dose of UCB6114 + 30 days. A pre-treatment AE which increases in 
severity on or after the first dose of UCB6114 will also be counted as a TEAE. Note that in this 
case, the pre-existing AE will have a stop date and an outcome of ‘worsened’ and a new AE 
(with the same verbatim) will be entered with the same start date and the increased severity 
recorded on the eCRF. Any AE (including SAEs) with an onset date later than the last dose of 
UCB6114 + 30 days will not be considered as treatment-emergent and therefore will not be 
included in the tabulations of TEAEs. These AEs will be considered as post-study AEs and will 
be listed only. Where onset dates are missing or partially missing, AEs will be assumed to be 
treatment-emergent, unless there is clear evidence to suggest that the AE started prior to the first 
dose of UCB6114 and did not increase in severity. Missing or partially missing dates for AEs 
will be handled as described in Section 4.4.1. 
Adverse events will be assigned an NCI CTCAE severity grade (Grade 1/Grade 2/Grade 3/Grade 
4/Grade 5), where possible. If a CTCAE toxicity grading is not possible, then the intensity of the 
AE (mild/moderate/severe) will be recorded on the eCRF. If the AE is not gradable, is serious, 
and is considered as life threatening, then the intensity for this AE will be missing and one of the 
reasons for seriousness will be recorded as life threatening. 
Adverse events will also be categorized according to their relationship to UCB6114 (related/not 
related), and whether the event is a DLT, as judged by the investigator. A DLT is defined as a 
TEAE at least possibly related to UCB6114 that occurs during Cycle 1 and fulfills any of the 
criteria listed in Section 4.1.2.4 of the protocol. The investigator is expected to record whether an 
AE is a DLT on the eCRF. 
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An overview of the number and percentage of participants who experience TEAEs will be 
presented. This summary will include the number and percentage of participants with any 
TEAEs, serious TEAEs, related TEAEs (related to UCB6114), discontinuations from study 
treatment (UCB6114) due to TEAE(s), discontinuations from the study due to TEAE(s), CTCAE 
Grade ≥ 3 TEAEs, CTCAE Grade ≥3 related TEAEs, DLTs, AEs leading to death and TEAEs 
leading to death; event counts will also be included against each of these categories. The 
overview of TEAEs may be presented by tumor type (CRC, Gastric/GEJ-Cancer and Pancreatic 
Adenocarcinoma) depending on the number of participants with specific tumor types. 
In addition, the following summaries will be presented by SOC, high level term (HLT) and PT, 
and, where indicated, also by tumor type (CRC, Gastric/GEJ-Cancer and Pancreatic 
Adenocarcinoma) depending on the number of participants with specific tumor types: 
• Incidence of TEAEs (overall and by tumor type); 
• Incidence of serious TEAEs (overall and by tumor type); 
• Incidence of non-serious TEAEs (overall and by tumor type); 
• Incidence of TEAEs leading to a temporary interruption of study treatment infusion 
and/or dose reduction (overall and by tumor type); 
• Incidence of TEAEs leading to discontinuation of study treatment (overall and by tumor 
type); 
• Incidence of TEAEs leading to discontinuation of study (overall and by tumor type); 
• Incidence of DLTs (overall and by tumor type); 
• Incidence of adverse events of special interest (AESIs) (Potential Hy’s Law – see Section 
8.2.1 below) (overall and by tumor type); 
• Incidence of UCB6114 infusion-related reactions (defined as hypersensitivity reactions, 
anaphylactic reactions and cytokine release syndrome – see Section 8.2.2) (overall and by 
tumor type); 
• Incidence of TEAEs by maximum CTCAE severity grade (overall and by tumor type); 
• Incidence of TEAEs by maximum relationship to UCB6114 (overall and by tumor type); 
• Incidence of TEAEs by relationship; 
• Incidence of serious TEAEs by relationship; 
• Incidence of non-serious TEAEs by relationship; 
• Incidence of fatal TEAEs by relationship; 
• Incidence and event rate of TEAEs by treatment-emergent ADA positivity. 
The following summaries will be presented by SOC and PT for EudraCT reporting: 
• Incidence of non-serious TEAEs above the threshold of 5% of participants in any 
treatment group; 
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• Incidence of non-serious TEAEs above the threshold of 5% of participants in any 
treatment group by relationship; 
The above summaries of TEAEs will be ordered alphabetically by SOC, alphabetically by HLT 
within SOC and decreasing incidence of PT events within SOC /HLT in all study participants.  
For tables including only the number and percentage of participants, summaries will be ordered 
alphabetically by SOC, alphabetically by HLT within SOC and decreasing incidence of 
participants with each PT within SOC /HLT in all study participants. 
The incidence of TEAEs by maximum CTCAE severity grade will be presented by CTCAE 
term. CTCAE term will be obtained from the NCI CTCAE Version 5.0 via a mapping of 
MedDRA® lowest level terms (LLTs). This summary will be ordered by decreasing incidence of 
participants with each CTCAE term in all study participants. 
Summary tables will contain frequency counts and percentages, and the number of events, where 
applicable. A study participant who experiences the same event multiple times will be counted 
only once in the frequency counts for the PT, but all events will be included. 
In the summaries of TEAEs by relationship, participants will be counted in “Not related” and 
“Related” categories (or “Missing” in the case where an event has a missing relationship). A 
study participant who experiences the same event multiple times will be included in the most 
related category for the summaries by maximum relationship.  
In the overview summary of TEAEs, participants will be counted as having at least one TEAE 
with CTCAE severity grade ≥3, and in the summary of TEAEs by maximum CTCAE severity 
grade, participants will be counted as having at least one TEAE in the following categories: 
‘Grade 1’, ‘Grade 2’, ‘Grade 3’, ‘Grade 4’, ‘Grade 3 or 4’, ‘Grade 5’, and ‘Grade ≥3’. Events for 
which no CTCAE severity grade is recorded by the investigator but an intensity is recorded 
instead, the intensity of this event will be assigned to a CTCAE severity grade for the purpose of 
these summaries, i.e. ‘Mild’ will be included as ‘Grade 1’, ‘Moderate’ will be included as ‘Grade 
2’, ‘Severe’ will be included as ‘Grade 3’ and ‘Life Threatening’ will be included as ‘Grade 4’ 
and, if the participant dies due to the event, it will be included as ‘Grade 5’. The determination of 
whether the event is life threatening or results in death will be based on the reason for 
seriousness recorded as life-threatening or death on the eCRF, or on the event having a fatal 
outcome. Otherwise, if both the CTCAE severity grade and intensity is missing then the CTCAE 
severity grade in these summaries will be missing. A study participant who experiences the same 
event multiple times will be included in the highest severity grade category in the summary of 
TEAEs by maximum CTCAE severity grade.  
A glossary of all AEs will be presented including the MedDRA® SOC, HLT, PT, reported term 
and LLT.  
A listing of all AEs will be presented by study participant for the ES. The listing will include the 
onset date and stop date of the event (including relative days) and also the onset times and stop 
times of events where available. The period of onset of AEs will also be presented on this listing. 
Period of onset of AEs will be defined as follows for the purpose of the listing: 
• 
If the AE has an onset date prior to the date of the Screening visit, then Period=Pre-study; 
 
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• 
If the AE has an onset date on or after the date of the Screening visit and has an onset 
date and time prior to the start time of UCB6114 infusion on Day 1 of Cycle 1 then 
Period=Screening; 
 
• If the AE has an onset date and time on or after the start time of UCB6114 infusion on 
Day 1 of Cycle 1 and up to the date and time of the start of Cycle 2 (i.e. prior to the start 
time of the UCB6114 infusion on Day 1 of Cycle 2) then Period=Cycle 1; 
 
• If the AE has an onset date and time on or after the start time of UCB6114 infusion on 
Day 1 of Cycle 2 and up to the date and time of the start of Cycle 3 (i.e. prior to the start 
time of the UCB6114 infusion on Day 1 of Cycle 3) then Period=Cycle 2; 
 
• Same as above for subsequent cycles (Cycle 3 etc.); 
 
• If the AE has an onset date after the last dose of UCB6114 up to and including 30 days 
after the last dose of UCB6114, then Period=SFU; 
 
• If the event has an onset date after the 30-day period following the last dose of UCB6114, 
then Period=Post-study. 
The listing of all AEs will also include the AE duration (derived in days, hh:mm for AEs with 
onset and stop times recorded and derived in days for all other AEs with only onset and stop 
dates recorded), days since start of UCB6114 infusion (time if an onset time is recorded, days 
otherwise), seriousness and reason for seriousness, CTCAE severity grade, intensity (where a 
CTCAE severity grade is not recorded), pattern of event, relationship to UCB6114 and action 
taken with UCB6114 (including other action taken), the outcome of the AE, whether an autopsy 
was performed and cause of death. In addition, the listing will flag AEs that led to 
discontinuation from the study, TEAEs, AESIs, SAEs, infusion-related reactions, and DLTs. 
Whether an AE is related to a concomitant medication (which will include the COVID-19 
vaccination) and the names of any co-suspect medications will also be listed. 
Separate listings of all SAEs, TEAEs leading to discontinuation of UCB6114 and TEAEs leading 
to discontinuation of the study will also be presented.  
All deaths that occur on study (defined as during study treatment or within 30 days of the latest 
dose of UCB6114) will be listed separately. This listing will include the primary cause of death 
and the number of days between the date of the last dose of UCB6114 and death, defined as 
𝐷𝑎𝑦𝑠 𝑠𝑖𝑛𝑐𝑒 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114 ) + 1 
8.2.1 
Adverse events of special interest  
An AESI is any AE that a regulatory authority has mandated be reported on an expedited basis, 
regardless of the seriousness, expectedness, or relatedness of the AE to the administration of a 
UCB product/compound.  
For ONC001, potential Hy’s Law is used to identify AESIs and is defined using the laboratory 
data and the following potential drug-induced liver injury (PDILI) criteria: 
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• ≥3x upper limit of normal (ULN) alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin on the same day, in the 
absence of ≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the 
biochemical abnormality; 
• Study participants who have evidence of liver metastases may be considered to have an 
alternate etiology for the described laboratory abnormalities. 
All AESIs will be flagged on the listing of AEs. 
8.2.2 
Infusion-related reactions  
Infusion-related reactions are defined as hypersensitivity reactions, anaphylactic reactions and 
cytokine release syndrome with onset within 24 hours after the start of the UCB6114 infusion.   
All potential infusion-related reactions will be identified programmatically and will then undergo 
medical review for confirmation based on participant characteristics and other signs and 
symptoms. The final assessment from the medical review will be used in the programming to 
ensure that all infusion-related reactions are flagged correctly in the listings and included in the 
relevant summaries. 
Hypersensitivity reactions will be programmatically identified as any TEAE with a PT from both 
a narrow and broad scope search of category A terms of the ‘Hypersensitivity’ SMQ. 
Anaphylactic reactions will be programmatically identified using an algorithmic approach based 
on the ‘Anaphylactic Reaction’ SMQ. Further details on this algorithm are given in Section 13.1. 
Note that if the MedDRA® version is increased from 25.1 during the study, any changes to the 
terms included in the ‘Anaphylactic Reaction’ SMQ should be applied. 
Cytokine release syndrome will be programmatically identified as any TEAE with a PT of 
‘Cytokine release syndrome’ from the broad scope search of category A terms of the 
‘Hypersensitivity’ SMQ. Since this disorder is characterized by fever, headache, tachycardia, 
hypotension, rash, tachypnoea and/or hypoxia, a further medical review of participants with 
these events occurring within 24 hours after the start of the infusion of UCB6114 will be 
performed to confirm any further infusion-related reactions. 
Note that any other AEs (i.e. not identified as infusion-related reactions using the rules above) 
which result in a temporary interruption or permanent discontinuation of a UCB6114 infusion 
will not be considered as an infusion-related reaction. 
8.3 Clinical laboratory evaluations 
Laboratory tests will be performed at the Screening visit, predose on UCB6114 dosing visits 
(Days 1 and 15 of each cycle for participants in Cohorts 1 and 2 and on Day 1 of each cycle for 
participants in Cohorts 3 and 4) and at the SFU visit. In addition, participants in Cohort 4 will 
have laboratory tests performed on non-dosing Day 15 of Cycle 1 and 2 only. 
 
Due to the use of multiple local laboratories (1 per site in the UK and US) in Part A1 of this 
study, results will potentially be recorded in different units and with reference to different normal 
ranges. Further, for some laboratory tests, different normal ranges will be applied to males and 
females and age groups. As a first step to ensure comparability of laboratory results, results and 
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normal ranges will be converted to the same International System of Units (SI) units using 
UCB’s standard conversion factors. This will be programmed at the Study Data Tabulation 
Model (SDTM) level. Note though that the simple conversion to SI units does not represent a full 
homogenization of results from different local laboratories using different methods. To ensure 
full comparability, the observed laboratory results will be normalized to a unique set of standard 
reference ranges (for hematology, clinical chemistry and coagulation parameters) using the 
location-scale normalization formula (Chuang-Stein, 1992).  
𝑠= 𝐿𝑆+ (𝑥− 𝐿𝑋) (𝑈𝑆−𝐿𝑆)
(𝑈𝑋− 𝐿𝑋) 
and when the standard lower limit is 0: 𝑠= 𝑥
𝑈𝑆
𝑈𝑋  where: 
s = normalized observed value 
x = original observed value in SI units 
LS = Lower Limit of the reference range chosen to be the standard reference range 
US = Upper Limit of the reference range chosen to be the standard reference range 
LX = Lower Limit of the reference range associated with the original observed value in 
SI units (local laboratory reference range) 
UX = Upper Limit of the reference range associated with the original observed value in 
SI units (local laboratory reference range) 
 
This transformation preserves the distance of the original laboratory result from the lower limit 
of normal as a multiple of the specified standard reference range. 
Note that the choice of the standard reference range is arbitrary, however, the most recent 
reference ranges used by ICON Central Laboratories (including the age and gender specific 
reference ranges for parameters, where available) will be used to normalize the results in this 
study. 
Normalization of the laboratory results will be performed in the ADaM programming by ICON. 
All laboratory data (hematology, serum chemistry and coagulation) and changes from Baseline 
for numeric variables will be listed for participants who have at least one value outside of the 
reference range. All urinalysis data will be listed for all participants. Data will be listed by study 
participant, laboratory panel, laboratory parameter and visit within each treatment group. Any 
laboratory measurements that are BLQ or ALQ will be handled as described in Section 4.4. For 
the relevant numeric laboratory parameters, the reference ranges supplied by the local analytical 
laboratory will be used to flag values outside the reference range as low or high in this listing. 
For the parameters for which the local laboratory cannot supply the reference ranges, the 
reference ranges provided by ICON Central Laboratories will be used instead. A listing of all 
laboratory results outside of the reference range will also be presented. The reference ranges will 
also be reported in the listings. 
In addition, for the relevant hematology, clinical chemistry and coagulation laboratory tests, 
CTCAE severity grades (Grade 1, Grade 2, Grade 3, Grade 4) will be applied (where possible) in 
the ADaM programming according to NCI CTCAE Version 5.0, and these grades will also be 
listed for the relevant laboratory parameters. Note that Grade 0 will be applied in cases where a 
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result is normal for the relevant laboratory test and Grade 5 is not applicable in the grading of 
laboratory data. 
Observed values and changes from Baseline in the hematology, serum chemistry and coagulation 
parameters presented below in Table 8-1 will be summarized at each visit.   
The summaries of normalized hematology, serum chemistry and coagulation values and changes 
from Baseline may be presented by tumor type (CRC, Gastric/GEJ-Cancer and Pancreatic 
Adenocarcinoma) depending on the number of participants with specific tumor types. 
For those laboratory parameters with a CTCAE toxicity assigned, shift tables for the change 
from Baseline in CTCAE severity grade at each visit will be presented.  
Table 8-1: 
Clinical Laboratory Assessments 
Laboratory Assessment 
Laboratory Parameters 
Hematology 
Platelet Count, RBC Count, Hemoglobin, Hematocrit, RBC Indices 
(MCV, MCH, MCHC), WBC Count with Differential (Absolute 
Neutrophils, Absolute Lymphocytes, Absolute Monocytes, 
Absolute Eosinophils, Absolute Basophils) 
Clinical Chemistry 
ALT, AST, ALPa , Bicarbonate, Sodium, Potassium, Magnesium, 
Chloride, Calcium, Total Bilirubin, BUN or Urea, Serum 
Creatinine, Glucose (non-fasted), Phosphorus or Phosphate, 
Albumin, Total Protein, Uric Acid, Amylase, GGT, Cholesterol, 
Creatine Kinase, CRP, LDH, Lipase, Triglycerides 
Coagulation 
aPTT and either prothrombin time or INR  
Routine Urinalysis 
Specific Gravity, pH, Glucose, Protein, Blood, Ketones, Bilirubin, 
Urobilinogen, Nitrite, Leukocyte Esterase by Dipstick 
Microscopic Examination (if blood or protein is abnormal, 
including crystals) 
Screening Tests 
Pregnancy tests: FSH and estradiol (for women of non-childbearing 
potential only); serum or urine hCG pregnancy test (for women of 
childbearing potential)  
Bone turnover markers: blood BAP, blood CTx, urinary NTx and 
urinary CTxII  
Tumor markers: e.g. PSA, CA125, CA19-9 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BAP=bone alkaline phosphatase; BUN=blood urea nitrogen; CA=cancer antigen; CRP=C-reactive protein; CTx=C-terminal telopeptide; 
FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; hCG=human chorionic gonadotropin; INR=international normalized 
ratio; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume; NTx=N-terminal telopeptide; PSA=prostate specific antigen; RBC=red blood cell; WBC=white blood cell.  
a including liver-specific ALP for use in assessing participants with bone metastases at Screening. In the case of bone metastases liver function 
abnormalities considered potential Hy’s law cases, the liver-specific ALP must be separated from the total in participants with bone metastases 
and used to assess the liver function instead of the total ALP. 
The screening laboratory tests included above in Table 8-1 (as available for Part A1) will be 
listed only. 
Liver function abnormalities will be defined using the following criteria: 
• ALT or AST ≥2xULN 
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• ALT or AST ≥3xULN 
• Total bilirubin ≥2xULN 
• Total bilirubin ≥3xULN 
• ALT or AST ≥5xULN 
• ALT or AST ≥8xULN 
• ALT or AST ≥3xULN AND total bilirubin ≥2xULN (>35% direct bilirubin) 
For the subgroups of participants with liver metastases and without liver metastases at Baseline, 
the number and percentage of participants in each liver function abnormality category will be 
summarized at each visit. 
In addition, participants with PDILI criteria are those that fulfill the following laboratory data 
(based on liver function tests) criteria at a visit: 
• AST or ALT and total bilirubin within the normal range at Baseline and AST or ALT 
≥3xULN concurrent with total bilirubin ≥2xULN; 
• AST, ALT or total bilirubin above ULN at Baseline and AST or ALT ≥2 times Baseline 
values AND AST or ALT ≥3xULN (participants without liver metastases at 
Baseline)/AST or ALT ≥8xULN (participants with liver metastases at Baseline) 
concurrent with total bilirubin above ULN at Baseline and total bilirubin ≥2 times 
Baseline value or ≥3xULN (whichever is lower). 
All relevant laboratory data collected for participants with a PDILI event (i.e. liver function tests) 
will be listed at the visits at which at least one of the above criteria was fulfilled.  
The number and percentage of participants meeting different combinations of the ALT, AST and 
total bilirubin criteria defined above will be summarized by treatment group. This summary will 
be presented for all participants as well as for the subgroups of participants who had liver 
metastases at Baseline and participants without liver metastases at Baseline. 
A separate listing will also be produced containing drug-induced liver injury relevant family 
medical history, lifestyle data (alcohol consumption or drug abuse in the previous 6 months), 
hepatic event supplemental medical history and any hepato-toxic medications taken for 
participants in the SS with a PDILI event. 
8.4 Vital signs, physical findings, and other observations related to safety 
8.4.1 
Vital signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include:  
• Systolic and diastolic blood pressure; 
• Pulse rate; 
• Oral body temperature; 
• Respiratory rate. 
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Vital signs will be measured at the Screening visit, on UCB6114 dosing visits (Days 1 and 15 of 
each cycle for participants in Cohorts 1 and 2 and on Day 1 of each cycle for participants in 
Cohorts 3 and 4) and at the SFU visit. In addition, participants in Cohort 4 will have vital signs 
measured on non-dosing Day 15 of Cycle 1 and 2 only.  
On UCB6114 dosing visits, vital signs will be measured at multiple timepoints relative to the 
UCB6114 infusion: predose, 10 minutes (±5 minutes) and 30 minutes (±10 minutes), after the 
start of the infusion, at the end of the infusion (+15 minutes) and at 2 hours (+15 minutes) after 
the end of the infusion.  
In addition, on Cycle 1 Day 1, vital signs will also be assessed at 5 hours (+2 hours) after the end 
of the infusion. All vital signs measurements on UCB6114 dosing visits and at the SFU visit will 
be performed prior to the collection of PK samples. 
Observed vital sign measurements and changes from Baseline will be listed by visit and 
timepoint and summarized using descriptive statistics.   
For the multiple vital signs measurements on UCB6114 dosing visits (i.e. on Days 1 and 15 of 
each cycle for participants in Cohorts 1 and 2 and on Day 1 of each cycle for participants in 
Cohorts 3 and 4), changes from the predose value will be calculated at each postdose timepoint 
and summarized using descriptive statistics.   
For each vital signs parameter, the mean (±standard deviation) change from Baseline value will 
be plotted over scheduled visit and timepoint with treatment group overlaid on the same plot. 
Vital signs may be presented by tumor type (CRC, Gastric/GEJ-Cancer and Pancreatic 
Adenocarcinoma) depending on the number of participants with specific tumor types. 
The incidence of treatment-emergent markedly abnormal (TEMA)/potentially clinically 
significant (PCS) vital signs based on blood pressure and pulse rate measurements will be 
summarized by visit and timepoint using frequency counts and percentages. The criteria for 
identifying a TEMA/PCS are included in Table 8-2. 
Table 8-2: 
TEMA/PCS Criteria for Vital Signs 
Variable (unit) 
Lowa 
Higha 
Systolic Blood Pressure (mmHg)  
 
Value <90 and ≥20 decrease 
from Baseline 
Value >140 and ≥20 increase from 
Baseline 
Diastolic Blood Pressure 
(mmHg)  
Value <50 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
Pulse Rate (bpm) 
Value <45 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
bpm=beats per minute; PCS=potentially clinically significant; mmHg=millimeter of mercury; TEMA=treatment-emergent  
markedly abnormal. 
a Both conditions must be satisfied for a measurement to be considered PCS. 
8.4.2 
12-Lead Electrocardiograms  
ECGs will be performed at the Screening visit, on Day 1 of each cycle and at the SFU visit. On 
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Day 1 of Cycle 1, ECGs will be performed prior to dosing, at the end of the infusion and at 2 
hours after the end of the infusion. ECGs at each scheduled timepoint will be performed in 
triplicate with the participant in a supine position after a minimum of 5 minutes rest. When an 
ECG assessment coincides with PK (and PD) sampling, the ECG should be performed first.  
All ECGs will be evaluated for any clinically relevant changes by the investigator.  
Electrocardiograms will also be collected for central reading, the data from which will be 
analyzed separately and reported in an addendum to the CSR.   
All summaries and listings of ECG data will be based on the local (site) 12-lead ECG 
measurements. 
The following ECG parameters will be reported: 
• PR interval;  
• QT interval; 
• QRS interval; 
• QTcF interval (QT corrected for heart rate using Fridericia’s formula [QTcF]); 
• Heart rate.  
Observed values and changes from Baseline in these ECG parameters will be listed and 
summarized by visit using descriptive statistics. The mean of the triplicate measurements taken 
for each parameter will be used in the summary at each visit and timepoint. If less than 3 of the 
triplicate measurements are taken then the mean of the available measurements will be used (if 
only 1 of the 3 triplicate measurements is available, then this value will be used in the 
summaries). The Baseline value will be the mean of the last scheduled or unscheduled triplicate 
measurements taken prior to the first dose of study treatment on Day 1 of Cycle 1. If no predose 
triplicate measurements are taken then the mean of the triplicate measurements taken at 
Screening will be used. The mean of only the scheduled triplicate measurements at each Post-
Baseline visit and timepoint will be included in the summary.   
For the multiple ECGs performed, changes from the predose value will be calculated at each 
postdose timepoint and summarized using descriptive statistics.   
Mean (±standard deviation) change from Baseline in QTcF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot. Individual observed values of QTcF will be 
presented over actual time in a spaghetti plot. Plots may be presented by tumor type (CRC, 
Gastric/GEJ-Cancer and Pancreatic Adenocarcinoma) depending on the number of participants 
with specific tumor types. 
The following cut-points in QTcF will be applied for observed data and changes from Baseline:  
For observed QTcF data: 
• <450 msec; 
• ≥450 to <480 msec; 
• ≥480 to <500 msec; 
• ≥500 msec. 
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For changes from Baseline in QTcF: 
• <30 msec; 
• ≥30 to <60 msec; 
• ≥60 msec. 
The incidence of participants in each of these categories will be summarized using frequency 
counts and percentages by visit. 
A listing of 12-lead ECG abnormal findings will be presented. 
8.4.3 
Echocardiogram 
Echocardiograms will be performed at the Screening visit, on Day 1 of Cycle 3 (+/- 7 days), as 
clinically indicated afterwards, and at the SFU visit.  
All details on the echocardiogram assessments performed at each visit will be listed including the 
observed LVEF measurements and changes from Baseline, as well as information on whether the 
result was normal, abnormal not clinically significant (NCS) or abnormal clinically significant 
(CS). 
Observed values and changes from Baseline in LVEF will be summarized by visit using 
descriptive statistics. In addition, shift tables for the change from Baseline in normal, abnormal 
NCS, abnormal CS LVEF results will be summarized by visit. 
Mean (±standard deviation) change from Baseline in LVEF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot. Individual observed LVEF results will be 
presented over actual time in a spaghetti plot. Plots may be presented by tumor type (CRC, 
Gastric/GEJ-Cancer and Pancreatic Adenocarcinoma) depending on the number of participants 
with specific tumor types. 
8.4.4 
ECOG performance status 
ECOG performance status will be assessed at the Screening visit, on Day 1 of each cycle and at 
the SFU visit. ECOG performance status will be listed by participant and visit and will be 
summarized using frequency counts and percentages. A shift table summarizing the changes 
from Baseline to each post-Baseline visit will also be presented. Further details on the ECOG 
performance scale, the listings and summaries are included in Section 10.2. 
8.4.5 
Physical examination 
Physical examination will be undertaken at the Screening visit and on Cycle 1 Day 1 prior to 
dosing with UCB6114. Symptom-directed physical examinations will be performed prior to 
dosing with UCB6114 (Days 1 and 15 of each cycle for participants in Cohorts 1 and 2 and on 
Day 1 of each cycle for participants in Cohorts 3 and 4) and at the SFU visit. In addition, 
participants in Cohort 4 may have symptom-directed physical examinations performed on non-
dosing Day 15 in Cycle 1 and 2 only. 
All physical examination data will be listed. 
 
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9 PHARMACOKINETICS AND PHARMACODYNAMICS  
9.1 Pharmacokinetics 
9.1.1 
Secondary pharmacokinetic endpoint 
9.1.2 
Exploratory pharmacokinetic endpoints 
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9.2 Pharmacodynamics 
The following exploratory PD and biomarker endpoints/analyses will be obtained/performed 
from blood samples which will be analyzed at a number of external laboratory vendors: 
• cGremlin-1;  
• Serum protein/proteomic analysis;  
• Transcriptomic analysis;  
• Genetic analysis;  
• ctDNA.
For all cohorts, blood samples for cGremlin-1 analysis will be collected on Day 1 of Cycle 1 at 
the following timepoints relative to the UCB6114 infusion: predose (within 30 minutes prior to 
the infusion), end of the infusion (+15 minutes) and 4 hours (+1 hour) postinfusion. For Cohorts 
1, 2 and 4, a blood sample will be collected predose (within 30 minutes prior to the infusion) on 
Day 15 or on the day of the Day 15 visit if this is not a dosing day (Cohort 4). For Cohort 3, a 
blood sample will be taken on Day 15. In all subsequent cycles for all cohorts, blood samples 
will be collected at predose (within 30 minutes prior to the infusion) on Day 1 and at the SFU 
visit. For Cycle 3 only, an additional sample will be taken on Day 1. An additional sample 
should also be collected on the day of the On-Treatment biopsy (only if taking place on a day 
where no samples for cGremlin-1 are scheduled).  
cGremlin-1 will be reported as concentration in blood by nominal (scheduled) assessment and 
treatment group. Concentrations of cGremlin-1 will be listed for the SS and summarized for the 
PDS using descriptive statistics by treatment group and nominal (scheduled) sampling timepoints 
(n, arithmetic mean, median, standard deviation, minimum, maximum, geoMean, geoCV and 
95% CI for the geoMean [assuming lognormally distributed data]). Changes from Baseline will 
also be summarized. Individual study participant cGremlin-1 concentration-time profiles will be 
displayed graphically in spaghetti plots and geoMean cGremlin-1 concentration and 95% CI will 
be plotted at each nominal (scheduled) timepoint with treatment group overlaid on the same plot. 
Serum protein/proteomic analysis, transcriptomic analysis, genetic analysis and the analysis of 
the test results from the blood samples taken for ctDNA will be performed and reported 
separately outside of the CSR. 
Hematoxylin and eosin (H & E) staining and immunohistochemistry (IHC) will be used to 
analyze tissue samples obtained from any available historical tumor biopsies taken prior to 
participants’ entry into the study (e.g. at the time of diagnosis), from the tumor biopsy performed 
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at Baseline [between Day -28 and Day -1 during the Screening Period] and from the On-
Treatment tumor biopsy performed within 2 weeks post Cycle 1 Day 15 [i.e. between Cycle 1 
Day 15 and Cycle 2 Day 1] for Cohorts 1, 2 and 4, and within 2 weeks post Cycle 2 Day 1 [i.e. 
between Cycle 2 Day 1 and Cycle 2 Day 15] for Cohort 3).  
Test results from the H & E staining and for target genes, phosphatase and tensin homolog 
(PTEN), Ki67 (cellular marker for proliferation in tumors), Gremlin-1, mothers against 
decapentaplegic homolog 4 (SMAD4), fibroblast activation protein (FAP) and phosphorylated 
mothers against decapentaplegic homolog 1/5/8 (pSMAD1/5/8) will be listed by variable, 
timepoint and sample analyzed (multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant).  
The following key/component variables will be derived based on H & E staining, PTEN, Ki67, 
Gremlin-1, FAP and pSMAD1/5/8 test results. Selected raw test results and key variables will be 
listed and summarized as described below. No derived variables will be generated for SMAD4; 
only raw test results and changes from Baseline (where relevant) will be listed and summarized.  
Listings will be generated for the SS and summaries will be based on the PDS. 
Changes from Baseline will be calculated for selected raw test results and key variables. Since a 
participant may have multiple tissue samples analyzed from the Baseline tumor biopsy, the mean 
of the test results at Baseline will be used in the calculation of the change from Baseline for each 
On-Treatment sample result. 
Summaries of the selected key derived variables and raw test results (observed values and 
changes from Baseline) will be generated on a tissue sample level basis, i.e. results for all 
samples analyzed for all participants at each timepoint will be included.   
H & E: Tissue Integrity (Percentage of Necrosis in Tumor Area) 
All H & E raw test results will be listed. 
In order to assess tissue integrity, percentage of necrosis in the tumor area will be categorized as 
‘<20%’ and ‘>=20%’. If percentage of necrosis data are missing but other H & E staining and 
IHC data are available for tumor biopsy samples analyzed, then results will be categorized as 
‘Not done’.  
This categorical variable will be listed and summarized using frequency counts and percentages 
at each timepoint (i.e. historical, Baseline and On-Treatment) by treatment group.  
PTEN: Tissue Sample Quality Control 
The presence/absence of staining of intrinsic control elements on the slides and the level of 
staining intensity will be listed together with the staining pattern, staining artifacts and any 
assay-specific comments. Since the percent of tumor cells with staining intensity 0/1/2/3 and the 
H-score (test results for which will be provided by the laboratory) are less relevant to assessing 
the quality control of the tissue sample, these raw test results will not be listed. 
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The presence of staining of intrinsic control elements on the slides together with the level of 
staining intensity will be used to determine the tissue sample quality control. 
If staining of intrinsic control elements on stained slides=’YES’ and staining intensity of intrinsic 
control elements on stained slides is 1, 2 or 3 then the tissue sample quality control is ‘Good’, 
otherwise, if the staining intensity of intrinsic control elements=0 then the tissue sample quality 
control is ‘Questionable’. If staining of intrinsic control elements on stained slides=’NOT 
PRESENT’ then the tissue sample quality control is ‘No staining present’. If both variables are 
missing but other IHC results are available for tumor biopsy samples analyzed, then results will 
be categorized as ‘Not done’.  
This categorical variable will be listed and summarized using frequency counts and percentages 
at each timepoint (i.e. historical, Baseline and On-Treatment) by treatment group.  
Ki67 – Proliferative Activity of the Tumor  
All Ki67 raw test results will be listed together with changes from Baseline in the number of 
Ki67-positive cell objects in the tumor region divided by the total number of cell objects in the 
tumor region, and the number of Ki67-positive cell objects in the tumor region divided by the 
area of the tumor region for each On-Treatment test result. 
In order to assess the proliferative activity of the tumor mass, cellular proliferation reflected by 
the number of Ki67-positive cell objects in the tumor region divided by the total number of cell 
objects in the tumor region will be categorized as ‘<=10%’ or ‘>10%’ with the latter category 
indicating an actively/moderately proliferating tumor. If the test result is ‘NOT EVALUABLE’ 
or missing but IHC results are available for tumor biopsy samples analyzed, then results will be 
categorized as ‘Not done’.  
This categorical variable will be listed and summarized using frequency counts and percentages 
at each timepoint (i.e. Historical, Baseline and On-Treatment) by treatment group. The number 
of Ki67-positive cell objects in the tumor region divided by the total number of cell objects in the 
tumor region will also be summarized at each timepoint together with the change from Baseline 
at the On-Treatment timepoint using descriptive statistics (n, arithmetic mean, standard 
deviation, median, minimum and maximum) by treatment group.  
Gremlin-1: Cytoplasmic Histoscore  
Tissue sample results will be available for Gremlin-1 from historical tumor biopsies and biopsies 
performed at Baseline (during the Screening period prior to the first dose of UCB6114), where 
available. 
All Gremlin-1 raw test results will be listed. 
The cytoplasmic histoscore will be calculated as a weighted score based on the percentage of 
tumor cells with Gremlin-1 cytoplasmic staining intensity 1, 2 or 3 as follows: 
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(1 x percent tumor cells with Gremlin-1 cytoplasmic staining intensity 1) + (2 x percent tumor 
cells with Gremlin-1 cytoplasmic staining intensity 2) + (3 x percent tumor cells with Gremlin-1 
cytoplasmic staining intensity 3). 
The histoscore will be missing if the participant had tumor biopsy samples analyzed but there are 
no test results for percent tumor cells with Gremlin-1 cytoplasmic staining intensity 1, 2 or 3. 
Summary statistics (n, arithmetic mean, standard deviation, median, minimum and maximum) 
will be presented at each timepoint (Historical and Baseline) by treatment group for the 
cytoplasmic histoscore and the tumor proportion score. The cytoplasmic histoscore will be listed 
together with the Gremlin-1 raw test results. 
SMAD4 
All SMAD4 raw test results will be listed together with the changes from Baseline in percent 
SMAD4 protein expression loss for each On-Treatment test result. 
Observed values of percent SMAD4 protein expression loss will be summarized using 
descriptive statistics (n, arithmetic mean, standard deviation, median, minimum and maximum) 
at each timepoint (Historical, Baseline and On-Treatment) by treatment group. In addition, 
changes from Baseline at the On-Treatment timepoint will be summarized by treatment group.  
FAP 
During the image analyses of FAP-stained slides from tumor biopsies at each timepoint, the 
tumor will be classified into 2 regions: the cancer (CN) tumor region and the invasive margin 
(IM) region using a pre-established digital automated algorithm. The IM region is usually a small 
proportion of the whole tumor and, per standard procedures at the analytical laboratory, will be 
identified first. As a result, there is a risk that some parts of the CN tumor region may be 
inaccurately classified as part of the IM region, particularly in cases when the tumor is small. 
Therefore, instead of using the results for the percentage of high, medium and low intensity FAP 
provided by the laboratory, a decision was made to back-calculate the areas of the CN tumor 
region and the IM region and add these together in order to re-calculate the percentage of high, 
medium and low intensity FAP in the whole tumor. 
These back-calculated results and derived variables based on FAP test results at each timepoint 
are defined in Table 9-1. 
Table 9-1: 
FAP Derived Variables 
Variable 
No. 
FAP Derived Variable 
Description and Calculation 
1[a] 
Total Analyzed Tumor 
Area (um2) 
This is the total tumor area (um2) across the CN tumor region 
and the IM region and will be calculated as the sum of the areas 
of the CN tumor region (um2) and the IM region (um2) where a 
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Variable 
No. 
FAP Derived Variable 
Description and Calculation 
non-missing numeric test result is available for both the area of 
the CN tumor region and the area of the IM region. Note that, in 
cases where no IM region is defined, the area of the IM region 
will be recorded as 0 or ‘NOT APPLICABLE’, or may be 
missing. If the area of the IM region is recorded as ‘NOT 
APPLICABLE’ or is missing, then 0 will be assumed in this 
calculation and the total analyzed tumor area will be equal to 
the area of the CN tumor region. 
This variable will be missing if both the areas of the CN tumor 
region and IM region are missing, or if one or both are ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
2  
Measured Area of Weakly 
Stained FAP in the CN 
Tumor Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
CN tumor region (weak positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of weakly stained FAP in the CN tumor region (%) 
where a non-missing numeric test result is available for both the 
area of the CN tumor region and the relative area of weakly 
stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
3  
Measured Area of 
Moderately Stained FAP 
in the CN Tumor Region 
(um2)  
This is the back-calculated area of moderately stained FAP in 
the CN tumor region (moderate positive) and will be calculated 
by multiplying the area of the CN tumor region (um2) and the 
relative area of moderately stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
moderately stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
4  
Measured Area of 
Strongly Stained FAP in 
the CN Tumor Region 
(um2)  
This is the back-calculated area of strongly stained FAP in the 
CN tumor region (strong positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of strongly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
strongly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
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Variable 
No. 
FAP Derived Variable 
Description and Calculation 
5  
Measured Area of Weakly 
Stained FAP in the IM 
Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
IM region (weak FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative area 
of weakly stained FAP in the IM region (%) where a non-
missing numeric test result is available for both the area of the 
IM region and the relative area of weakly stained FAP in the IM 
region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
6  
Measured Area of 
Moderately Stained FAP 
in the IM Region (um2)  
This is the back-calculated area of moderately stained FAP in 
the IM region (moderate FAP-positive) and will be calculated 
by multiplying the area of the IM region (um2) and the relative 
area of moderately stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area of 
the IM region and the relative area of moderately stained FAP in 
the IM region. 
This variable will be set to 0 if one or both are ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
7 
Measured Area of 
Strongly Stained FAP in 
the IM Region (um2)  
This is the back-calculated area of strongly stained FAP in the 
IM region (strong FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative area 
of strongly stained FAP in the IM region (%) where a non-
missing numeric test result is available for both the area of the 
IM region and the relative area of strongly stained FAP in the 
IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
8[a] 
Total FAP-Positive 
Tumor Area (um2) 
This is the total FAP-positive area across the CN tumor region 
and the IM region (whole tumor) and will be calculated as the 
sum of component derived variables 2-7. 
If all 6 component variables are 0 then this derived variable will 
be missing. 
9[a] 
Total Measured Area of 
Weakly Stained FAP 
(um2) 
This is the total weak FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be calculated 
as the sum of component FAP derived variables 2 and 5. 
10[a] 
Total Measured Area of 
Moderately Stained FAP 
(um2) 
This is the total moderate FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
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Variable 
No. 
FAP Derived Variable 
Description and Calculation 
calculated as the sum of component FAP derived variables 3 
and 6. 
11[a] 
Total Measured Area of 
Strongly Stained FAP 
(um2) 
This is the total strong FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be calculated 
as the sum of component FAP derived variables 4 and 7. 
12[a] 
Total Relative Area of 
Weakly Stained FAP (%) 
This is the percentage of weak FAP expression across the CN 
tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 9 as   
(Total Measured Area Of Weakly Stained FAP / Total Analyzed 
Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
13[a] 
Total Relative Area of 
Moderately Stained FAP 
(%) 
This is the percentage of moderate FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 10 as   
(Total Measured Area Of Moderately Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
14[a] 
Total Relative Area of 
Strongly Stained FAP (%) 
This is the percentage of strong FAP expression across the CN 
tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 11 as   
(Total Measured Area Of Strongly Stained FAP / Total Analyzed 
Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
15[a] 
Total Relative FAP-
Positive Tumor Area 
(TPS) (%) 
This is the total proportion score which is the percentage of 
FAP-positive area across the CN tumor region and the IM 
region (whole tumor) and will be calculated using component 
derived variables 1 and 8 as  
(Total FAP-Positive Tumor Area / Total Analyzed Tumor Area) 
x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
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Variable 
No. 
FAP Derived Variable 
Description and Calculation 
16[a] 
Total FAP Histoscore 
This is a histoscore for the combined CN tumor region and IM 
region (whole tumor) and will be calculated as a weighted score 
based on component derived variables 12, 13 and 14 as  
(1 x Total Relative Area of Weakly Stained FAP) + (2 x Total 
Relative Area of Moderately Stained FAP) + (3 x Total Relative 
Area of Strongly Stained FAP) 
CN=cancer; FAP=fibroblast activation protein, IM=invasive margin, TPS=total proportion score. 
[a] Included in the listing of FAP test results. 
The derived variables containing the [a] flag in Table 9-1 above will be listed together with 
information on staining artifacts and any assay-specific comments provided by the laboratory. 
Observed values for total relative FAP-positive tumor area (TPS) and total FAP histoscore will 
be summarized using descriptive statistics (n, arithmetic mean, standard deviation, median, 
minimum and maximum) at each timepoint (Historical, Baseline and On-Treatment) by 
treatment group. In addition, changes from Baseline in TPS and total FAP histoscore at the On-
Treatment timepoint will be listed and summarized by treatment group.  
pSMAD1/5/8: Nuclear Histoscore 
All pSMAD1/5/8 raw test results will be listed. 
The nuclear histoscore will be calculated as a weighted score based on the percentage of tumor 
cells with pSMAD1/5/8 nuclear staining intensity 1+, 2+ or 3+ as follows:  
(1 x percent tumor cells with pSMAD1/5/8 nuclear staining intensity 1+) + (2 x percent tumor 
cells with pSMAD1/5/8 nuclear staining intensity 2+) + (3 x percent tumor cells with 
pSMAD1/5/8 nuclear staining intensity 3+). 
The histoscore will be missing if the participant had tumor biopsy samples analyzed but there are 
no test results for percent tumor cells with pSMAD1/5/8 nuclear staining intensity 1+, 2+ or 3+. 
Summary statistics (n, arithmetic mean, standard deviation, median, minimum and maximum) 
will be presented at each timepoint (Historical, Baseline and On-Treatment) by treatment group 
the nuclear histoscore and the tumor proportion score.   
Further informal analyses may be performed to explore the relationship between the PD and 
biomarker endpoints with antitumor activity and ADA status. The PK-PD effects of UCB6114 
may be assessed using a population analysis approach. These analyses will also be performed 
separately outside of the CSR and the details of analysis methods will be included in a separate 
analysis plan.  
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The incidence of PD samples taken from the blood and tumor biopsies will be summarized by 
visit/timepoint and treatment group.  
9.3 Immunogenicity 
Anti-drug (UCB6114) antibody status and classification, changes from Baseline in titer over time 
and the incidence of treatment-emergent ADA positivity are exploratory immunogenicity 
endpoints in Part A1 of this study. Potential relationships between ADA and PK, PD, antitumor 
activity and safety will also be explored but this will be reported separately outside of the CSR. 
Serum samples will be collected from all study participants for the measurement of ADA and the 
evaluation of immunogenicity according to the Schedule of Activities in the protocol.  
All listings of ADA will be presented for the SS and summaries of the ADA data will be 
summarized by treatment group for the ADAS. 
Anti-drug (UCB6114) antibodies will be measured using a three-tiered assay approach: 
Screening assay, confirmatory assay and titration assay.  
Samples will first be evaluated in the Screening assay (reported as ‘negative screen’ or ‘positive 
screen’), followed by analysis of screened positive samples in the confirmatory assay to confirm 
the positivity of the samples (reported as ‘negative immunodepletion’ or ‘positive 
immunodepletion’). Samples that are confirmed as positive in the confirmatory assay will be 
evaluated in a titration assay to assess the ADA level and this will be reported as titer (reciprocal 
dilution factor including minimum required dilution [MRD]). 
The ADA sample status will be determined as follows from the pre-treatment sample taken on 
Day 1 of Cycle 1 (Baseline) and all post-treatment (post-Baseline) samples.  
• Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
• Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
Anti-drug (UCB6114) antibody sample status will be listed for each participant at each visit by 
treatment group. This listing will include sampling dates and times, the Screening assay result, 
the confirmatory assay result and the derived ADA sample status. In addition, the titer from the 
titration assay (if applicable) will be listed together with the change from Baseline in titer. The 
number and percentage of participants with a positive or negative sample at each visit will be 
summarized by treatment group. Percentages will be calculated based on the number of 
participants with a non-missing/sufficient sample at the visit. 
Based on the ADA status of the samples, study participants will be categorized according to the 
following 6 ADA classifications in Table 9-2: 
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Table 9-2: 
ADA Classifications 
Classification Classification Label 
Definition 
1 
Pre-ADA negative – treatment 
induced ADA negative 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA negative status at all sampling 
timepoints post-Baseline (including SFU).  
Participants with missing post-Baseline samples are 
included as long as the missing samples do not 
result in an unmonitored period greater than 16 
weeks. 
2 
Pre-ADA negative – treatment 
induced ADA positive 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA positive status at any sampling 
timepoint post-Baseline (including SFU).  
3 
Pre-ADA positive – treatment 
reduced ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA negative status at all 
sampling timepoints post-Baseline (including SFU)  
4 
Pre-ADA positive – treatment 
unaffected ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with titer values of the same magnitude as Baseline 
(≤1.80-fold difference from the Baseline value) or 
with decreased titer values compared to Baseline 
(>1.80-fold decrease from the Baseline value). 
5 
Pre-ADA positive – treatment 
boosted ADA positive 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with increased titer values compared to Baseline 
(>1.80-fold increase from the Baseline value. 
6 
Inconclusive 
Includes participants who do not satisfy the criteria 
for classifications 1-5 
ADA=anti-drug (UCB6114) antibody; SFU=Safety Follow-up. 
Note: The terminology ‘treatment unaffected’ is ambiguous as the criteria refers to ADA responses that are not increased upon 
dosing compared to Baseline level whereas titers may reduce. 
A study participant will be classified as having treatment-emergent ADA positivity if they 
satisfy one of the following criteria: 
• The Baseline result is ADA negative and at least one post-Baseline result is ADA 
positive (pre-ADA negative – treatment induced ADA positive) – ADA classification 2 in 
Table 9-2; 
• The Baseline result is ADA positive and at least one post-Baseline result shows a pre-
defined fold increase in titer from the Baseline value (the fold increase from Baseline 
required to meet this criterion will be defined with the development of the assay and will 
be included in the TFLs) (pre-ADA positive – treatment boosted ADA positive) – ADA 
classification 5 in Table 9-2. 
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Total anti-drug (UCB6114) antibody incidence will be determined by the number and 
percentage of participants with treatment-emergent ADA positivity (as defined above). The 
denominator for the percentage calculation will be the number of participants with at least one 
available/reported post-Baseline result.  
Total prevalence of pre-ADA will be determined by the number and percentage of participants 
who are pre-ADA positive (i.e. participants who have a positive ADA sample status at Baseline).  
The denominator for the percentage calculation will be the number of participants with an 
available/reported Baseline sample result. 
Total anti-drug (UCB6114) antibody prevalence will be determined by the number and 
percentage of participants with ADA classifications 2, 4 and 5 in Table 9-2 (i.e. an ADA positive 
status at any post-Baseline sampling timepoint. The denominator for the percentage calculation 
will be the number of participants with at least one available/reported sample result (either at 
Baseline and/or post-Baseline). 
The ADA classification for each participant will be listed by treatment group. This listing will 
also include whether or not the participant achieved treatment-emergent ADA positivity (ADA 
incidence), whether the participant was pre-ADA positive (pre-ADA prevalence) and whether 
the participant had an ADA positive status at any post-Baseline sampling timepoint (ADA 
prevalence). In addition, the visit at which the participant first achieved treatment-emergent 
ADA positivity will be included.  
The number and percentage of participants in each of the 6 ADA classifications defined above in 
Table 9-2 will be presented by treatment group. The denominator for the percentage calculations 
will be the number of participants who have a non-missing ADA classification. Also, in this 
tabulation, ADA incidence and prevalence (as defined above) will be summarized. 
The first occurrence of treatment-emergent ADA positivity (based on the criteria above) will be 
summarized using frequency counts and percentages at each post-Baseline visit by treatment 
group. This tabulation will include a count of the number of participants at each post-Baseline 
visit who fulfill at least one of the above defined criteria for treatment-emergent ADA positivity; 
participants will be counted in the numerator based on the earliest visit at which one of these 
criteria is fulfilled. At other visits, participants will be counted in the denominator (assuming an 
assessment of treatment-emergent positivity is available) and this will be used in the percentage 
calculations. 
Individual study participant ADA titer profiles over actual time will be presented graphically on 
the linear and the semi-logarithmic scale. The linear scale plots will be repeated for the subset of 
participants who achieve treatment-emergent ADA positivity during Part A1.   
Mean (±standard deviation) Cmin will be plotted by ADA sample status over scheduled time with 
treatment groups overlaid on the same plot. 
 
10 
EFFICACY ANALYSES 
10.1 Antitumor activity 
The analysis of antitumor activity is exploratory in Part A1 of this study. 
 
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Tumor assessments will be performed at the Screening visit, every 8 weeks from Day 1 of Cycle 
1, and at the SFU visit. 
10.1.1 
Definitions of the antitumor activity endpoints 
The following endpoints are defined based on RECIST (Version 1.1) which standardizes solid 
tumor measurements and provides guidelines for the objective assessment of changes in tumor 
size during anti-cancer treatment.   
Appendix 9 (Section 11.9) of the protocol contains the RECIST 1.1 guidelines to be used in this 
study, adapted from Eisenhauer (2009), and includes the definitions of target and non-target 
lesions, the definitions of target and non-target lesion responses at each tumor assessment, the 
criteria for determining overall tumor response at each tumor assessment based on target lesion 
response, non-target lesion response and the presence/absence of new lesions, and a participant’s 
best overall response (BOR). Further details on the rules to apply in the derivation of BOR are 
included in the Derivation of Efficacy Endpoints document Version 0.6 (dated 21 JAN 2022) 
which has been developed to support this SAP. 
At each post-Baseline tumor assessment, the investigator will record responses for target lesions 
and non-target lesions, whether or not there has been an appearance of any new lesions, and the 
participant’s overall tumor response based on their target lesion response, non-target lesion 
response and the presence/absence of new lesions. Note that target lesion response and non-
target lesion response assessments will be based on the changes in the pre-existing lesions at 
Baseline and the appearance of new lesions will only factor in the determination of an overall 
tumor response of PD at that tumor assessment visit (i.e. per Tables A and B in Section 11.9.2 of 
Appendix 9 of the protocol). 
Objective response rate (ORR) is defined as the percentage of participants with a BOR of 
complete response (CR) or partial response (PR) during Part A1.   
Disease Control Rate (DCR) is defined as the percentage of participants with a BOR of CR, 
PR, or stable disease (SD) during Part A1.   
Best overall response (BOR) is defined for each study participant as the best overall tumor 
response from each tumor assessment (scheduled and unscheduled assessments performed every 
8 weeks from Day 1 of Cycle 1 (±7 days)) according to the RECIST criteria for changes in target 
and non-target lesions and the appearance of new lesions. Best overall response is determined 
from the start of study treatment (first dose of UCB6114) until documented objective disease 
progression or the date of subsequent anti-cancer therapy (systemic therapy, surgery or 
radiotherapy for cancer), whichever occurs first. If anti-cancer therapy is started on the same day 
as a tumor assessment, then the overall tumor response from that assessment will be used in the 
derivation of BOR. If a participant does not have objective disease progression and does not start 
a subsequent anti-cancer therapy, then all tumor assessments (scheduled and unscheduled) up to 
the SFU visit will be included in the derivation of BOR. For a BOR of SD, a participant’s tumor 
measurements must have met the SD criteria at least once after the start of study treatment at a 
minimum interval of no less than 49 days.   
 
For Part A1, BOR determination requires confirmation of CR or PR responses at a subsequent 
assessment ≥4 weeks (28 days) after the criteria for CR or PR responses are first met, however, 
an unconfirmed BOR will also be derived for each participant for the purpose of reporting (as 
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described below in Section 10.1.2). Table C in Appendix 11.9 of the protocol and Table 1 and 
subsequent text in the Derivation of Efficacy Endpoints document provides detail on the 
derivation of BOR when confirmation of CR and PR responses is required. The definition of an 
unconfirmed BOR is also included in this document. Although the derivation of unconfirmed 
BOR does not include the requirement for a CR or PR response to be confirmed ≥4 weeks (28 
days) after the initial response, a participant's CR or PR response may, in fact, be confirmed at a 
subsequent assessment ≥4 weeks (28 days) after the criteria for the CR or PR response are first 
met.  
Confirmed BOR and unconfirmed BOR will be derived programmatically based on the overall 
tumor assessment data recorded on the eCRF by the investigator.  
Duration of response (DOR) will be calculated for participants with a confirmed BOR of CR or 
PR as the time in days from the start date of the confirmed CR or PR (i.e. the date of the first 
overall tumor response of CR or PR, which is at least 4 weeks before a second overall tumor 
response of CR or PR) to the first date that recurrent or progressive disease is objectively 
documented (i.e. according to the RECIST guidelines). This will be referred to as the duration of 
confirmed response and the following calculation will be performed: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
Duration of response will also be calculated for participants with an unconfirmed BOR of CR or 
PR (which may either be confirmed at a later tumor assessment or unconfirmed) as the time in 
days from the start date of the CR or PR to the date of the first documented objective disease 
progression (i.e. according to the RECIST guidelines). The following calculation will be 
performed: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For the purpose of a sensitivity analysis of both duration of confirmed response and duration of 
unconfirmed response, the above calculations will take into consideration the occurrence of both 
objective disease progression (per RECIST 1.1) and clinical disease progression (as described in 
Appendix 11.9 of the protocol and as determined by the investigator and recorded as a reason for 
study treatment discontinuation on the eCRF), whichever occurs first. If clinical disease 
progression occurs on the same date that a participant’s objective disease progression is 
determined, then the participant will be included in the sensitivity analyses as having objective 
disease progression. 
The following calculations will therefore be performed for the sensitivity analyses: 
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𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For participants who die without objective disease progression, duration of confirmed response 
and duration of unconfirmed response will be censored on the date of death, regardless of cause. 
For a participant who discontinues early from Part A1 of the study with no objective disease 
progression, DOR will be censored on the date of their last available (scheduled or unscheduled) 
tumor assessment at which a lack of objective disease progression was determined. Participants 
who discontinue study treatment but who do not have documented objective disease progression 
(i.e. according to the RECIST guidelines), duration of confirmed response and duration of 
unconfirmed response will be censored at the date of their last available (scheduled or 
unscheduled) tumor assessment at which a lack of objective disease progression was determined. 
Such participants might include those that are ongoing in Part A1 at the time of any defined data 
cut-off. Likewise, participants who have not discontinued early and do not have documented 
objective disease progression after a confirmed or unconfirmed response, duration of confirmed 
response and duration of unconfirmed response will be censored at the date of their last available 
(scheduled or unscheduled) tumor assessment. 
In the sensitivity analyses of duration of confirmed response and duration of unconfirmed 
response, the same censoring rules will apply except that the date of last contact will be used for 
the censoring of participants who discontinue early from Part A1 without objective disease 
progression, clinical disease progression or death. 
Date of last contact will be the latest of the dates of premature study termination and of last 
contact recorded on Study Termination eCRF page, the date of death, the date of last dose of 
study treatment, the dates of all visits, AE start and end dates (with partial dates imputed as 
earliest possible) and the date of contact recorded on the Survival Safety Follow-up and Survival 
Final Follow-up eCRF forms. 
Further details on the rules to apply in the derivation of duration of confirmed response and 
duration of unconfirmed response are included in the Derivation of Efficacy Endpoints document 
Version 0.6 (dated 21 JAN 2022) which has been developed to support this SAP. 
Progression-free survival (PFS) will be calculated as the time in days from the first dose of 
study treatment to the date of the first documented objective disease progression (i.e. according 
to the RECIST guidelines), or death due to any cause, whichever occurs first. The following 
calculation will be performed: 
𝑃𝐹𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒/𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒) + 1  
Participants who die due to any cause without a documented objective disease progression will 
be considered to have progressed on the date of their death. Participants who do not have any 
post-Baseline tumor assessments will be censored on the date of their first dose of study 
treatment. Participants who discontinue early from Part A1 or discontinue study treatment 
without documented objective disease progression or death, will be censored on the date of their 
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last available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who start anti-cancer therapy during Part A1 without a 
prior documented objective disease progression will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment prior to the initiation of the subsequent 
anti-cancer therapy. If anti-cancer therapy starts on the same date as the participant’s tumor 
assessment and determination of objective disease progression, or the participant’s death (due to 
any cause), then the participant will not be censored and the participant will be included as 
having an uncensored event on this date. This censoring rule will also be applied to participants 
who are ongoing at any data cut-off for an analysis of Part A1 data who have no documented 
objective disease progression. The use of anti-cancer therapy during Part A1 will be identified 
via ongoing medical review of the concomitant medications together with the start dates of 
further anti-cancer therapy information recorded on the survival follow-up pages of the eCRF. 
As a sensitivity analysis, PFS will also be calculated as the time in days from the first dose of 
study treatment to the date of the first documented objective disease progression (per RECIST 
1.1), the date of clinical disease progression, as determined by the investigator, or the date of 
death due to any cause, whichever occurs first. Last contact date (as defined above for DOR) will 
be used for the censoring of participants still alive with no reported disease progression 
(objective or clinical). The same rules described above for the censoring of participants who start 
anti-cancer therapy will be applied in this sensitivity analysis. 
Further details on the rules to apply in the derivation of PFS are included in the Derivation of 
Efficacy Endpoints document Version 0.6 (dated 21 JAN 2022) which has been developed to 
support this SAP. 
Overall survival (OS) will be calculated as the time in days from the date of first dose of 
UCB6114 to the date of death from any cause. Participants will be followed up to ascertain their 
survival status at the SFU visit (within 30 days after their last dose of UCB6114) and at the Final 
Visit (3 months after their last dose of UCB6114); they will not be followed up beyond this 
timepoint. 
The following calculation will be performed: 
𝑂𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114) + 1 
For participants who discontinue early from Part A1 of the study or who discontinue study 
treatment due to disease progression but continue in the study, who complete Part A1, or who are 
ongoing in the study at a data cut-off for Part A1, but are not known to have died, OS will be 
censored on the date of their last contact. 
Further details on the rules to apply in the derivation of OS are included in the Derivation of 
Efficacy Endpoints document Version 0.6 (dated 21 JAN 2022) which has been developed to 
support this SAP. 
10.1.2 
Analysis of the antitumor activity endpoints 
The analyses of the antitumor activity endpoints in Part A1 will be performed for the PPS. As a 
sensitivity analysis, all analyses will be repeated for the SS. All listings will be presented for the 
SS. Summaries and listings will be presented by treatment group. 
All lesion assessment data recorded at Baseline (Screening) and during the Treatment Period 
(every 8 weeks from Day 1 of Cycle 1 [±7 days]) will be listed separately for target lesions, non-
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target lesions and new lesions. Each post-Baseline tumor assessment will be labelled as ‘Tumor 
Assessment 1, Tumor Assessment 2 etc. – see further details below). These listings will include 
lesion number and lesion type (nodal/non-nodal), location, method of assessment, dimension (or 
an indication that the lesion is too small to measure, for target lesions only) and lesion response 
evaluation (for non-target lesions at post-Baseline assessments). The listing for target lesions will 
also include the derived eCRF component data used for the determination of the overall target 
lesion response at each post-Baseline assessment (e.g. sum of all dimensions across target lesions 
and percentage change from Baseline in the sum). In addition, the overall response assessment 
for target lesions and non-target lesions, as determined by the investigator, will be listed for each 
post-Baseline tumor assessment (Tumor Assessment 1, Tumor Assessment 2 etc.) together with 
the presence of new lesions and the investigator's overall tumor response assessment.    
The investigator's overall tumor response assessment will be summarized using frequency counts 
and percentages over time (tumor assessment). Post-Baseline tumor assessments are scheduled to 
be performed per protocol every 8 weeks from Day 1 (±7 days). For the purpose of this 
summary, the first post-Baseline tumor assessment (scheduled or unscheduled) will be assigned 
to ‘Tumor Assessment 1’ using the protocol-defined window of Day 50 to 64 (Day 57 ± 7 days) 
relative to Day 1 (first dose of UCB6114). For all subsequent post-Baseline tumor assessments 
(scheduled or unscheduled, but excluding tumor assessments performed at the SFU visit), these 
will be assigned to ‘Tumor Assessment 2’, ‘Tumor Assessment 3’ etc. using the protocol-defined 
window of Day 50-64 relative to the previous post-Baseline tumor assessment. If a post-Baseline 
tumor assessment is missed, then the scheduled day of the missed assessment will be used to 
window the next tumor assessment. In cases where a scheduled and unscheduled tumor 
assessment occurs in the same window, the investigator’s overall tumor response at both 
assessments will be considered. If the overall tumor response is NE at one of the assessments, 
then the overall tumor response from the other assessment will be included in the summary table. 
If the overall tumor response is not NE at both assessments, then the tumor assessment that is 
closest to the target day of the tumor assessment will be included in the summary table. In the 
event that the two tumor assessments are equidistant from the target day of the tumor assessment 
and neither have an overall tumor response of NE, then the worst case overall tumor response 
will be included in the summary table. Otherwise, if the post-Baseline tumor assessment falls 
outside of the protocol-defined window, it will be classified as an unscheduled assessment and 
not included in the summary of overall tumor response. 
Bar charts will also be produced for overall tumor response rate by treatment group over time 
(tumor assessment). In addition, waterfall plots of participants’ percentage change from Baseline 
in the sum of dimensions for all target lesions will be presented by treatment group over time 
(tumor assessment). The individual participants’ bars will be colored by overall tumor response 
at each timepoint. 
Confirmed and unconfirmed BOR for each participant will be derived programmatically using 
the investigator's overall tumor response assessments (scheduled and unscheduled) performed 
every 8 weeks from Day 1 of Cycle 1 and the RECIST criteria. Whether a BOR of CR or PR is 
confirmed or unconfirmed will be indicated on this listing. Using a participant’s confirmed BOR 
and unconfirmed BOR, whether the participant achieves an objective tumor response (i.e. a BOR 
of CR or PR) and/or disease control (i.e. a BOR of CR, PR or SD) during study treatment will be 
determined. These derived data will be listed for the SS. 
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Confirmed BOR and unconfirmed BOR will be summarized using frequency counts and 
percentages. Bar charts will be produced for confirmed BOR and unconfirmed BOR by treatment 
group. 
 
The number and percentage of participants achieving objective tumor response and disease 
control (ORR and DCR) based on confirmed BOR and unconfirmed BOR will be presented and, 
if data allow, exact 95% CIs for binomial proportions will be calculated using the Clopper-
Pearson method and presented for the response rates. In the calculation of ORR and DCR, the 
denominator will include all participants in the analysis set. Objective response rate and DCR 
(based on confirmed BOR and unconfirmed BOR) will also be summarized in bar charts by 
treatment group overall and by tumor type and ECOG performance status at Baseline. 
 
In addition, waterfall plots of each participant’s best percentage change from Baseline in the sum 
of the dimensions for all target lesions will be presented by treatment group overall and by tumor 
type and ECOG performance status at Baseline with the individual participants’ bars colored by 
confirmed BOR and unconfirmed BOR. 
 
The summaries and analyses of DOR, PFS and OS will be carried out as described below, if the 
data allow. 
Duration of confirmed response, duration of unconfirmed response and PFS will be listed and 
summarized descriptively using Kaplan-Meier estimation. These summaries will be repeated for 
the sensitivity analyses of these endpoints (defined in Section 10.1.1 above) and will include the 
number and percentage of participants with the event, the number and percentage of participants 
censored, minimum and maximum values and Kaplan-Meier estimates of the 25th percentile, 
median, 75th percentile and corresponding 95% CIs calculated using Greenwood’s formula. In 
addition, DOR and PFS rates at 3 months, 6 months and 9 months will be derived from the 
Kaplan-Meier estimation and presented together with associated 95% CIs. 
Kaplan-Meier curves will be presented for duration of confirmed response and duration of 
unconfirmed response and PFS, and for the associated sensitivity analyses. Treatment groups 
will be overlaid on each plot.   
Survival status collected on the eCRF at the SFU visit and at the Final Visit will be listed for 
each participant by treatment group. This listing will include the participant’s survival status, 
date and cause of death, whether an autopsy was performed and date of autopsy, whether the 
participant had received any further antitumor treatment after the last dose of study treatment and 
the type of treatment, and whether the participant’s disease had been assessed since the end of 
study treatment including method of assessment and the overall response.  
Overall survival times will be listed and summarized descriptively using Kaplan-Meier 
estimation. Note that since participants are only followed up for survival until the Final Visit in 
Part A1 of the study, a summary of OS may not be meaningful (i.e. if no participants die then OS 
cannot be assessed).   
Additional exploratory analyses of selected antitumor activity endpoints may be performed based 
on subgroups of participants in the SS.  
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Additionally, the relationship of the antitumor activity variables with key PK parameters may be 
explored but this will be reported separately. 
10.2 ECOG performance status 
ECOG performance status is an additional efficacy assessment performed in Part A1 of this 
study and is defined in Table 10-1. 
Table 10-1: ECOG Performance Status Scale 
Grade 
ECOG performance status scale 
0 
Fully active, able to carry on all pre-disease performance 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 for more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group. 
ECOG performance status will be listed by treatment group at each visit for the SS. 
ECOG performance status will be summarized as an ordinal categorical variable using frequency 
counts and percentages. Shift tables for the change from Baseline in each grade will be 
summarized by visit. 
 
11 
OTHER ANALYSES  
Not applicable. 
 
12 
REFERENCES 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-center 
clinical trials. Drug Information Journal. Vol 26, 77-84, 1992. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
European Medicines Agency, Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronovirus) Pandemic, accessed 29-March-2020.  
(https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf) 
International Council for Harmonization/Food and Drug Administration E9 Guidance (ICH-E9) 
(Phillips et al, 2003). 
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US Food and Drug Administration FDA Guidance on Conduct of Clinical Trials of Medical 
Products During COVID-19 Public Health Emergency Guidance for Industry, Investigators and 
Institutional Review Boards, accessed 29-March-2020. 
(https://www.fda.gov/media/136238/download) 
 
13 
APPENDICES 
13.1 SMQ algorithm for identification of anaphylactic reactions 
Based on MedDRA® Version 25.1 or higher, the SMQ=‘Anaphylactic reaction’ consists of 3 
parts: 
1) A narrow search containing PTs that represent core anaphylactic reaction terms:  
Category A 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Circulatory collapse 
Dialysis membrane reaction 
Kounis syndrome 
Procedural shock 
Shock 
Shock symptom 
Type I hypersensitivity
2) A broad search:  
Category B 
Acute respiratory failure 
Asthma 
Bronchial oedema 
Bronchospasm 
Cardio-respiratory distress 
Chest discomfort 
Choking 
Choking sensation 
Circumoral oedema 
Cough 
Cough variant asthma 
Cyanosis 
Dyspnoea 
Hyperventilation 
Irregular breathing 
Laryngeal dyspnoea 
Laryngeal oedema 
Laryngospasm 
Laryngotracheal oedema 
Mouth swelling 
Nasal obstruction 
Oedema mouth 
Oropharyngeal oedema 
Oropharyngeal spasm 
Oropharyngeal swelling 
Pharyngeal oedema 
Pharyngeal swelling 
Respiratory arrest 
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Respiratory distress 
Respiratory failure 
Reversible airways obstruction 
Sensation of foreign body 
Sneezing 
Stridor 
Swollen tongue 
Tachypnoea 
Throat tightness 
Tongue oedema 
Tracheal obstruction 
Tracheal oedema 
Upper airway obstruction 
Vaccine associated enhanced respiratory 
disease 
Wheezing
Category C 
Allergic oedema 
Angioedema 
Circumoral swelling 
Erythema 
Eye oedema 
Eye pruritus 
Eye swelling 
Eyelid oedema 
Face oedema 
Flushing 
Injection site urticaria 
Lip oedema 
Lip swelling 
Nodular rash 
Ocular hyperaemia 
Oedema 
Oedema blister 
Periorbital oedema 
Periorbital swelling 
Pruritus 
Pruritus allergic 
Rash 
Rash erythematous 
Rash pruritic 
Skin swelling 
Swelling 
Swelling face 
Swelling of eyelid 
Urticaria 
Urticaria papular
Category D 
Blood pressure decreased 
Blood pressure diastolic decreased 
Blood pressure systolic decreased 
Cardiac arrest 
Cardio-respiratory arrest 
Cardiovascular insufficiency 
Diastolic hypotension 
Hypotension 
Hypotensive crisis 
Post procedural hypotension
 
Note that if the MedDRA® version is increased from 25.1 during the study, any changes to the 
terms in the above categories should be applied. 
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The following algorithmic approach will be applied: A or (B and C) or [D and (B or C)], i.e.  
If a participant has a TEAE which codes to a PT included in Category A, then the event will be 
flagged as an anaphylactic reaction. Note that participants with a TEAE coded to a PT=’Type 1 
hypersensitivity’ will also be flagged as having a hypersensitivity reaction as this PT is also 
included in the Category A narrow search for the ‘Hypersensitivity’ SMQ. 
OR 
If a participant has a TEAE which codes to a PT included in Category B AND has a TEAE 
which codes to a PT included in Category C, and both TEAEs have the same start date, then 
both events will be flagged as anaphylactic reactions. 
OR 
If a participant has a TEAE which codes to a PT included in Category D AND has (either a 
TEAE which codes to a PT included in Category B OR a TEAE which codes to a PT included in 
Category C), and both TEAEs have the same start date, then both events will be flagged as 
anaphylactic reactions. 
13.2 SAP Amendment 1 changes 
The main rationale for SAP Amendment 1 is to include details on the additional key derived and 
component exploratory variables required based on the results from the analyses of historical 
tumor biopsy samples and tumor biopsy samples taken during the Screening period and, 
wherever possible, during study treatment (within 2 weeks post Cycle 1 Day 15 for cohorts 1, 2 
and 4, and within 2 weeks post Cycle 2 for cohort 4) in Part A1. It was decided that these 
additional variables were needed to improve the interpretability of the test results received from 
the laboratory.  
This SAP amendment also provides some clarifications relating to the handling of data for the 
purpose of summarizing safety and exploratory anti-tumor activity endpoints. 
The key changes are summarized in the table below (note that additional minor corrections and 
clarifications were also applied in this amendment but are not included in this table). 
Section  
Description of Change 
1 
The versions and dates of supporting study documentation were 
updated. 
5.1 
An update was made to the example illustrating the definition of a 
complete cycle of UCB6114. 
8.1 
The additional summary of the total number of doses of study 
treatment received was included. 
8.2 
Rules for handling missing relationship to study treatment for an 
adverse event were updated. 
8.4.2 
Clarification on the handling of triplicate ECG measurements was 
included. 
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Section  
Description of Change 
9.2 
Details on the analysis of the historical, Baseline and On-
Treatment tumor biopsy samples was included together with rules 
for defining key and component derived variables based on the test 
results received from the laboratory. A description of the raw test 
results to be listed for each target gene and the required summary 
tables was also included. 
9.3 
A predefined fold-increase of 1.80 was included. 
10.1.2 
Rules for applying the protocol-defined window around the post-
Baseline tumor assessments (scheduled and unscheduled) for the 
purpose of summarizing the investigator’s overall tumor response 
assessment were included. 
General 
MedDRA® version number was updated to 25.1 (latest version) 
throughout the document. 
 
 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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STATISTICAL ANALYSIS PLAN 
PART B  
DOSE ESCALATION (COMBINATION THERAPY) 
Study: ONC001 
Product: UCB6114 
A PHASE 1/2 OPEN-LABEL, MULTICENTER STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND 
ANTITUMOR ACTIVITY OF UCB6114 ADMINISTERED 
INTRAVENOUSLY TO PARTICIPANTS WITH ADVANCED 
SOLID TUMORS 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
SAP/Amendment Number Date 
Version 1.0 
24 August 2021 
Amendment 1 Version 1.0 
13 October 2023 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
INTRODUCTION ..................................................................................................................... 8 
PROTOCOL SUMMARY ......................................................................................................... 8 
2.1 
Study objectives ....................................................................................................... 8 
2.1.1 
Primary objective ........................................................................................... 8 
2.1.2 
Secondary objective ....................................................................................... 9 
2.1.3 
Exploratory/Tertiary objectives ..................................................................... 9 
2.2 
Study endpoints ........................................................................................................ 9 
2.2.1 
Safety endpoints ............................................................................................. 9 
2.2.1.1 Primary safety endpoints.................................................................................... 9 
2.2.1.2 Other safety endpoints ....................................................................................... 9 
2.2.2 
Pharmacokinetic and pharmacodynamic endpoints ..................................... 10 
2.2.2.1 Secondary pharmacokinetic endpoint .............................................................. 10 
2.2.2.2 Exploratory pharmacokinetic endpoints .......................................................... 10 
2.2.2.3 Exploratory pharmacodynamic endpoints ....................................................... 10 
2.2.2.4 Exploratory immunogenicity endpoints ........................................................... 10 
2.2.3 
Efficacy endpoints ....................................................................................... 10 
2.2.3.1 Exploratory antitumor activity endpoints ........................................................ 10 
2.2.3.2 Other exploratory efficacy endpoint ................................................................ 10 
2.3 
Study design and conduct ...................................................................................... 10 
2.4 
Determination of sample size ................................................................................. 13 
DATA ANALYSIS CONSIDERATIONS .............................................................................. 14 
3.1 
General presentation of summaries and analyses .................................................. 14 
3.2 
General study level definitions .............................................................................. 17 
3.2.1 
First and last dose of study treatment .......................................................... 17 
3.2.2 
Relative day and time .................................................................................. 17 
3.2.3 
Study periods ............................................................................................... 17 
3.2.4 
Visits ............................................................................................................ 18 
3.3 
Definition of Baseline values ................................................................................. 18 
3.4 
Protocol deviations................................................................................................. 19 
3.5 
Analysis sets........................................................................................................... 20 
3.5.1 
Enrolled Set (ES) ......................................................................................... 20 
3.5.2 
Safety Analysis Set (SS) .............................................................................. 20 
3.5.3 
Per-protocol Set (PPS) ................................................................................. 20 
3.5.4 
Pharmacokinetic Set (PKS) ......................................................................... 20 
3.5.5 
Anti-drug Antibody Set (ADAS) ................................................................. 20 
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3.5.6 
Pharmacodynamic Set (PDS) ....................................................................... 21 
3.5.7 
DLT Evaluable Set (DES) ........................................................................... 21 
3.6 
Treatment assignment and treatment groups ......................................................... 21 
3.7 
Center pooling strategy .......................................................................................... 21 
3.8 
Coding dictionaries ................................................................................................ 21 
3.9 
Changes to protocol-defined analyses ................................................................... 22 
STATISTICAL/ANALYTICAL ISSUES ............................................................................... 22 
4.1 
Adjustments for covariates .................................................................................... 22 
4.2 
Handling of dropouts or missing data .................................................................... 22 
4.2.1 
Pharmacokinetics and pharmacodynamics .................................................. 22 
4.2.2 
Safety laboratory data .................................................................................. 22 
4.2.3 
Dates and times ............................................................................................ 22 
4.2.4 
Impact of COVID-19 ................................................................................... 24 
4.3 
Handling of repeated and unscheduled measurements .......................................... 25 
4.4 
Handling of measurements obtained for early withdrawals .................................. 25 
4.5 
Interim analyses and data monitoring .................................................................... 26 
4.6 
Multicenter studies ................................................................................................. 26 
4.7 
Multiple comparisons/multiplicity ......................................................................... 26 
4.8 
Use of an efficacy subset of participants ............................................................... 27 
4.9 
Active-control studies intended to show equivalence ............................................ 27 
4.10 
Examination of subgroups ..................................................................................... 27 
STUDY POPULATION CHARACTERISTICS ..................................................................... 27 
5.1 
Study participant disposition.................................................................................. 27 
5.2 
Protocol deviations................................................................................................. 29 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................................ 29 
6.1 
Demographics ........................................................................................................ 29 
6.2 
Cancer history ........................................................................................................ 30 
6.3 
Prior anti-cancer therapy ........................................................................................ 30 
6.4 
Cancer status at Screening ..................................................................................... 32 
6.5 
Medical history and concomitant diseases ............................................................. 32 
6.6 
Prior and concomitant medications ........................................................................ 33 
MEASUREMENTS OF TREATMENT COMPLIANCE....................................................... 33 
SAFETY ANALYSES............................................................................................................. 34 
8.1 
Extent of exposure ................................................................................................. 35 
8.1.1 
UCB6114 ..................................................................................................... 35 
8.1.2 
TFD/TPI ....................................................................................................... 36 
8.2 
Adverse events ....................................................................................................... 36 
8.2.1 
Adverse events of special interest ................................................................ 40 
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8.2.2 
Infusion-related reactions ............................................................................ 40 
8.3 
Clinical laboratory evaluations .............................................................................. 41 
8.4 
Vital signs, physical findings, and other observations related to safety ................ 44 
8.4.1 
Vital signs .................................................................................................... 44 
8.4.2 
12-Lead Electrocardiograms ........................................................................ 45 
8.4.3 
Echocardiogram ........................................................................................... 47 
8.4.4 
ECOG performance status ........................................................................... 47 
8.4.5 
Physical examination ................................................................................... 48 
PHARMACOKINETICS AND PHARMACODYNAMICS .................................................. 48 
9.1 
Pharmacokinetics ................................................................................................... 48 
9.1.1 
Secondary pharmacokinetic endpoint .......................................................... 48 
9.1.2 
Exploratory pharmacokinetic endpoints ...................................................... 48 
9.2 
Pharmacodynamics ................................................................................................ 49 
9.3 
Immunogenicity ..................................................................................................... 55 
EFFICACY ANALYSES ........................................................................................................ 58 
10.1 
Antitumor activity .................................................................................................. 58 
10.1.1 
Definitions of the antitumor activity endpoints ........................................... 58 
10.1.2 
Analysis of the antitumor activity endpoints ............................................... 61 
10.2 
ECOG performance status ..................................................................................... 64 
OTHER ANALYSES .............................................................................................................. 64 
REFERENCES ........................................................................................................................ 64 
APPENDICES ......................................................................................................................... 65 
13.1 
SMQ algorithm for identification of anaphylactic reactions ................................. 65 
13.2 
SAP Amendment 1 Changes .................................................................................. 67 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 68 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ADA 
anti-drug (UCB6114) antibody 
ADaM 
Analysis Data Model 
ALP 
alkaline phosphatase 
ALQ 
above limit of quantification 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
bid 
twice daily 
BLQ 
below limit of quantification 
BMI 
body mass index 
BOR 
best overall response 
BSA 
body surface area  
CA 
cancer 
CDISC 
Clinical Data Interchange Standards Consortium 
CDMS 
clinical data management system 
cGremlin-1 
circulating gremlin-1 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CPPC 
CDMS postproduction change 
CR 
complete response 
CS 
clinically significant 
CRC 
colorectal adenocarcinoma  
CSR 
clinical study report 
ctDNA 
circulating tumor DNA 
CTMS 
clinical trial management system 
DCR 
disease control rate 
DEM 
data evaluation meeting 
DES 
DLT evaluable set 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ES 
enrolled set 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAP 
fibroblast activation protein 
FDA 
Food and Drug Administration 
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part B 
 
 
 
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Gastric cancer 
gastric adenocarcinoma 
GEJ cancer 
adenocarcinoma of the gastroesophageal junction 
geoCV 
geometric coefficient of variation 
geoMean 
geometric mean 
hh:mm 
hours:minutes 
H & E 
hematoxylin and eosin 
HLT 
high level term 
IHC 
immunohistochemistry 
ICH 
International Council for Harmonization 
IM 
invasive margin 
iv 
intravenous 
IPD 
important protocol deviations 
LLOQ 
lower limit of quantification 
LLT 
low level term 
LVEF 
left ventricular ejection fraction 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
n 
number of study participants 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for AEs  
NC 
not calculable 
NCS 
not clinically significant  
NEst 
not estimable 
NV 
no value 
ORR 
objective tumor response rate 
OS 
overall survival 
PCS 
potentially clinically significant 
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PDS 
pharmacodynamic set 
PK 
pharmacokinetic(s) 
PKS 
pharmacokinetic set 
PFS 
progression-free survival 
PPS 
per-protocol set 
PR 
partial response 
PT 
preferred term 
PTEN 
phosphatase and tensin homolog 
Q2W 
every 2 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D-T 
recommended Phase 2 dose of UCB6114 when used in combination 
with TFD/TPI 
SAE 
serious adverse event 
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part B 
 
 
 
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SAP 
statistical analysis plan 
SD 
stable disease 
SDTM 
Study Data Tabulation Model 
SFU 
safety follow-up 
SI 
International System of Units 
SMAD4 
mothers against decapentaplegic homolog 4 
SMC 
Safety Monitoring Committee 
SoC 
standard of care 
SOC 
system organ class 
SS 
safety analysis set 
SSC 
Study Steering Committee 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
TFD/TPI 
trifluridine/tipiracil 
TFL 
Table, Figure and Listing 
TNM 
TNM Classification of Malignant Tumors  
TPS 
tumor proportion score 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 
 
 
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ONC001 – Part B 
 
 
 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of the dose escalation (combination therapy) module 
(Part B) of study ONC001. It also describes the summary tables, figures and listings (TFLs) to be 
generated for Part B according to: 
Protocol amendment 6, dated 26 June 2023;  
Electronic case report form (eCRF) (Clinical Data Management System [CDMS] 
postproduction change [CPPC] #14, version 23.0, dated 14 April 2023); 
UCB’s standards for TFL shells version 2023Q1; 
Part A TFL shells, final version 2.4, dated 04 July 2023; 
Part B and C Mocks draft version 1.4, dated 4 September 2023 (under development); 
Part A, B and C List of TFLs (LoT) draft version 1.2, dated 04 July 2023 (under development); 
UCB’s Derivation of Efficacy Endpoints document, version 0.6, dated 21 January 2022. 
Unless specified in the sections below, Part B of the study will be analyzed as described in the 
most recent version of the protocol. If a future protocol amendment necessitates a substantial 
change to the analysis of the Part B study data, this SAP will be amended accordingly. In 
addition, if the methodology for the analysis of key study endpoints must be modified or updated 
prior to the final database lock for Part B of this study, a SAP amendment will be required. 
Protocol amendments that do not affect the statistical analysis will not necessitate an amendment 
to the SAP.  If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the clinical study report (CSR) 
together with the associated rationale.  
Note that there may be a number of data cut-offs defined prior to the final database lock for Part 
B due to the regulatory safety reporting requirements for this study.  
The content of this SAP is compatible with the International Council for Harmonization 
(ICH)/Food and Drug Administration (FDA) E9 Guidance (ICH-E9). 
UCB is the Sponsor and ICON PLC is the contract research organization (CRO) for this study. 
 
2. 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective of Part B (dose escalation module) of this study is to characterize the 
safety profile of UCB6114 administered in combination with a trifluridine/tipiracil (TFD/TPI) 
standard of care (SoC) regimen in participants with locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the gastroesophageal junction. 
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part B 
 
 
 
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2.1.2 
Secondary objective 
The secondary objective of Part B of this study is to characterize the pharmacokinetics (PK) of 
UCB6114 administered in combination with a TFD/TPI SoC regimen in participants with locally 
advanced or metastatic colorectal adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma 
of the gastroesophageal junction. 
2.1.3 
Exploratory/Tertiary objectives 
The exploratory/tertiary objectives of Part B of this study are: 
• To document any antitumor activity observed with UCB6114 administered in 
combination with a TFD/TPI SoC regimen according to relevant Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria; 
• To explore pharmacodynamics (PD) biomarkers of UCB6114 administered in 
combination with a TFD/TPI SoC regimen; 
• To evaluate the immunogenicity of UCB6114 administered in combination with a 
TFD/TPI SoC regimen. 
2.2 
Study endpoints 
2.2.1 
Safety endpoints 
2.2.1.1 Primary safety endpoints 
The primary safety endpoints for Part B of this study are the incidence and severity of treatment-
emergent adverse events (TEAEs) (including serious adverse events [SAEs]) from the first dose 
of UCB6114 on Day 1 of Cycle 1 to the Safety Follow-up (SFU) visit, and the incidence of dose 
limiting toxicities (DLTs) from the first dose of UCB6114 on Day 1 of Cycle 1 to the end of the 
DLT Observation Period (Day 28 of Cycle 1). 
2.2.1.2 Other safety endpoints 
The following other safety data will be assessed during Part B of the study to further support the 
characterization of the safety profile of UCB6114 administered in combination with a TFD/TPI 
SoC regimen. 
• Clinical laboratory data (hematology, serum chemistry, coagulation and urinalysis); 
• Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature); 
• 12-lead electrocardiogram (ECG); 
• Echocardiogram (left ventricular ejection fraction [LVEF]); 
• Eastern Cooperative Oncology Group (ECOG) performance status;  
• Physical examination. 
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part B 
 
 
 
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2.2.2 
Pharmacokinetic and pharmacodynamic endpoints 
2.2.2.1 Secondary pharmacokinetic endpoint 
The secondary PK endpoint in Part B is the UCB6114 concentration by scheduled assessment for 
each UCB6114 dose level. 
2.2.2.2 Exploratory pharmacokinetic endpoints 
 will be exploratory PK endpoints in Part B. 
2.2.2.3 Exploratory pharmacodynamic endpoints 
The following PD endpoints will be assessed in Part B and reported separately outside of the 
CSR: 
• Change in protein marker levels in blood by scheduled assessment and UCB6114 dose 
level; 
• Change in circulating tumor deoxyribonucleic acid (ctDNA) levels in blood by 
scheduled assessment and UCB6114 dose level. 
2.2.2.4 Exploratory immunogenicity endpoints 
Immunogenicity in Part B will be explored using anti-drug (UCB6114) antibody (ADA) sample 
status and participant classification, and changes in titer over time.  Potential relationships 
between ADA and PK, PD, anti-tumor activity and safety may also be explored but these 
analyses will be reported separately outside of the CSR. 
2.2.3 
Efficacy endpoints 
2.2.3.1 Exploratory antitumor activity endpoints 
Antitumor activity in Part B will be explored using the following endpoints: 
• Objective tumor response rate (ORR); 
• Disease control rate (DCR); 
• Duration of antitumor response (DOR); 
• Progression-free survival (PFS); 
• Overall survival (OS). 
2.2.3.2 Other exploratory efficacy endpoint 
To further explore efficacy in Part B of the study, changes from Baseline in the ECOG 
performance status scale will be assessed. 
2.3 
Study design and conduct 
Study ONC001 is a multicenter, nonrandomized, open-label, Phase 1/2 study evaluating the 
safety, PK, efficacy (as assessed by antitumor activity), PD, biomarkers, and immunogenicity 
(ADA activity) of intravenous (iv) UCB6114 as monotherapy and in combination with selected 
SoC regimens in study participants with advanced solid tumors. 
The study has a modular design including up to 3 dose escalation modules (Parts A, B, and C), 
1 dose adaptation module (Part A1), and up to 4 dose expansion modules (Parts D, E, F, and G). 
Depending on emerging data, not all modules may open. This SAP is focused only on the 
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part B 
 
 
 
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ascending dose escalation module of the study evaluating UCB6114 in combination with a 
TFD/TPI SoC regimen (Part B). 
Part B consists of a Screening Period (28 days), a Treatment Period (consisting of 28-day 
cycles), a SFU visit (approximately 30 days after the last dose of study treatment), and a Final 
Visit (approximately 3 months after the last dose of study treatment).  
In Part B, eligible participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the gastroesophageal junction 
will receive UCB6114 as an iv infusion in combination with orally administered TFD/TPI. The 
starting dose and schedule of UCB6114 will depend on the dose level evaluated in Cohort 3 of 
Part A (anticipated to be 500mg every 2 weeks [Q2W] iv), the emerging safety profile of 
UCB6114 monotherapy, and any predicted overlapping toxicities with TFD/TPI. Up to 3 
UCB6114 dose levels (anticipated to be 500mg, 1000mg, and 2000mg administered Q2W iv) 
will be explored and up to 27 participants may be enrolled. Dose escalation decisions in this 
module will be guided by a model-based estimation of the probability of DLT in Cycle 1. 
Part B will be undertaken using the modified toxicity probability interval (mTPI) method. The 
mTPI design uses a Bayesian decision framework to inform dose-escalation and dose de-
escalation decisions.  A target DLT rate of 25% with an equivalence interval (20% to 30%) will 
be used to estimate the maximum tolerated dose (MTD) of the combination regimen during dose 
escalation. For all UCB6114 dose levels, enrolled participants will be treated in cohorts of 2 to 4 
participants (target of 3), who can be treated in parallel. Each UCB6114 dose level may have 
more than one cohort and will have a minimum of 3 and a maximum of 9 evaluable participants. 
For further detail on the mTPI method, the calculated model-based dose-escalation/dose de-
escalation decisions to help inform the Safety Monitoring Committee (SMC)'s decision, and the 
determination of the MTD, please refer to Section 4.1.3.2.2 of the protocol.  Detail on the 
operating characteristics for the mTPI design is included in Section 2.4 below. 
The planned duration of study treatment during Part B is 2 cycles. Participants may remain on 
study for additional cycles if they are receiving therapeutic benefit or until they fulfill one of the 
criteria for study discontinuation. Participants will continue treatment until disease progression, 
unmanageable toxicity, or withdrawal of consent. Upon discontinuation of treatment, participants 
will be referred to appropriate follow-up care per the investigator’s judgment. 
From Part B, a recommended Phase 2 dose for UCB6114 in combination with TFD/TPI (RP2D-
T) will be determined based upon the totality of information, including the safety profile, PK 
data, PD biomarker data, and available antitumor activity. 
Part B of the study is planned to be conducted at study sites in the United Kingdom (UK) and 
United States (US). 
A schematic diagram of Part B of the study is provided in Figure 2-1. 
 
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UCB6114 
ONC001 – Part B 
 
 
 
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Figure 2-1: Study Schematic for Part B 
 
 
bid=twice daily; D=Day; DLT=dose-limiting toxicity; iv=intravenous; mTPI= modified toxicity probability interval; 
po=oral; TFD/TPI=trifluridine/tipiracil 
*Dose must not exceed 80mg/dose 
Notes: A dose may be given in more than 1 cohort 
Escalation to the next dose level or de-escalation to the previous dose level will be guided by the mTPI algorithm. 
A Study Steering Committee (SSC) will be implemented prior to the start of Part B.  In 
consultation with the SMC, the SSC will recommend to the Sponsor the dose and dosing regimen 
to be taken forward for Part B. Part B of ONC001 is planned to be initiated after Cohort 3 of Part 
A has completed the 28-day DLT assessment period, after consultation with the SMC, and when 
the SCC has provided a recommendation to dose escalate to the next protocol-defined level in 
Part A of the study. The SSC members will include the coordinating investigator, supporting co-
investigators, and clinical experts not involved in the study. The medical, scientific, and clinical 
study expertise of the SSC will assist the Sponsor in identifying and resolving any study related 
issues, such as study design, study implementation and conduct, and data analysis and reporting.  
During the Treatment Period, UCB6114 will be administered as an iv infusion Q2W, while 
TFD/TPI will be administered orally twice daily (bid) within 1 hour of completion of morning 
and evening meals at home on Days 1 to 5 and Days 8 to 12 of each 28-day cycle. For the 
convenience of the participants, TFD/TPI can be administered at home to allow for the 12-hour 
interval between TFD/TPI doses associated with meals. The starting dose of TFD/TPI in adults is 
35mg/m2 administered orally bid (total daily dose of 70mg/m2) with dosage calculated for each 
participant according to body surface area (BSA) (see Table 4-4 of the protocol). The dosage 
must not exceed 80mg/m2 (based on the trifluridine component). 
It is expected that up to 3 dose levels of UCB6114 will be explored in combination with the 
standard TFD/TPI dosing regimen. However, additional dose levels may be added based on 
emerging data and recommendations of the SMC. Dose escalation steps are currently planned at 
a maximum of 2-fold. Escalating dose levels in Part B will not exceed a dose level tested and 
considered safe by the SMC to allow dose escalation in monotherapy (Part A). 
Eligible participants who withdraw from the study before receiving study treatment will be 
replaced. Participants who fail to receive the second planned dose of UCB6114 within 7 days of 
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part B 
 
 
 
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the scheduled administration day during the 28-day DLT Observation Period for reasons not 
related to toxicity will be replaced by a new participant in that cohort. Safety data for replaced 
participants will be included in the data listings and in the summary tables, as applicable. 
2.4 
Determination of sample size 
No formal statistical sample size calculation has been performed for the dose escalation modules 
in study ONC001.  
The number of participants likely to be enrolled in Part B depends on how many dose levels are 
needed to define the RP2D-T for combination therapy. In Part B, up to 27 eligible participants 
will be enrolled. It is expected that up to 3 dose levels of UCB6114 will be explored in 
combination with the TFD/TPI dosing regimen, respectively. However, additional dose levels 
may be added based on emerging data and recommendations of the SMC. 
Between 3 and 9 participants are expected to be enrolled at each dose level of UCB6114 
depending on the observed toxicity/observation of DLTs. An administrative decision to stop 
enrolling into Part B may be made by the Sponsor at any time. “Dose level” refers to a particular 
UCB6114 dose, that can be given to one or more cohorts, not necessarily consecutively.  
The operating characteristics of the mTPI design were evaluated using a simulation approach 
under four scenarios (see Table 2-1) and based on no DLTs observed in the first 2 cohorts in Part 
A monotherapy treatment (UCB6114 100mg and 250mg). The results of this evaluation can be 
seen in Table 2-2.  
Table 2‒1: 
Scenarios used for evaluating the operating characteristics of the 
mTPI design. Orange cells indicate the correct decision assuming 
a maximum tolerated toxicity of 25% (equivalence limits 20%, 30%) 
 
Probability of a DLT 
UCB6114 Dose 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Dose 1 (500 mg) 
0.05 
0.05 
0.15 
0.25 
Dose 2 (1000 mg) 
0.05 
0.15 
0.25 
0.35 
Dose 3 (2000 mg) 
0.05 
0.25 
0.35 
0.50 
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Table 2‒2: Evaluation of the operating characteristics of the mTPI design with a 
target maximum tolerated toxicity of 25%, using 5000 simulated 
trials for each scenario. Orange cells indicate the correct decision. 
Final UCB6114 Dose Selected 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
% of Simulations (Number of Simulations) 
 Dose 1 (500 mg) 
3.9% (196) 
5.2% (262) 
31.6% (1580) 
53.3% 
(2666) 
 Dose 2 (1000 mg) 
3.9% (195) 
35.1% (1755) 
40% (1999) 
26.7% 
(1337) 
 Dose 3 (2000 mg) 
91.4% (4571) 
58.9% (2947) 
21.6% (1080) 
3.8% (191) 
 Overly Toxic at First Cohort 
0.8% (38) 
0.7% (36) 
6.7% (336) 
15.2% (758) 
 Overly Toxic after First Cohort 
0 
0 
0.1% (5) 
1% (48) 
 
3. 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
All TFLs will be produced by ICON PLC using SAS® Version 9.4 or higher (SAS Institute, Cary, 
North Carolina, USA). ICON PLC will also produce the analysis datasets which will adhere to 
the Clinical Data Interchange Standards Consortium (CDISC) guidance documents for Analysis 
Data Model (ADaM) and follow the Sponsor’s interpretation. General statistical and reporting 
conventions will follow the current UCB Global Conventions Document Version 1.1.  
Data will be summarized by UCB6114 dose level (treatment group), visit and timepoint, as 
applicable. All relevant reported and derived data will be listed and will be presented by 
treatment group, study participant and visit, as applicable. 
Categorical variables will be summarized using frequency counts and percentages. Unless 
otherwise stated, the denominator for the percentages will be based on the number of participants 
in the respective analysis set, treatment group, visit and timepoint (as applicable) with non-
missing data. 
When reporting frequency counts and percentages, the following rules apply: 
• For categories where all participants fulfill certain criteria, the percentage value will be 
displayed as 100; 
• For categories where zero participants fulfill certain criteria, there will be no percentage 
displayed; 
• All other percentage displays will use 1 decimal place. 
Summary statistics will be presented for continuous variables including number of participants 
(n), arithmetic mean, standard deviation, median, minimum and maximum. 95% confidence 
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ONC001 – Part B 
 
 
 
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intervals (CIs) for the arithmetic mean may also be included depending on the variable and 
where stated in the SAP. Geometric mean (geoMean), geometric coefficient of variation (geoCV) 
and 95% CI for the geoMean will also be presented in the summaries of UCB6114 concentration 
data.  In all relevant outputs the 95% confidence limits will be restricted to the possible values 
that the variable can take.  
 
When reporting descriptive statistics for data other than UCB6114 concentration data, the 
following rules will apply: 
• n will be an integer; 
• Mean (arithmetic and geometric), standard deviation, median and quartiles will use 1 
decimal place more, or 1 significant figure more – depending on the reporting format of 
the original data – than the original data.  Original data may be data as reported directly 
onto the eCRF or summary data based on data reported onto the eCRF (e.g. mean of 
triplicates or percentage change from Baseline); 
• Confidence intervals will be presented to the same number of decimal places as the value 
around which the CI is constructed; 
• Minimum and maximum will be reported using the same number of decimal places or 
significant figures as the original value; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “);  
• If no participants have data at a given timepoint, then only n=0 will be presented; 
• Percentage change from Baseline values will be calculated and displayed to 1 decimal 
place in the listings.  In the summaries, where applicable, the mean, standard deviation 
and median percentage change from Baseline values will be presented to 2 decimal places 
and the minimum and maximum values presented to 1 decimal place. 
When reporting individual UCB6114 concentration data in listings and figures, and presenting 
summary statistics in tables, the following rules will apply: 
• UCB6114 concentration data should be reported in the listings to the same level of 
precision as received from the bioanalytical laboratory; 
• Missing data should be reported as ‘NV’ (no value) in the listings; 
• Concentrations below the lower limit of quantification (LLOQ) should be reported as 
BLQ (below the limit of quantification) in the listings; 
• BLQ values prior to Cmax should be set to 0 for purposes of plotting a figure (to capture 
lag-time);  
• Actual sampling times will be used in the spaghetti plots of individual PK concentrations 
over time, and nominal sampling times will be used in the summaries of geoMean 
concentrations over time; 
• UCB6114 concentration data should be plotted on both linear and semi-logarithmic 
scales;  
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ONC001 – Part B 
 
 
 
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• To calculate summary statistics, BLQ values should be set to half the LLOQ value and 
missing values should be excluded; 
• When the total number of BLQ and missing values exceeds one third of the total then 
only minimum and maximum should be reported for this timepoint. Other summary 
statistics should be reported as missing (“-“). The minimum should be reported as BLQ; 
• When the mean value includes one or more replaced BLQ values then a footnote should 
be included to say “contains one or more BLQ values replaced by half the LLOQ value”; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “); 
• If no participants have data at a given timepoint, then only n=0 will be presented; 
• Summary statistics for UCB6114 concentration data will be reported to the same level of 
precision as the individual data for the minimum and maximum, and to 1 additional 
decimal place or 1 additional significant figure – depending on the reporting format of the 
original data with a maximum of 3 significant figures - for the mean (arithmetic and 
geometric), median and standard deviation. The 95% CI for the geoMean will use the 
same number of decimal places or significant figures as the geoMean. It will be left blank 
if the geoCV is 0; 
• Geometric coefficient of variation will be reported as a percentage to 1 decimal place. 
The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data: 
𝐺𝑒𝑜𝐶𝑉(%) = √exp 𝑆𝐷2 −1 × 100 
When reporting PK parameters in listings and figures, and presenting summary statistics in 
tables, the following rules will apply: 
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ONC001 – Part B 
 
 
 
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3.2 
General study level definitions 
3.2.1 
First and last dose of study treatment  
For each participant the start of study treatment is defined as the date and time of the first dose of 
UCB6114.  This will be considered as the starting point of the combination therapy. 
Note that TFD/TPI is taken by the participant at home prior to attending the clinic for the 
infusion of UCB6114 on C1D1. 
Similarly, for each participant, the last dose of study treatment will be the date of the last dose of 
UCB6114. 
3.2.2 
Relative day and time 
For each participant, the relative day of an event or assessment will be derived using the date of 
their first dose of UCB6114 as reference.  
Relative days for an event or assessment occurring before the date of first dose of UCB6114 are 
calculated as follows: 
Relative Day = Event/Assessment Date - Date of First Dose of UCB6114 
The relative day for an event or assessment occurring on the date of first dose of UCB6114 is 1. 
The relative day for an event or assessment occurring on or after the first dose of UCB6114 to 
the date of the last dose of UCB6114 will be calculated as follows: 
Relative Day = (Event/Assessment Date – Date of First Dose of UCB6114) + 1 
For events or assessments occurring after the date of the last dose of UCB6114, relative day will 
be prefixed with ‘+’ in the data listings and will be calculated as follows: 
Relative Day = Event/Assessment Date – Date of Last Dose of UCB6114 
There is no relative Day 0. Relative day will not be calculated in cases where dates are partial 
and should be presented as “--” in the relevant data listing. 
Relative time of TEAEs recorded on, but not limited to, the day of UCB6114 infusion (Days 1 
and 15 of each cycle) will be derived in minutes as follows using the infusion start time as 
reference: 
Relative Time of TEAE = Onset Time of TEAE – Start Time of UCB6114 Infusion 
Relative times of PK and PD sampling will be derived in hours using the end of UCB6114 
infusion time on the day of dosing as reference, i.e. on Days 1 and 15 of each cycle: 
Relative Sampling Time = Sampling Time – End Time of UCB6114 Infusion 
3.2.3 
Study periods 
Part B of the study will consist of the following study periods: 
• Screening Period – up to 28 days; 
• Treatment Period – Successive 28-day cycles of study treatment (UCB6114 will be 
administered as an iv Q2W dose on Day 1 and Day 15 of each cycle and TFD/TPI will be 
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administered [bid] within 1 hour of completion of morning and evening meals at home on 
Days 1 to 5 and Days 8 to 12, continuing until disease progression, unmanageable 
toxicity, or participant withdrawal). Within the first cycle of the Treatment Period, a 28-
day DLT Observation Period is defined to determine safety events for dose escalation 
decisions using mTPI;   
• Safety Follow-up Period – up to 30 days after the last dose of UCB6114. 
There will be a further extended follow-up period, up to 3 months after the last dose of 
UCB6114, at which time the Final Visit will be performed.   
For each participant, the end of the Treatment Period is defined by the date of their last dose of 
UCB6114.   
The end of Part B of the study is defined by the date of the Final Visit for the last participant (3 
months after the last participant’s last dose of UCB6114), or the date of the SFU visit, if they 
discontinue prior to attending the Final Visit, or their last contact date if they discontinue early 
from the study without attending the SFU visit. 
3.2.4 
Visits 
Unless otherwise specified, in the TFLs, visits will be labelled as follows (as applicable) using 
timepoints as recorded in the database: 
Screening 
Baseline 
Cycle 1, Day X 
Cycle 2, Day X  
Cycle 3, Day X 
Cycle 4, Day X 
Cycle X, Day X 
Etc. 
SFU 
Final Visit 
3.3 
Definition of Baseline values 
Baseline in Part B will be the last available value prior to the first dose of UCB6114. Both 
scheduled and unscheduled values, as well as any repeated values, should be used when defining 
Baseline. 
Measurement-specific Baseline definitions are presented in Table 3-1.  
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Table 3-1: 
Definition of Baseline 
Measurement 
Definition of Baseline 
Echocardiogram (LVEF) 
Tumor assessments (antitumor activity) 
Screening value 
12-lead ECG 
Physical examination and weight 
Vital signs 
Clinical laboratory data 
ECOG performance status 
Predose value obtained on Cycle 1, Day 1, or, if 
missing, Screening value  
Serum and urinary markers of bone turnover  
Circulating gremlin-1 (cGremlin-1) 
Immunogenicity (ADA) 
Predose sample value obtained on Cycle 1, Day 1 
ADA=anti-drug (UCB6114) antibody; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
LVEF=left ventricular ejection fraction. 
3.4 
Protocol deviations 
Per ICH definition, important protocol deviations (IPDs) are a subset of protocol deviations that 
may significantly impact the completeness, accuracy, and/or reliability of the study data or that 
may significantly affect a participant’s rights, safety, or well-being. The criteria for identifying 
potentially important protocol deviations will be defined within the IPD specifications 
document.  
 
For Part B of this study, IPDs will be categorized as follows:   
• 
Inclusion/exclusion criteria deviations  
• 
Incorrect treatment or dose administered  
• 
Procedural non-compliance  
• 
Prohibited concomitant medication use (see Section 6.5.5 of the protocol) 
• 
Withdrawal criteria deviation   
All protocol deviations will be reviewed as part of the ongoing data cleaning process and Data 
Evaluation Meetings (DEMs), and decisions made on whether they should be considered 
important or not, and whether they warrant a participant’s exclusion from an analysis set, or 
partial exclusion from an analysis due to being an IPD (e.g. prohibited concomitant medication 
use).  Multiple DEMs will be scheduled prior to the final database lock for Part B, in line with 
regulatory safety reporting requirements, with the final one held after all data have been 
verified/coded/entered into the database.  
More specifically, participants who have IPDs relating to dosing of study treatment (e.g. 
interrupted, discontinued and missed infusion, incomplete/incorrect dose administered, 
additional dose received, or infusions administered outside of the defined visit window) will be 
reviewed at the DEM for potential exclusion of UCB6114 concentration data from the by-visit 
summaries at an individual visit or from the visit at which the dosing deviation was observed 
onwards. 
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Any protocol deviations that are considered related to coronavirus disease 2019 (COVID-19) 
will be reviewed on an ongoing basis in case they collectively or individually give reason to 
consider a protocol amendment (e.g. study design changes or changes to primary analysis 
methods etc.).  To facilitate this ongoing review, protocol deviations will be categorized as 
‘related to COVID-19’ within the Clinical Trial Management System (CTMS) (ICOTrial).  The 
COVID-19-related IPDs will then be listed separately for review and discussion at the DEMs. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set (ES) 
The Enrolled Set (ES) consists of all study participants who sign the Informed Consent Form. 
This analysis set includes screening failures and will be used for the summary of disposition of 
study participants and for selected data listings (which will include all available data for the 
screening failures).  
3.5.2 
Safety Analysis Set (SS) 
The Safety Analysis Set (SS) consists of all study participants who receive at least 1 full or 
partial dose of UCB6114.   
This analysis set will be used for the reporting of demographic, baseline characteristics, safety 
and immunogenicity data. All summaries of the exploratory antitumor activity endpoints will be 
repeated for the SS as a sensitivity analysis.    
3.5.3 
Per-protocol Set (PPS) 
The Per-protocol Set (PPS) consists of all study participants in the SS who do not have IPDs that 
may substantially affect antitumor activity. Potential exclusions will be reviewed at the DEMs 
and a final determination of the composition of this analysis set will be made prior to the final 
database lock for Part B.  
The PPS will be the primary analysis set for the analysis of the exploratory antitumor activity 
endpoints.  
3.5.4 
Pharmacokinetic Set (PKS) 
The Pharmacokinetic Set (PKS) consists of all study participants in the SS who have at least 
1 evaluable postdose UCB6114 concentration sample (i.e. a sample which is above the lower 
limit of quantitation and for which the date and time of the sample and prior date and time of 
dosing are known). Additional participants or specific samples may be excluded from the PKS at 
the discretion of the Advanced Modeling and Simulation scientist/Quantitative Clinical 
Pharmacologist at UCB. 
Pharmacokinetic analysis will be performed for the PKS. 
3.5.5 
Anti-drug Antibody Set (ADAS) 
The Anti-drug Antibody Set (ADAS) consists of all study participants in the SS who have at 
least 1 evaluable ADA assessment.  
Immunogenicity analyses will be performed for the ADAS. 
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3.5.6 
Pharmacodynamic Set (PDS) 
The Pharmacodynamic Set (PDS) consists of all study participants in the SS who have at least 
1 evaluable PD assessment (where appropriate, the sample should be above the lower limit of 
quantitation and the date and time of the sample should be known). 
Pharmacodynamic analysis will be performed for the PDS. 
3.5.7 
DLT Evaluable Set (DES) 
The DLT Evaluable Set (DES) will include all study participants who, during the 28-day DLT 
assessment period receive the planned dose of UCB6114 and at least 80% of the planned dose of 
TFD/TPI or stopped treatment due to DLT. 
The DES will be used by the SMC for all dose escalation/de-escalation decision making. 
3.6 
Treatment assignment and treatment groups 
In Part B, it is planned that study participants will be dosed with UCB6114 Q2W at ascending 
dose levels and TFD/TPI will be administered orally bid.  Treatment groups will be defined by 
each UCB6114 dose level and will be presented in ascending order and labelled in the TFLs as 
illustrated in Table 3-2. 
Table 3-2: 
Treatment Group Labels 
UCB6114 Dose Level 
Planned Treatment Group Label 
Dose Level 1 (any cohort) 
UCB6114 500mg + TFD/TPI SoC 
Dose Level 2 (any cohort)  
UCB6114 1000mg + TFD/TPI SoC 
Dose Level 3 (any cohort) 
UCB6114 2000mg + TFD/TPI SoC 
UCB6114 dose level will be referred to as ‘treatment group’ from this point onwards in the SAP 
and in the TFLs. 
 
3.7 
Center pooling strategy 
Each study site will contribute to the summaries of data from Part B according to the number of 
evaluable participants recruited; no separate summaries for each site will be presented.  
3.8 
Coding dictionaries 
Adverse events and medical history will be coded by UCB, using the latest available version of 
the Medical Dictionary for Regulatory Activities (MedDRA®) (Version 25.1 or higher).  The 
National Cancer Institute Common Terminology Criteria for AEs (Version 5.0) (NCI CTCAE) 
dictionary will also be used by the investigator to assign CTCAE severity grades to each adverse 
event (AE) and will be merged with the clinical database to define a CTCAE code and term to be 
used in the summaries of TEAEs by maximum CTCAE severity grade. 
Medications (including prior anti-cancer systemic therapies) will be coded according to the 
World Health Organization Drug Dictionary (WHODD) (Version SEP/2020). Medical 
procedures will not be coded. 
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The versions of the coding dictionaries used will be displayed in the relevant TFLs. 
3.9 
Changes to protocol-defined analyses 
The following changes to the protocol have been incorporated into the SAP: 
• Other safety data have not been defined as safety endpoints in the protocol, e.g. clinical 
laboratory data, vital signs, ECG, echocardiogram, ECOG performance status and 
physical examination.  These have been listed in Section 2.2.1 of the SAP as ‘other safety 
endpoints’ to support the characterization of the safety profile of UCB6114 and to 
provide supporting evidence of any measurements that are deemed abnormal and 
clinically significant and reported as an AE. 
• ECOG performance status is defined as an efficacy assessment in Section 9.6.2 of the 
protocol, however, it will also be assessed from a safety perspective in Part B.  The SAP 
therefore includes ECOG performance status as both a safety endpoint (Section 2.2.1) 
and an exploratory efficacy endpoint (changes from Baseline during Part B in Section 
2.2.3). 
• Section 9.4.2.1 of the protocol does not explicitly define the analysis set to be used for 
the antitumor activity endpoints but defines the denominator as the number of treated 
participants, which matches the protocol definition for the SS in Section 9.1 of the 
protocol. The SAP has been written to clarify that the PPS will be the primary analysis 
set for the analysis of the antitumor activity endpoints (Section 3.5.3) and that the SS will 
be used for the sensitivity analysis (Section 3.5.2). 
 
4. 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
There will be no imputation of missing data unless otherwise stated in the sections below. 
4.2.1 
Pharmacokinetics and pharmacodynamics 
The reporting and handling of missing values and values that are BLQ in the TFLs is described 
in Section 3.1.  Zero values will be assumed at the predose timepoint on Day 1 of Cycle 1. 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ in the safety laboratory data will be the same as those 
described for PK data in Section 3.1. Any values above the limit of quantification (ALQ) will be 
assigned as the value of upper limit of quantification. 
4.2.3 
Dates and times 
Partial dates may be imputed for the following reasons: 
• Classification of adverse events (AEs) as treatment-emergent; 
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• Classification of medications recorded on the concomitant medications log as prior or 
concomitant; 
• Calculation of time since initial diagnosis, time since completion of most recent line of 
anti-cancer therapy and time since progression/relapse on most recent line of anti-cancer 
therapy. 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial onset/start dates: 
• If only the month and year are specified and the month and year of the first dose of 
UCB6114 is not the same as the month and year of the start date then the 1st of the month 
will be used, or the date of the Screening visit if this is later (if the latter imputation 
results in an end date that is earlier than the start date, then the 1st of the month will be 
used); 
• If only the month and year are specified and the month and year of the first dose of 
UCB6114 is the same as the month and year of the start date, then the date of the first 
dose of UCB6114 will be used. If this results in an imputed start date that is after the 
specified end date, then the 1st of the month will be used, or the date of Screening if this 
is later (if the latter imputation results in an end date that is earlier than the start date, then 
the 1st of the month will be used). If the imputed date is the same date as the date of the 
first dose of UCB6114 then, for AEs, the event will be regarded as treatment-emergent. 
For medications, the medication will be classified as concomitant; 
• If only the year is specified, and the year of the first dose of UCB6114 is not the same as 
the year of the start date then January 01 will be used; 
• If only the year is specified, and the year of the first dose of UCB6114 is the same as the 
year of the start date, then the date of the first dose of UCB6114 will be used. If this 
results in an imputed start date that is after the specified end date, then January 01, or the 
date of the Screening visit if this is later will be used (if the latter imputation results in an 
end date that is earlier than the start date, then January 01 will be used). If the imputed 
date is the date of the first dose of UCB6114 then, for AEs, the event will be regarded as 
treatment-emergent.  For medications, the medication will be classified as concomitant; 
• If the onset/start date is completely missing then the onset/start date will be imputed to 
the date of first dose of UCB6114 and therefore, for AEs, the event will be regarded as 
treatment-emergent and, for medications, the medication will be classified as 
concomitant. 
The following rules will be applied to partial end/stop dates: 
• If only the month and year are specified, then the last day of the month will be used; 
• If only the year is specified, then December 31 of the known year will be used; 
• If the stop date is completely unknown, the stop date will not be imputed. 
Note that the start date or stop date of a prior medication (partial or otherwise) should not be 
imputed past the Screening date - 1.  
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In addition to onset and stop dates, the onset and end times of AEs occurring on the day of 
UCB6114 infusion will be collected on the eCRF. Onset and end times may also be recorded for 
other AEs that do not occur on the same day as the UCB6114 infusion.  The duration of AEs 
with onset and end times will be calculated in days and hours:minutes (hh:mm) as: 
Duration of AE = End Date and Time – Onset Date and Time 
In cases where only the onset and stop dates are recorded for an AE, the duration of an AE will 
be calculated in days as:  
Duration of AE = (Stop Date – Onset Date) + 1 
Note that for participants who have an AE which starts and stops on the same day, but with only 
a start time or only a stop time recorded, it will be assumed that their AE started from 00:00 (if 
no start time is recorded) and ended at 23:59 (if no stop time is recorded) on that day. 
If the date of a participant’s initial diagnosis is incomplete, it will be imputed to the most recent 
feasible date for the calculation of time since initial diagnosis as follows: 
 
• If only the day is missing, it will be imputed to the last day of the known month; 
• If the day and month are missing, it will be imputed to December 31 in the known year; 
• If the date of initial diagnosis is completely missing, then time since initial diagnosis will 
not be calculated. 
 
 
The above date imputation rules will be applied to partially missing stop dates of a participant’s 
last prior anti-cancer systemic therapy as well as partially and completely missing dates of 
progression/relapse on last prior anti-cancer systemic therapy. 
In cases where the stop date of a participant’s last prior anti-cancer systemic therapy and/or a 
participant’s date of progression on last line of prior anti-cancer systemic therapy is completely 
missing, the participant’s Screening date - 1 will be used in the calculation of the time since 
completion of most recent line of prior anti-cancer systemic therapy and the time since 
progression/relapse on most recent line of prior anti-cancer systemic therapy, respectively. 
Note that partial dates will not be imputed as a participant’s first dose of UCB6114 in the 
calculation of time since initial diagnosis, time since completion of most recent line of prior anti-
cancer systemic therapy and time since progression/relapse on most recent line of prior anti-
cancer systemic therapy. 
4.2.4 
Impact of COVID-19 
The FDA and European Medicines Agency (EMA) have provided guidance (see references listed 
in Section 12) to help assure the safety of all trial participants, maintaining compliance with good 
clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.  
At the time of writing this SAP, the impact of the pandemic is still evolving and regulators 
continue to clarify their position, and how to handle missing or delayed assessments resulting 
from the pandemic is part of the risk assessment of the impact of COVID-19 on trial integrity.  
For this purpose, the impact at a visit level will be assessed by data collected on a specific 
COVID-19 impact eCRF form and protocol deviations related to COVID-19.  Due to the timing 
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of the start-up of recruitment of participants into this study, the consequences for Part B are not 
expected to be significant and, as a result, no details on strategies for handling missing data are 
included in this version of the SAP.  However, should the ongoing review of COVID-19-related 
protocol deviations suggest that the impact is more significant than expected, e.g. in the case of a 
new wave, the SAP may be updated to include further details of handling missing data and/or 
any sensitivity analyses required.  Note that there are no guidelines regarding how much missing 
data is too much, and there is no proportion of missing data under which valid results and 
preservation of study power can be guaranteed. In accordance with the EMA guidance, an 
independent Data Monitoring Committee (DMC) may be convened to make an assessment 
regarding the scientific integrity of the study.  
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. Repeated measurements are defined as more than 1 measurement at the same 
timepoint. For example, the same laboratory parameters assessed twice using the same batch of 
blood samples due to issues with the first assessment. The following general rules will apply to 
all repeated and unscheduled measurements: 
• Unscheduled and repeated measurements prior to the first dose of UCB6114 will be used 
in the determination of Baseline and hence in the calculation of summary statistics at 
Baseline; 
• Unscheduled and repeated measurements performed after the first dose of UCB6114 will 
not be included in the calculation of change from Baseline, summary measures such as 
minimum, maximum, average and last post-Baseline value calculated for the summaries 
of laboratory data (see Section 8.3), vital signs (see Section 8.4.1) and 12-lead ECG (see 
Section 8.4.2), or summary statistics, i.e. only the scheduled measurements will be used 
and summarized.  Similarly, only scheduled visits will be used in the summaries of shifts 
from Baseline to the worst post-Baseline CTCAE severity grade for laboratory data (see 
Section 8.3);  
• For the summaries of the investigator’s overall tumor response assessment, protocol-
defined windows will be applied to all post-Baseline tumor assessments (scheduled or 
unscheduled, but excluding tumor assessments performed at the SFU visit), as detailed in 
Section 10.1.2. Those tumor assessments which fall outside of the window will be 
considered as unscheduled assessments and not included in the summaries; 
• Best overall response, DOR and PFS derivations will use data from all scheduled and 
unscheduled tumor assessments.; 
• All data from unscheduled visits will, however, be included on the relevant data listings. 
4.4 
Handling of measurements obtained for early withdrawals 
Participants who withdraw early from the study for any reason will be asked to return to the 
clinic to complete the SFU visit.  The SFU procedures performed at this visit are as shown in the 
Schedule of Activities for Part B in the protocol and will be summarized together with all other 
SFU visit data in the tables. 
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4.5 
Interim analyses and data monitoring 
No formal interim analyses are planned during Part B of this study. 
A SSC will be implemented prior to the start of Part B.  In consultation with the SMC, the SSC 
will recommend to the Sponsor the dose and dosing regimen to be taken forward for Part B. The 
SSC members will include the coordinating investigator, supporting co-investigators, and clinical 
experts not involved in the study. The medical, scientific, and clinical study expertise of the SSC 
will assist the Sponsor in identifying and resolving any study related issues, such as study design, 
study implementation and conduct, and data analysis and reporting.  
 
The SMC already established for Part A of the study, comprising investigators from UK sites 
participating in Part A and key Sponsor personnel, will continue as the SMC for Part B as long 
as they are actively enrolling study participants into the study.  In addition, investigators from 
US sites who are actively enrolling study participants into Part B of the study will also become 
members of the SMC for Part B. 
Responsibilities of the SMC for Part B include: 
• Review of safety data for study participants including review and provision of 
adjudication of individual DLTs, if needed; 
• Review of available PK and PD biomarker data; 
• Make dose escalation recommendations; 
• Determination of the MTD, if applicable. 
The SMC will convene after the last participant in a given cohort has completed the required 28-
day DLT Observation Period. The SMC will decide whether to halt dose escalation, further 
expand the dose level to gain additional safety data, or determine the next dose level to be tested.  
All data presented to the SMC will be cumulative in order that the members can review and 
discuss the data in its totality at the end of all completed cohorts, i.e. all safety information 
beyond Cycle 1 for all previous cohorts will be presented cumulatively for review during each 
subsequent SMC meeting. 
In addition to the planned SMC data review meetings, the Sponsor and the SMC will have the 
ability to hold/request ad hoc meetings should they be deemed necessary (e.g. if safety concerns 
arise during Part B of the study and/or during other ongoing nonclinical and clinical studies). 
4.6 
Multicenter studies 
Part B of this study is planned to be conducted at study sites in the UK and US. With the 
exception of participant disposition, no summaries will be presented by site. 
4.7 
Multiple comparisons/multiplicity 
Not applicable. 
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4.8 
Use of an efficacy subset of participants 
The PPS will be used as the primary analysis set for the summaries of the exploratory antitumor 
activity endpoints in Part B. 
4.9 
Active-control studies intended to show equivalence 
Not applicable. 
4.10 
Examination of subgroups 
Not applicable. 
 
5. 
STUDY POPULATION CHARACTERISTICS 
5.1 
Study participant disposition 
The number of study participants who were screened for Part B of this study, the number and 
percentage of screen failures and the primary reasons for screen failure will be summarized for 
the ES.  A listing of participants who did not meet the eligibility criteria for Part B will also be 
presented for the ES. In addition, the disposition of study participants screened and who received 
study treatment will be summarized by country and site.  This table will include, for each site 
and overall, site number, principal investigator name, the dates of the first participant in and the 
last participant out, the number of participants screened (ES), the number of screen failures, the 
number of participants who were treated (SS) and included in the PPS, PKS, ADAS and PDS.  
Disposition in each analysis set across all study sites will be summarized by treatment group.  
The number of study participants who received study treatment and the primary reason for 
discontinuation of UCB6114 and TFD/TPI study treatment during Part B will be summarized by 
treatment group, together with the number and percentage of participants who continued 
participation in the study after discontinuation of study treatment (at subsequent scheduled visits 
and/or SFU visit and Final Visit). This summary will be based on the SS. 
The number of study participants enrolled into Part B, who were screen failures as well as the 
number of eligible participants who were not treated will be presented for the ES.  For those 
participants who did not receive study treatment, the reasons for early discontinuation from the 
study will be summarized.   
Of those participants who received UCB6114, the number and percentage of participants who 
completed the study (i.e. participants who received at least 2 complete cycles of UCB6114 and 
attended the SFU visit), who received at least 2 complete cycles of UCB6114 but who did not 
attend the SFU visit and who discontinued early from Part B, together with the primary reasons 
for study discontinuation will be presented for all participants.  
The number and percentage of participants who discontinued due to AEs will be summarized 
separately for all participants, based on the SS. This will be used for European Union Drug 
Regulating Authorities Clinical Trials (EudraCT) reporting. 
The following study disposition tables will also be presented by gastric adenocarcinoma, 
adenocarcinoma of the gastroesophageal junction (Gastric/GEJ-Cancer) and colorectal 
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adenocarcinoma (CRC) tumor type depending on the number of participants with specific tumor 
types. 
• Disposition and Reasons for Discontinuation of Study Treatment; 
• Disposition and Study Discontinuation Reasons; 
• Discontinuation of the Study Due to AEs. 
Visits impacted by COVID-19 will be listed for the ES.  This listing will include, visit, visit date, 
relative day, impact category (e.g. visit performed out of window, visit performed by telephone, 
visit not done, missed study drug administration/dispensation, termination of study 
participation), relationship to COVID-19 (confirmed COVID-19 infection, suspected COVID-19 
infection, general circumstances around COVID-19 or other) and a narrative for the event.  The 
number and percentage of participants with visits impacted by COVID-19 will be presented by 
treatment group and by impact category.  This summary will be presented for the different 
relationships to COVID-19.  The denominator for the percentage calculations will be the number 
of participants in the SS. 
In addition, the following listings will be presented: 
• Study participant disposition (ES); 
• Study treatment discontinuation (SS); 
• Study discontinuation (ES); 
• Visit dates (ES); 
• Participant analysis sets and exclusions from analysis sets (ES)*. 
*DES is not included in this listing as it is only relevant for the SMC, and not required for the 
CSR. 
The listing of study participant disposition will include the date of informed consent, date and 
time of first and last dose of study treatments (UCB6114 and TFD/TPI), date of early study 
discontinuation (if applicable) and primary reason for discontinuation.   
Separate listings of UCB6114 and TFD/TPI study treatment discontinuation will include date 
and time of first and last dose of study treatments, date of decision to discontinue study treatment 
and primary reason for discontinuation of study treatments, date of clinical progression (if 
applicable), number of doses of study treatments received (based on 2 doses per cycle for 
UCB6114), total dose of study treatment received across all cycles, number of complete cycles 
of study treatment received, and whether or not the participant had continued participation in the 
study (at subsequent visits, the SFU visit or the Final Visit).   
Note that a participant is deemed to have completed a full cycle of study treatment if they 
received the planned dose of UCB6114 on Days 1 and 15 of the cycle (i.e. the infusion was not 
permanently discontinued due to an AE or other reason such that less than the planned dose was 
received) and a decision was not made to discontinue UCB6114 up to and including Day 28 
relative to Day 1 of the cycle. This will be derived based on a participant’s last dose of UCB6114 
and whether or not the participant attended the visit at which they were scheduled to receive their 
next dose of UCB6114. For example, if a participant received UCB6114 on Day 1 and Day 15 of 
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Cycle 1 and attended the clinic for their UCB6114 infusion on Day 1 of Cycle 2 then the 
participant will be counted as having completed Cycle 1.  If the participant did not attend Day 1 
of a subsequent cycle, then it is likely that a decision was made to discontinue their UCB6114 
treatment and/or the study. Therefore, the date that the decision was made to discontinue 
UCB6114 will be used to determine whether the participant completed a cycle of study 
treatment.  If a decision was made to discontinue UCB6114 on >Day 28 relative to Day 1 of the 
particular cycle then the participant will be counted as having completed the cycle. For any 
interim deliveries at a data cut-off, if the participant did not attend Day 1 of their next cycle and 
there was no decision to discontinue UCB6114, then the latest date available for that participant 
should be used to determine whether they have completed a 28-day cycle. 
Whether or not a participant has completed the study is defined as having received at least 2 
complete cycles of UCB6114 and attended the SFU visit. The investigator will record a study 
participant’s disposition status at study termination according to this definition of a ‘completed’ 
participant, however, a study completion flag will also be programmatically derived based on the 
relevant data on the database and the above rules for defining completion of a full cycle of 
UCB6114. 
The listing of study discontinuation will include the primary reason for early study 
discontinuation, the number of cycles of UCB6114 received, and the total number of days on 
UCB6114. 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types defined in 
the IPD specification document, as per Section 3.4.  
A listing of all IPDs identified at the DEM will be presented for all study participants based on 
the SS and will include the deviation type and description. In addition, a listing of all protocol 
deviations related to COVID-19 (whether considered important or not) will be presented for the 
SS. The number and percentage of participants in the SS with IPDs will be summarized by 
treatment group and for all participants for each deviation type. The number and percentage of 
participants who were excluded from the PPS will also be presented. The denominator for the 
percentage calculations will be the number of participants in the SS. A summary will also be 
presented for all protocol deviations related to COVID-19, all IPDs related to COVID-19 and all 
IPDs related to COVID-19 leading to exclusion from the PPS. 
 
6. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographics 
A by-participant listing of demographics will be presented based on the ES. This will include the 
year of birth, age (as entered by investigator in the eCRF in years), sex, race, ethnicity, height (in 
cm), weight (in kg) and body mass index (BMI, in kg/m2). Height will be the measurement 
obtained at the Screening visit and weight will be the last non-missing value prior to the first 
dose of UCB6114. 
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The BMI will be derived in the database using the height and weight measurements recorded at 
the Screening visit and will be automatically reported to 1 decimal place on the eCRF. 
All demographic characteristics (except for date of birth) will be summarized by treatment group 
and for all study participants based on the SS. The summary of age will include descriptive 
statistics and categorical summaries, the latter based on requirements for EudraCT and 
clinicaltrials.gov reporting. In addition, the summary of demographic characteristics will be 
presented by Gastric/GEJ-Cancer and CRC tumor type depending on the number of participants 
with each specific tumor type. 
For the EudraCT reporting, the categories will include: 
• 18 to <65 years; 
• 65 to <85 years. 
For clinicaltrials.gov reporting, the categories will include: 
• ≤18 years; 
• 19 to <65 years; 
• ≥65 years. 
Childbearing potential and method of birth control will be listed for the ES. 
6.2 
Cancer history 
All cancer history data for Part B participants will be listed for the ES.  This listing will include 
date of initial diagnosis, tumor type, TNM Classification of Malignant Tumors (TNM) 
classifications and stage, Duke’s score (participants with colorectal adenocarcinoma only), 
histological and cytological diagnosis details (as relevant), whether the participant had any 
metastases and associated anatomical location, and whether the participant had received any 
prior anti-cancer therapies (including the number of lines of any prior systemic therapies, prior 
radiation therapies and prior anti-cancer surgeries). 
Time since initial diagnosis (calculated in months using date of Screening visit and date of initial 
diagnosis and multiplying the duration in days by 12/365.25), tumor type, T, N, and M 
classifications and TNM stage, Duke’s score (participants with colorectal adenocarcinoma only), 
presence of metastases and anatomical location of metastases will be summarized by treatment 
group and for all study participants based on the SS. In the summaries of categorical variables, 
percentages will be calculated based on the number of study participants with non-missing data.  
Further, for the Duke’s score, the denominator for the percentage calculation will be the number 
of study participants with colorectal adenocarcinoma. 
Cancer history will be presented by Gastric/GEJ-Cancer and CRC tumor type depending on the 
number of participants with specific tumor types. 
6.3 
Prior anti-cancer therapy 
Details recorded for each line of prior anti-cancer systemic therapy received by a study 
participant will be listed for the ES.  This listing will include the line and type of systemic 
therapy, intent, drug name and dose, formulation, indication (current/ultimate), start and end 
dates, number of cycles received and the number of days per cycle, the participant’s best 
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response and the date of that best response, reason for discontinuation and whether the 
participant had disease progression prior to the next line of systemic therapy.  If there was 
progression, then the date of progression will also be listed.  In addition, time from completion of 
the last prior anti-cancer systemic therapy to the start of UCB6114 , whether the participant had 
progression after the last line of systemic therapy and, if so, the time from progression to the start 
of UCB6114 will be derived and listed. 
For those participants in the ES who received prior radiotherapy, the following data will be 
listed: treatment site, type of radiotherapy, intent, settings (concurrent with other anti-cancer 
systemic therapy or stand-alone radiation therapy), and, if concurrent radiotherapy, the anti-
cancer systemic therapy line that the radiotherapy was given with and the drug name.  In 
addition, the start and stop dates, total cumulative dose (if known), number of fractions (if 
known), the participant’s best response to radiotherapy and whether the tumor at the treatment 
site had progressed since radiotherapy will be included in this listing. 
A further listing of prior anti-cancer radiotherapy with systemic therapy regimens will be 
presented for participants in the ES who had concurrent prior systemic therapy and radiotherapy 
as their prior anti-cancer therapy.  This listing will include the relevant data described above 
together with the participant’s best response to that regimen. 
Date of surgery/procedure, anatomical location, description of the surgical procedure and 
whether the tumor was completely removed will be listed for those study participants in the ES 
who had prior anti-cancer surgeries or procedures. 
The following summaries of prior anti-cancer therapy regimens and surgeries will be presented 
by treatment group and for all participants for the SS: 
• Number of prior anti-cancer therapy regimens (0, 1, 2, 3, >3) (including all anti-cancer 
systemic therapy lines given alone and concurrently with radiotherapy)  
• Best response to the most recent prior anti-cancer therapy regimen 
• Number of prior anti-cancer systemic therapy + radiotherapy regimens (0, 1, 2, 3, >3) 
• Best response to the most recent anti-cancer systemic therapy + radiotherapy regimen 
• Reasons for discontinuation of the most recent line[a]   
• Time from completion of most recent line[a] to the start of UCB6114 (<1 month, 1-<3 
months, 3-6 months, >6 months)[b] 
• For participants that progressed after their most recent line[a], the time from progression 
to the start of UCB6114 (<1 month, 1-<3 months, 3-6 months, >6 months)[b] 
• Number of prior anti-cancer radiotherapies (including radiotherapies given alone and 
concurrently with anti-cancer systemic therapy) (0, 1, 2, >2) 
• Number of prior anti-cancer surgeries and procedures (0, 1, 2, >2) 
[a] Most recent line is the last prior anti-cancer therapy regimen received which may be a prior 
anti-cancer systemic therapy given alone or concurrently with radiotherapy. 
[b] 1 month = 30 days. 
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Time from completion and time from progression relative to the last line of anti-cancer systemic 
therapy will also be summarized using frequency counts and percentages as well as summary 
statistics. 
The number and percentage of participants with any prior anti-cancer systemic therapy, and any 
prior anti-cancer systemic therapy given concurrently with radiotherapy will be summarized for 
the SS by treatment group and for all participants, and by WHODD Anatomical Main Group 
[Level 1 term text], Pharmacological Subgroup [Level 3 term text] and PT. 
Prior anti-cancer therapy will be presented by Gastric/GEJ-Cancer and CRC tumor type 
depending on the number of participants with specific tumor types. 
6.4 
Cancer status at Screening 
The current cancer status of study participants at entry into Part B of this study will be assessed 
at the Screening visit and listed for the ES.  This listing will include tumor type, T, N and M 
classifications and TNM stage and Duke's score (participants with colorectal adenocarcinoma 
only), histological and cytological diagnosis details (as relevant), whether the participant has any 
metastases and associated anatomical location, whether the tumor is recurrent and whether the 
participant had relapsed from their last line of anti-cancer therapy.  
Tumor type, T, N and M classifications and TNM stage, Duke’s score (participants with 
colorectal adenocarcinoma only), presence of metastases and anatomical location of metastases, 
and time since relapse on last line of therapy (calculated in days using the date of the Screening 
visit and date of relapse) will be summarized by treatment group and for all study participants 
based on the SS.  In the summaries of categorical variables, percentages will be calculated based 
on the number of study participants with non-missing data. Further, for Duke’s score, the 
denominator for the percentage calculation will be the number of study participants with 
colorectal adenocarcinoma. 
Cancer status will be presented by Gastric/GEJ-Cancer and CRC tumor type depending on the 
number of participants with specific tumor types. 
6.5 
Medical history and concomitant diseases 
Medical history will be listed for the ES and summarized by MedDRA® system organ class 
(SOC) and preferred term (PT) by treatment group and for all study participants for the SS. The 
reported term will be included in the listing. Previous medical history (any previous medical 
conditions with a stop date prior to the start of UCB6114) and ongoing medical history (any 
ongoing medical conditions with a missing stop date but recorded as ongoing on the eCRF) will 
be summarized separately. These summaries will include the number and percentage of study 
participants and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the incidence in all study participants.  
Non-anti-cancer procedure history will be listed for the ES and concomitant medical procedures 
performed during the study will be listed for the SS. 
Medical history and concomitant disease will be presented by Gastric/GEJ-Cancer and CRC 
tumor type depending on the number of participants with specific tumor types. 
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6.6 
Prior and concomitant medications 
Prior medications will include any medications that started prior to the date of the first dose of 
UCB6114. This will include medications that started prior to the first dose of UCB6114 and 
continued after. 
Concomitant medications will include medications with a start date on or after the first dose of 
UCB6114 and prior to the date of the last dose of UCB6114 + 30 days, and whose stop date is 
either missing, or on or after the date of the first dose of UCB6114. Any medications with a start 
date prior to the first dose of UCB6114 and a stop date after, or continued to be ongoing during 
the study, will also be classified as concomitant medications. Medications with a start date > 30 
days after the last dose of UCB6114 will be considered as post-study medications and will not be 
included in the summaries of concomitant medication.  
Any medication that started prior to, and stopped after the first dose of UCB6114 or continued to 
be ongoing during the study, will be classified as both prior and concomitant.  
Any medications with missing start dates will be classified as both prior and concomitant. 
Any medications with partially missing dates will be handled as described in Section 4.2.3 to 
classify them as prior or concomitant provided that a stop date is not present or a stop date is 
present but prior to the first dose of UCB6114. 
All medications (prior, concomitant and post-study) will be listed for the ES.  Any prohibited 
concomitant medications, rescue medications or steroid use will be identified via a medical 
review and flagged in this listing.   
Prior and concomitant medications (per the definitions above) will be summarized for the SS by 
treatment group and by WHODD Anatomical Main Group [Level 1 term text], Pharmacological 
Subgroup [Level 3 term text] and PT. The reported term will be included in the listing. Separate 
summaries will be presented for prior medications and concomitant medications. As per the 
definitions above, prior medications which continued into the Treatment Period will also be 
classified as concomitant and will be included in both summaries. 
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in all study participants. 
A glossary of all prior and concomitant medications will be presented for the SS including the 
Anatomical Main Group (Level 1), Pharmacological Subgroup (Level 3), PT and reported term.  
Prior and concomitant medications will be presented by Gastric/GEJ-Cancer and CRC tumor 
type depending on the number of participants with specific tumor types. 
 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
During Part B of this study, administration of UCB6114 will be performed via iv infusion at the 
study site under the supervision of the designated site personnel and in compliance with the 
Guideline for First in Human clinical studies (EMEA/CHMP/SWP/28367/07Rev. 1). 
Compliance will be monitored at the site through a review of accountability logs which will be 
used to record UCB6114 dispensing and return information to ensure that each study participant 
received the correct UCB6114 dose level. 
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Study participant compliance with respect to the actual dose of TFD/TPI taken will be evaluated 
through the use of a participant diary, data from which will be transcribed onto the TFD/TPI 
study medication administration form in the eCRF which includes the total dose of TFD/TPI 
taken in the 15mg and 20mg tablets prescribed to a participant on Days 1 to 5 and Days 8 to 12 
of each cycle.  Percentage compliance will be calculated overall and by cycle as defined below: 
Compliance (%) = 
(Actual dosage administered)
Expected dosage 
𝑥 100 
Where  
The actual dosage administered is calculated as the sum of the actual dose administered on 
Days 1 to 5 and Days 8 to 12 (inclusive) during each cycle and overall. 
Expected dosage in a cycle = Prescribed total daily dose (as recorded on the eCRF) × 
Expected number of dosing days in a cycle.  
Expected dosage overall = Prescribed total daily dose (as recorded on the eCRF) × Expected 
number of dosing days overall. 
Expected number of dosing days in a cycle is defined as the sum of Days 1 to 5 and Days 8 
to 12 (inclusive) (10 days for participants who complete a cycle or up to the last scheduled 
dosing day for participants who discontinue TFD/TPI during a cycle).   
Expected number of dosing days overall is the number of cycles of TFD/TPI received x 10 
for participants who complete dosing in all cycles up to Day 12 or, for participants who 
discontinue TFD/TPI during a cycle, it is the number of completed cycles of TFD/TPI 
received x 10 + the number of scheduled dosing days up to the discontinuation of TFD/TPI). 
Note that, per protocol, intake of TFD/TPI is twice a day, every 12 hours, and the prescribed 
number of tablets should be taken within 1 hour of completion of morning and evening meals. In 
cases where the first intake on Day 1 and/or Day 8 of a cycle is delayed into the afternoon then 
TFD/TPI dosing in this cycle may extend into Day 6 and/or Day 13.  This is acceptable and 
therefore all dosing days should be taken into account in the compliance calculation. 
Any dosing deviations will be reviewed as IPDs at the DEMs and assessed for possible impact 
on the PPS and the summaries of PK endpoints.  If considered important, these deviations will be 
included in the summary and listing of IPDs. 
 
8. 
SAFETY ANALYSES 
All safety summaries and listings will be presented by Gastric/GEJ-Cancer and CRC treatment 
group based on the SS, unless otherwise stated. 
All safety summaries may be presented by tumor type depending on the number of participants 
with specific tumor types. 
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8.1 
Extent of exposure 
Extent of exposure to UCB6114 and TFD/TPI administered in Part B will be summarized and 
listed. In addition, a separate summary table and listing of participant compliance, with respect to 
taking TFD/TPI tablets, will be presented.  
8.1.1 
UCB6114  
Details of UCB6114 treatment administration on Day 1 and Day 15 of each cycle of study 
treatment will be listed. This listing will be split into two parts.  The first part will include the 
start and stop dates and times of infusion, duration of infusion, infusion rate, whether the 
infusion was temporarily stopped/interrupted, whether the infusion was permanently 
discontinued and, if this was the case, whether the interruption or permanent discontinuation was 
due to an AE or other reason.  The second part of this listing will include, for each visit, infusion 
site, total volume delivered, volume infused, planned total dose and total dose actually 
administered at infusion. In addition, the percentage of planned dose received, total dose 
administered across all cycles, the number of complete cycles of UCB6114 received and the total 
number of doses of UCB6114 received will be listed. 
The percentage of planned UCB6114 dose received will be calculated for each study participant 
at each dosing visit within each cycle as follows: 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑜𝑓 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑= 100 × 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒
 
 
Actual duration of each UCB6114 infusion will be calculated in minutes only for those study 
participants who did not have any temporary interruption(s) of their infusion using the infusion 
start and stop times and included on this listing. Length of interruption(s) will be calculated for 
those study participants who had temporary interruption(s) of their infusion. 
The number of complete cycles of UCB6114 received (0, 1, 2, 3, 4, >4) will be summarized 
using frequency counts and percentages, and summary statistics will be presented for the total 
dose of UCB6114 received across all cycles, the total number of doses of UCB6114 received and 
the total duration of exposure to UCB6114.   
Total duration of exposure will be calculated in days as follows: 
Total Duration of Exposure = (Date of Last Dose of UCB6114-Date of First Dose of 
UCB6114) + 30  
Note that 30 days is added to this calculation to account for a participant’s continued exposure to 
UCB6114 following their last dose of study treatment.  
Note that a participant is deemed to have completed a full cycle of UCB6114 if they receive the 
planned dose of UCB6114 on Day 1 and Day 15 of the cycle and a decision was not made to 
discontinue UCB6114 up to and including Day 28 relative to Day 1 of a cycle.   
 
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8.1.2 
TFD/TPI 
Details of TFD/TPI treatment administration on Days 1 to 5 and Days 8 to 12 of each cycle of 
study treatment will be listed. The listing will include prescribed total daily dose, date of 
TFD/TPI administration, time of morning dose, number of 15mg and 20mg tablets taken in the 
morning, time of evening dose, number of 15mg and 20mg tablets taken in the evening and total 
daily dose administered. A separate listing of compliance to TFD/TPI treatment will be 
presented.  This will include, overall and in each cycle, the total dosage administered, the 
prescribed total daily dose, expected number of dosing days, expected dosage and the percentage 
compliance. 
Summary statistics will be presented for the total dose of TFD/TPI received across all cycles and 
for the total duration of exposure to TFD/TPI. 
Total duration of exposure will be calculated in days as follows: 
Total duration of Exposure = (Date of Last Dose of TFD/TPI -Date of First Dose of 
TFD/TPI) + 30  
Summary statistics will be presented for overall percentage compliance, and by cycle, together 
with a categorical summary of the number and percentage of participants who were <80%, 80-
90%, and >90% compliant with respect to taking the prescribed TFD/TPI dose.  
8.2 
Adverse events 
The primary safety endpoints for Part B of this study are the incidence and severity of TEAEs 
(including SAEs) from the first dose of UCB6114 treatment on Day 1 of Cycle 1 until the end of 
the SFU Period (up to 30 days following the last dose of UCB6114 treatment), and the incidence 
of DLTs from the first dose of UCB6114 on Day 1 of Cycle 1 until the end of the 28-day DLT 
Observation Period (Day 28 of Cycle 1). 
All AEs in Part B of the study will be coded using MedDRA® and classified as pre-treatment and 
treatment-emergent relative to the first dose of UCB6114 treatment.  Adverse events with a start 
date prior to the first infusion of UCB6114 will be defined as pre-treatment AEs. A TEAE is 
defined as any AE with a start date on or after the first dose of UCB6114 up until the last dose of 
UCB6114 + 30 days.  A pre-treatment AE which increases in severity on or after the first dose of 
UCB6114 will also be counted as a TEAE. Note that in this case, the pre-existing AE will have a 
stop date and an outcome of ‘worsened’ and a new AE (with the same verbatim) will be entered 
with the same start date and the increased severity recorded on the eCRF. Any AE (including 
SAEs) with an onset date later than the last dose of UCB6114 + 30 days will not be considered 
as treatment-emergent and therefore will not be included in the tabulations of TEAEs.  These 
AEs will be considered as post-study AEs and will be listed only. Where onset dates are missing 
or partially missing, AEs will be assumed to be treatment-emergent, unless there is clear 
evidence to suggest that the AE started prior to the first dose of UCB6114 and it has not 
increased in severity. Missing or partially missing dates for AEs will be handled as described in 
Section 4.2.3 All AEs for a participant will be recorded in the eCRF from the time of informed 
consent until completion or early discontinuation of Part B of this study. Serious adverse events 
are to be reported up to 30 days after the Final Visit (i.e. up to 150 days after the last dose of 
study treatment). 
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Adverse events will be assigned an NCI CTCAE severity grade (Grade 1/Grade 2/Grade 3/Grade 
4/Grade 5), where possible.  If a CTCAE toxicity grading is not possible, then the intensity of the 
AE (mild/moderate/severe) will be recorded on the eCRF. If the AE is not gradable, is serious, 
and is considered as life threatening, then the intensity for this AE will be missing and one of the 
reasons for seriousness will be recorded as life threatening.  Adverse events will also be 
categorized according to their relationship to UCB6114 and/or TPD/TPI treatment (related/not 
related), and whether the event is a DLT, as judged by the investigator. A DLT is defined as a 
TEAE at least possibly related to UCB6114 that occurs during Cycle 1 and fulfills any of the 
criteria listed in Section 4.1.1.4 of the protocol.  The investigator is expected to record whether 
an AE is a DLT on the eCRF. 
An overview of the number and percentage of participants who experience TEAEs will be 
presented.  This summary will include the number and percentage of participants with any 
TEAEs, serious TEAEs, related TEAEs (related to UCB6114 only and related to UCB6114 
and/or TFD/TPI), discontinuations from study treatment (UCB6114  and TFD/TPI and TFD/TPI 
only) due to TEAE(s), discontinuations from the study due to TEAE(s), CTCAE Grade ≥ 3 
TEAEs, CTCAE Grade >=3 TEAEs related to UCB6114 only, CTCAE Grade >=3 TEAEs 
related to UCB6114 and/or TFD/TPI, DLTs, AEs leading to death and TEAEs leading to death; 
event counts will also be included against each of these categories. The overview of TEAEs will 
be presented by Gastric/GEJ-Cancer and CRC tumor type depending on the number of 
participants with specific tumor types. 
In addition, the following summaries will be presented by SOC, high level term (HLT) and PT, 
and where indicated also by Gastric/GEJ-Cancer and CRC tumor type depending on the number 
of participants with specific tumor types: 
• Incidence of TEAEs (overall and by tumor type); 
• Incidence of serious TEAEs (overall and by tumor type); 
• Incidence of non-serious TEAEs (overall and by tumor type); 
• Incidence of TEAEs leading to a temporary interruption of UCB6114 infusion and/or 
dose reduction (overall and by tumor type); 
• Incidence of TEAEs leading to a temporary interruption and/or reduction in dose of 
TFD/TPI (overall and by tumor type); 
• Incidence of TEAEs leading to discontinuation of UCB6114 and TFD/TPI (overall and 
by tumor type); 
• Incidence of TEAEs leading to discontinuation of TFD/TPI only (overall and by tumor 
type); 
• Incidence of TEAEs leading to discontinuation of study (overall and by tumor type); 
• Incidence of DLTs (separately for during the 28-day DLT Observation Period and after 
the 28-day DLT Observation Period) (overall and by tumor type); 
• Incidence of adverse events of special interest (AESIs) (Hy’s Law – see Section 8.2.1 
below) (overall and by tumor type); 
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• Incidence of UCB6114 infusion-related reactions (defined any TEAE with a PT from 
both a narrow and broad scope search of category A terms of the ‘Hypersensitivity’ 
Standardized MedDRA® Query (SMQ) – see Section 8.2.2) (overall and by tumor type); 
• Incidence of TEAEs by maximum CTCAE severity grade (overall and by tumor type); 
• Incidence of TEAEs related to UCB6114 only by maximum CTCAE severity grade 
(overall and by tumor type); 
• Incidence of TEAEs related to UCB6114 and/or TFD/TPI by maximum CTCAE severity 
grade (overall and by tumor type); 
• Incidence of TEAEs by maximum relationship to UCB6114 only (overall and by tumor 
type); 
• Incidence of TEAEs by maximum relationship to UCB6114 and/or TFD/TPI (overall and 
by tumor type); 
• Incidence of TEAEs by relationship to UCB6114 only; 
• Incidence of TEAEs by relationship to UCB6114 and/or TFD/TPI; 
• Incidence of serious TEAEs by relationship to UCB6114 only; 
• Incidence of serious TEAEs by relationship to UCB6114 and/or TFD/TPI; 
• Incidence of non-serious TEAEs by relationship to UCB6114 only; 
• Incidence of non-serious TEAEs by relationship to UCB6114 and/or TFD/TPI; 
• Incidence of fatal TEAEs by relationship to UCB6114 only; 
• Incidence of fatal TEAEs by relationship to UCB6114 and/or TFD/TPI; 
• Incidence and event rate of TEAEs by treatment-emergent ADA positivity. 
The following summary will be presented by SOC and PT for EudraCT reporting: 
• Incidence of non-serious TEAEs above the threshold of 5% of participants in any 
treatment group. 
The above summaries of TEAEs will be ordered alphabetically by SOC, alphabetically by HLT 
within SOC and decreasing incidence of PT events within SOC /HLT in all study participants.  
For tables including only the number and percentage of participants, summaries will be ordered 
alphabetically by SOC, alphabetically by HLT within SOC and decreasing incidence of 
participants with each PT within SOC /HLT in all study participants. 
The incidence of TEAEs by maximum CTCAE severity grade will be presented by CTCAE 
term.  CTCAE term will be obtained from the NCI CTCAE Version 5.0 via a mapping of 
MedDRA® lower level terms.  This summary will be ordered by decreasing incidence of 
participants with each CTCAE term in all study participants.   
Summary tables will contain frequency counts and percentages, and the number of events, where 
applicable. A study participant who experiences the same event multiple times will be counted 
only once in the frequency counts for the PT, but all events will be included. 
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In the summaries of TEAEs by relationship, participants will be counted in “Not related” and 
“Related” categories (or “Missing” in the case where an event has a missing relationship). A 
study participant who experiences the same event multiple times will be included in the most 
related category for the summaries by maximum relationship. 
In the overview summary of TEAEs, participants will be counted as having at least one TEAE 
with CTCAE severity grade ≥3, and in the summary of TEAEs by maximum CTCAE severity 
grade, participants will be counted as having at least one TEAE in the following categories: 
‘Grade 1’, ‘Grade 2’, ‘Grade 3’, ‘Grade 4’, ‘Grade 5’, ‘Grade 3 or 4’ and ‘Grade >=3’.  Events 
for which no CTCAE severity grade is recorded by the investigator but an intensity is recorded 
instead, the intensity of this event will be assigned to a CTCAE severity grade for the purpose of 
these summaries, i.e. ‘Mild’ will be included as ‘Grade 1’, ‘Moderate’ will be included as ‘Grade 
2’, ‘Severe’ will be included as ‘Grade 3’, ‘Life Threatening’ will be included as ‘Grade 4’ and, 
if the participant dies due to the event, it will be included as ‘Grade 5’. The determination of 
whether the event is life threatening or results in death will be based on the reason for 
seriousness recorded as life-threatening or death on the eCRF, or on the event having a fatal 
outcome. Otherwise, if both the CTCAE severity grade and intensity is missing then the CTCAE 
severity grade in these summaries will be missing. A study participant who experiences the same 
event multiple times will be included in the highest severity grade category in the summary of 
TEAEs by maximum CTCAE severity grade.  
A glossary of all AEs will be presented including the MedDRA® SOC, HLT, PT, reported term 
and low level term (LLT).  
A listing of all AEs will be presented by study participant for the ES. The listing will include the 
onset date and stop date of the event (including relative days) and also the onset times and stop 
times of events where available.  Period of onset of AEs will also be presented on this listing. 
Period of onset of AEs will be defined as follows for the purpose of the listing: 
• If the AE has an onset date prior to the date of the Screening visit, then Period=Pre-study; 
• If the AE has an onset date on or after the date of the Screening visit and has an onset 
date and time prior to the start time of UCB6114 infusion on Day 1 of Cycle 1 then 
Period=Screening; 
• If the AE has an onset date and time on or after the start time of UCB6114 infusion on 
Day 1 of Cycle 1 and up to the date and time of the start of Cycle 2 (i.e. prior to the start 
time of the  UCB6114 infusion on Day 1 of Cycle 2) then Period=Cycle 1; 
• If the AE has an onset date and time on or after the start time of UCB6114 infusion on 
Day 1 of Cycle 2 and up to the date and time of the start of Cycle 3 (i.e. prior to the start 
time of the UCB6114 infusion on Day 1 of Cycle 3) then Period=Cycle 2; 
• Same as above for subsequent cycles (Cycle 3 etc.); 
• If the AE has an onset date after the last dose of UCB6114 up to and including 30 days 
after the last dose of UCB6114, then Period=SFU; 
• If the event has an onset date after the 30-day period following the last dose of UCB6114, 
then Period=Post-study. 
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The listing of all AEs will also include the AE duration (derived in days, hh:mm for AEs with 
onset and stop times recorded and derived in days for all other AEs with only onset and stop 
dates recorded), days since start of UCB6114 infusion (time if an onset time is recorded, days 
otherwise), seriousness and reason for seriousness, CTCAE severity grade, intensity (where a 
CTCAE severity grade is not recorded), pattern of event, relationship to UCB6114 and TFD/TPI 
and action taken with UCB6114 and TFD/TPI (including other action taken), the outcome of the 
AE, whether an autopsy was performed and cause of death. In addition, the listing will flag AEs 
that led to discontinuation from the study, TEAEs, AESIs, SAEs, UCB6114 infusion-related 
reactions, and DLTs. Whether an AE is related to a concomitant medication, (and separately 
whether it is related to the COVID-19 vaccination), the names of any co-suspect medications 
will also be listed. 
Separate listings of all SAEs, TEAEs leading to discontinuation of UCB6114 and TFD/TPI, 
TEAEs leading to discontinuation of TFD/TPI only and TEAEs leading to discontinuation of the 
study will also be presented.  
All deaths that occur on study (defined as during study treatment or within 30 days of the last 
dose of UCB6114) will be listed separately.  This listing will include the primary cause of death 
and the number of days between the date of the last dose of UCB6114 and death, defined as 
𝐷𝑎𝑦𝑠 𝑠𝑖𝑛𝑐𝑒 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑡𝑒𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114 ) 
8.2.1 
Adverse events of special interest  
An AESI is any AE that a regulatory authority has mandated be reported on an expedited basis, 
regardless of the seriousness, expectedness, or relatedness of the AE to the administration of a 
UCB product/compound.  
For ONC001, potential Hy’s Law is used to identify AESIs and is defined using the laboratory 
data and the following potential drug-induced liver injury (PDILI) criteria: 
• ≥3x upper limit of normal (ULN) alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of 
≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the biochemical 
abnormality; 
• Study participants who have evidence of liver metastases may be considered to have an 
alternate etiology for the described laboratory abnormalities. 
All AESIs will be flagged on the listing of AEs. 
8.2.2 
Infusion-related reactions  
Infusion-related reactions are defined as hypersensitivity reactions, anaphylactic reactions and 
cytokine release syndrome with onset within 24 hours after the start of an infusion of UCB6114.   
All potential infusion-related reactions will be identified programmatically and will then undergo 
medical review for confirmation based on participant characteristics and other signs and 
symptoms.  The final assessment from the medical review will be used in the programming to 
ensure that all infusion-related reactions are flagged correctly in the listings and included in the 
relevant summaries. 
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Hypersensitivity reactions will be programmatically identified as any TEAE with a PT from both 
a narrow and broad scope search of category A terms of the ‘Hypersensitivity’ SMQ. 
Anaphylactic reactions will be programmatically identified using an algorithmic approach based 
on the ‘Anaphylactic Reaction’ SMQ.  Further details on this algorithm are given in Section 11. 
Note that if the MedDRA® version is increased from 25.1 during the study, any changes to the 
terms included in the ‘Anaphylactic Reaction’ SMQ should be applied. 
Cytokine release syndrome will be programmatically identified as any TEAE with a PT of 
‘Cytokine release syndrome’ from the broad scope search of category A terms of the 
‘Hypersensitivity’ SMQ.  Since this disorder is characterized by fever, headache, tachycardia, 
hypotension, rash, tachypnoea and/or hypoxia, a further medical review of participants with 
these events occurring within 24 hours after infusion of UCB6114 will be performed to confirm 
any further infusion-related reactions. 
Note that any other AEs (i.e. not identified as infusion-related reactions using the rules above) 
which result in a temporary interruption or permanent discontinuation of a UCB6114 infusion 
will not be considered as an infusion-related reaction. 
8.3 
Clinical laboratory evaluations 
The use of multiple local laboratories (1 per site in the UK and US) in Part B of this study has 
meant that results have been recorded in different units and with reference to different normal 
ranges, and further, for some laboratory tests, different normal ranges have been applied to males 
and females and age groups.  As a first step to ensure comparability of laboratory results, results 
and normal ranges will be converted to the same International System of Units (SI) units using 
UCB’s standard conversion factors.  This will be programmed at the Study Data Tabulation 
Model (SDTM) level.  Note though that the simple conversion to SI units does not represent a 
full homogenization of results from different local laboratories using different methods.  To 
ensure full comparability, the observed laboratory results will be normalized to a unique set of 
standard reference ranges using the location-scale normalization formula (Chuang-Stein, 1992) 
which normalizes all results in relation to a standard set of reference ranges (for hematology, 
clinical chemistry and coagulation parameters): 
𝑠= 𝐿𝑆+ (𝑥− 𝐿𝑋) (𝑈𝑆−𝐿𝑆)
(𝑈𝑋− 𝐿𝑋) 
and when the standard lower limit is 0: 𝑠= 𝑥
𝑈𝑆
𝑈𝑋  where: 
s = normalized observed value 
x = original observed value in SI units 
LS = Lower Limit of the reference range chosen to be the standard reference range 
US = Upper Limit of the reference range chosen to be the standard reference range 
LX = Lower Limit of the reference range associated with the original observed value in SI 
units (local laboratory reference range) 
UX = Upper Limit of the reference range associated with the original observed value in SI 
units (local laboratory reference range) 
 
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This transformation preserves the distance of the original laboratory result from the lower limit 
of normal as a multiple of the specified standard reference range. 
 
Note that the choice of the standard reference range is arbitrary, however, the most recent 
reference ranges used by ICON Central Laboratories (including the age and gender specific 
reference ranges for parameters, where available) will be used to normalize the results in this 
study. 
 
Normalization of the laboratory results will be performed in the ADaM programming by ICON. 
All normalized laboratory data (hematology, serum chemistry and coagulation) and changes 
from Baseline for numeric variables will be listed for participants who have at least one value 
outside of the reference range. All urinalysis data will be listed for all participants.  Data will be 
listed by study participant, laboratory panel, laboratory parameter and visit within each treatment 
group. Any laboratory measurements that are BLQ or ALQ will be handled as described in 
Section 4.2.2. For the relevant numeric laboratory parameters, the reference ranges supplied by 
the local analytical laboratory will be used to flag values outside the reference range as low or 
high in this listing. For the parameters for which the local laboratory cannot supply the reference 
ranges, the reference ranges provided by ICON Central Laboratories will be used instead. A 
listing of all laboratory results outside of the reference range will also be presented.  The 
reference ranges will also be reported in the listings. 
In addition, for the relevant hematology, clinical chemistry and coagulation laboratory tests, 
CTCAE severity grades (Grade 1, Grade 2, Grade 3, Grade 4) will be applied (where possible) in 
the ADaM programming according to NCI CTCAE Version 5.0, and these grades will also be 
listed for the relevant laboratory parameters.  Note that Grade 0 will be applied in cases where a 
result is normal for the relevant laboratory test and Grade 5 is not applicable in the grading of 
laboratory data. 
Observed normalized values and changes from Baseline in the hematology, serum chemistry and 
coagulation parameters presented below in Table 8-1 will be summarized at each visit.  In 
addition, for each of these parameters, the Baseline value, the minimum, maximum, average and 
last post-Baseline value for each participant will be summarized by cycle using descriptive 
statistics.  These post-Baseline summary measures will be calculated based on all available 
scheduled postdose values within each cycle, i.e. from Day 8 of the current cycle up to Day 1 
(pre-UCB6114) of the subsequent cycle. The last value in a cycle will be the predose value of the 
subsequent cycle where a subsequent cycle occurs, otherwise it will be the value at the last 
scheduled assessment.  If only one value is available then the average will not be calculated and 
presented but this value will be used for the minimum, maximum and last post-Baseline 
summary measures. These summary measures for each cycle will also be listed.  
The summaries of normalized hematology, serum chemistry and coagulation values and changes 
from Baseline will also be presented by Gastric/GEJ-Cancer and CRC tumor type depending on 
the number of participants with specific tumor types. 
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For those laboratory parameters with a CTCAE toxicity assigned, shift tables for the change 
from Baseline in CTCAE severity grade at each visit and to the worst post-Baseline CTCAE 
severity grade during the Treatment Period will be presented.  
Table 8-1: 
Clinical Laboratory Assessments 
Laboratory Assessment 
Laboratory Parameters 
Hematology 
Platelet Count, RBC Count, Hemoglobin, Hematocrit, RBC 
Indices (MCV, MCH, MCHC), WBC Count with Differential 
(Absolute Neutrophils, Absolute Lymphocytes, Absolute 
Monocytes, Absolute Eosinophils, Absolute Basophils) 
Clinical Chemistry 
ALT, AST, ALPa , Bicarbonate, Sodium, Potassium, 
Magnesium, Chloride, Calcium, Total Bilirubin, BUN or 
Urea, Serum Creatinine, Glucose (non-fasted), Phosphorus or 
Phosphate, Albumin, Total Protein, Uric Acid, Amylase, 
GGT, Cholesterol, Creatine Kinase, CRP, LDH, Lipase, 
Triglycerides 
Coagulation 
aPTT and either prothrombin time or INR  
Routine Urinalysis 
Specific Gravity, pH, Glucose, Protein, Blood, Ketones, 
Bilirubin, Urobilinogen, Nitrite, Leukocyte Esterase by 
Dipstick 
Microscopic Examination (if blood or protein is abnormal, 
including crystals) 
Screening Tests 
Pregnancy tests: FSH and estradiol (for women of 
non-childbearing potential only); serum or urine hCG 
pregnancy test (for women of childbearing potential)  
Bone turnover markers: blood BAP, blood CTx, urinary NTx 
and urinary CTxII  
Tumor markers: e.g. PSA, CA125, CA19-9 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPPT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; BAP=bone alkaline phosphatase; BUN=blood urea nitrogen; CA=cancer antigen; CRP=C-reactive protein; 
CTx=C-terminal telopeptide; FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; hCG=human chorionic 
gonadotropin; INR=international normalized ratio; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; NTx=N-terminal telopeptide; 
PSA=prostate specific antigen; RBC=red blood cell; WBC=white blood cell. 
a including liver-specific ALP for use in assessing participants with bone metastases at Screening. In the case of bone metastases 
liver function abnormalities considered potential Hy’s law cases, the liver-specific ALP must be separated from the total in 
participants with bone metastases and used to assess the liver function instead of the total ALP 
The screening laboratory tests included above in Table 8-1 will be listed only. 
Liver function abnormalities will be defined using the following criteria: 
• ALT or AST ≥2xULN 
• ALT or AST ≥3xULN 
• Total bilirubin ≥2xULN 
• Total bilirubin ≥3xULN 
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• ALT or AST ≥5xULN 
• ALT or AST ≥8xULN 
• ALT or AST ≥3xULN AND total bilirubin ≥2xULN (>35% direct bilirubin) 
For the subgroups of participants with liver metastases and without liver metastases at Baseline, 
the number and percentage of participants in each liver function abnormality category will be 
summarized at each visit. 
In addition, participants with PDILI criteria are those that fulfill the following laboratory data 
(based on liver function tests) criteria at a visit: 
• AST or ALT and total bilirubin within the normal range at Baseline and AST or ALT 
≥3xULN concurrent with total bilirubin ≥2xULN; 
• AST, ALT or total bilirubin above ULN at Baseline and AST or ALT ≥2 times Baseline 
values AND AST or ALT ≥3xULN (participants without liver metastases at 
Baseline)/AST or ALT ≥8xULN (participants with liver metastases at Baseline) 
concurrent with total bilirubin above ULN at Baseline and total bilirubin ≥2 times 
Baseline value or ≥3xULN (whichever is lower). 
All relevant laboratory data collected for participants with a PDILI event (i.e. liver function tests) 
will be listed at the visits at which at least one of the above criteria was fulfilled.  
The number and percentage of participants meeting different combinations of the ALT, AST and 
total bilirubin criteria defined above will be summarized by treatment group.  This summary will 
be presented for all participants as well as for the subgroups of participants who had liver 
metastases at Baseline and participants without liver metastases at Baseline. 
A separate listing will also be produced containing drug-induced liver injury -relevant family 
medical history, lifestyle data (alcohol consumption or drug abuse in the previous 6 months), 
hepatic event supplemental medical history and any hepato-toxic medications taken for 
participants in the SS with a PDILI event. 
8.4 
Vital signs, physical findings, and other observations related to 
safety 
8.4.1 
Vital signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include:  
• Systolic and diastolic blood pressure; 
• Pulse rate; 
• Oral body temperature; 
• Respiratory rate. 
On UCB6114 dosing visits (Days 1 and 15 of each cycle), vital signs will be assessed at multiple 
timepoints: predose, 10 minutes (±5 minutes) and 30 minutes (±10 minutes) after the start of the 
infusion, at the end of the infusion (+15 minutes); and at 1 hour (+15 minutes) after the end of 
the infusion. In addition, on Cycle 1 Day 1, vital signs will also be assessed at 2 hours (+1 hour) 
and 5 hours (+1 hour) after the end of the infusion. Where PK samples are taken on UCB6114 
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dosing days (predose, at the end of infusion and at 2 hours after the end of infusion on Day 1 of 
Cycles 1 and 2, and predose on all other UCB6114 dosing days), vital signs will be measured 
prior to PK sampling. 
At all other scheduled visits (Days 8 and 22 of Cycle 1), vital signs will be measured prior to 
UCB6114 dosing. At the SFU visit, vital signs measurements will be taken prior to PK sampling. 
Observed vital sign measurements and changes from Baseline will be listed by visit and 
timepoint and summarized using descriptive statistics. In addition, for each of the vital signs, the 
Baseline value, the minimum, maximum, average and last post-Baseline value for each 
participant will be calculated based on all available scheduled postdose values during each cycle 
up to the predose value on Day 1 of the subsequent cycle and will be summarized by cycle using 
descriptive statistics. The last value in a cycle will be the predose value of the subsequent cycle 
where a subsequent cycle occurs, otherwise it will be the value at the last scheduled assessment.  
If only 1 value is available then the average will not be calculated and presented but this value 
will be used for the minimum, maximum and last post-Baseline summary measures. These 
summary measures for each cycle will also be listed.   
For the multiple vital signs measurements on treatment days (i.e. on Days 1 and 15 of each 
cycle), changes from the predose value will be calculated at each postdose timepoint and 
summarized using descriptive statistics.   
For each vital signs parameter, the mean (±standard deviation) change from Baseline value will 
be plotted over scheduled visit and timepoint with treatment group overlaid on the same plot. 
The incidence of treatment-emergent markedly abnormal (TEMA)/ potentially clinically 
significant (PCS) vital signs based on blood pressure and pulse rate measurements will be 
summarized by visit and timepoint using frequency counts and percentages. The criteria for 
identifying a TEMA/PCS are included in Table 8-2. 
Table 8-2: 
TEMA/PCS Criteria for Vital Signs 
Variable (unit) 
Lowa 
Higha 
Systolic Blood Pressure (mmHg)  
 
Value <90 and ≥20 decrease 
from Baseline 
Value >140 and ≥20 increase from 
Baseline 
Diastolic Blood Pressure 
(mmHg)  
Value <50 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
Pulse Rate (bpm) 
Value <45 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
bpm=beats per minute; PCS=potentially clinically significant; mmHg=millimeter of mercury; TEMA=treatment-emergent 
markedly abnormal.  
a Both conditions must be satisfied for a measurement to be considered PCS. 
8.4.2 
12-Lead Electrocardiograms  
Electrocardiograms will be performed at each visit and timepoint in triplicate with the participant 
in a supine position after a minimum of 5 minutes rest.   
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On Days 1 and 15 of Cycle 1 only, ECGs will be performed in triplicate at multiple timepoints 
relative to UCB6114 dosing (predose, end of infusion, and 2 hours after the end of infusion).  
When ECG measurements coincide with blood sampling for PK (and PD), ECG will be 
performed first.  On Days 1 and 15 of Cycle 2 and on Day 1 of all subsequent cycles, ECGs will 
be performed in triplicate prior to UCB6114 dosing.  At the SFU visit, ECGs will be performed 
once in triplicate prior to PK sampling. 
All ECGs will be evaluated for any clinically relevant changes by the investigator.  
Electrocardiograms will also be collected for central reading, the data from which will be 
analyzed separately.   
All summaries and listings of ECG data will be based on the local (site) 12-lead ECG 
measurements. 
The following ECG parameters will be reported: 
• PR interval;  
• QT interval; 
• QRS interval; 
• QTcF interval (QT corrected for heart rate using Fridericia’s formula [QTcF]); 
• Heart rate.  
Observed values and changes from Baseline in these ECG parameters will be listed and 
summarized by visit using descriptive statistics.  The mean of the triplicate measurements taken 
for each parameter will be used in the summary at each visit and timepoint. If less than 3 of the 
triplicate measurements are taken then the mean of the available measurements will be used (if 
only 1 of the 3 triplicate measurements is available then this value will be used in the 
summaries). The Baseline value will be the mean of the last scheduled or unscheduled triplicate 
measurements taken prior to first dose of UCB6114 on Day 1 of Cycle 1. If no predose triplicate 
measurements are taken then the mean of the triplicate measurements taken at Screening will be 
used. The mean of only the scheduled triplicate measurements at each Post-Baseline visit and 
timepoint will be included in the summary. In addition, for each of the ECG parameters, the 
minimum, maximum, average and last post-Baseline value for each participant will be calculated 
based on the mean of the triplicate of all available scheduled postdose measurements during each 
cycle up to the predose value on Day 1 of the subsequent cycle, and will be summarized by cycle 
using descriptive statistics. The last value in a cycle will be the predose mean triplicate value of 
the subsequent cycle where a subsequent cycle occurs, otherwise it will be the mean triplicate 
value at the last scheduled assessment. If only 1 mean triplicate value is available then the 
average will not be calculated and presented but this value will be used for the minimum, 
maximum and last post-Baseline value summary measures. These summary measures for each 
cycle will also be listed.   
For the multiple ECGs performed on Days 1 and 15 of Cycle 1, changes from the predose value 
will be calculated at each postdose timepoint and summarized using descriptive statistics.   
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Mean (±standard deviation) change from Baseline in QTcF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot.  Individual observed values of QTcF will be 
presented over actual time in a spaghetti plot. 
The following cut-points in QTcF will be applied for observed data and changes from Baseline:  
For observed QTcF data: 
• <450 msec; 
• ≥450 to <480 msec; 
• ≥480 to <500 msec; 
• ≥500 msec. 
For changes from Baseline in QTcF: 
• <30 msec; 
• ≥30 to <60 msec; 
• ≥60 msec. 
The incidence of participants in each of these categories will be summarized using frequency 
counts and percentages by visit. 
A listing of 12-lead ECG abnormal findings will be presented. 
Electrocardiograms will also be collected for central reading; however, these data will be 
reported in an addendum to the CSR. 
8.4.3 
Echocardiogram 
Echocardiograms will be performed at the Screening visit, at Cycle 3 Day 1 (+/- 7 days), as 
clinically indicated afterwards, and at the SFU Visit. 
All details on the echocardiogram assessments performed at each visit will be listed including the 
observed LVEF measurements and changes from Baseline, as well as information on whether the 
result was normal, abnormal not clinically significant (NCS) or abnormal clinically significant 
(CS). 
Observed values and changes from Baseline in LVEF will be summarized by visit using 
descriptive statistics.  In addition, shift tables for the change from Baseline in normal, abnormal 
NCS, abnormal CS LVEF results will be summarized by visit. 
Mean (±standard deviation) change from Baseline in LVEF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot.  Individual observed LVEF results will be 
presented over actual time in a spaghetti plot. 
8.4.4 
ECOG performance status 
ECOG performance status will be listed by participant and visit and will be summarized using 
frequency counts and percentages. A shift table summarizing the changes from Baseline to each 
post-Baseline visit will also be presented.   Further detail on the ECOG performance scale, the 
listings and summaries are included in Section 10.2. 
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8.4.5 
Physical examination 
Physical examination abnormalities from the complete physical examination performed at 
Screening and predose on Day 1 of Cycle 1, and from the symptom-directed physical 
examinations performed at other visits (predose on dosing visits), will be listed. 
 
9. 
PHARMACOKINETICS AND PHARMACODYNAMICS  
9.1 
Pharmacokinetics 
9.1.1 
Secondary pharmacokinetic endpoint 
9.1.2 
Exploratory pharmacokinetic endpoints 
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9.2 
Pharmacodynamics 
The following exploratory PD and biomarker endpoints will be obtained from blood and urine 
samples which will be analyzed at a number of external laboratory vendors: 
• Serum markers of bone turnover;  
• Urinary markers of bone turnover;  
• cGremlin-1; 
• Genetic analysis; 
• ctDNA. 
The impact of UCB6114 on bone turnover will be explored using the serum and urinary markers 
provided by the analytical laboratory. These markers will be listed for the SS and summarized 
descriptively over time for the PDS by dose level (treatment group), as described for the clinical 
laboratory parameters in Section 8.3. For each marker of bone turnover, the mean (±standard 
deviation) value and the mean (±standard deviation) change from Baseline value will be plotted 
over scheduled visit with treatment group overlaid on the same plot. 
cGremlin-1 will be reported as concentration in blood by nominal (scheduled) assessment and 
dose level. Concentrations of cGremlin-1 will be listed for the SS and summarized for the PDS 
using descriptive statistics by dose level (treatment group) and nominal (scheduled) sampling 
timepoints (n, arithmetic mean, standard deviation, median, minimum, maximum, geoMean, 
geoCV and 95% CI for the geoMean [assuming lognormally distributed data]). Changes from 
Baseline will also be summarized. Individual study participant cGremlin-1 concentration-time 
profiles will be displayed graphically in spaghetti plots and geoMean cGremlin-1 concentration 
and 95% CI will be plotted at each nominal (scheduled) timepoint with treatment group overlaid 
on the same plot. 
Genetic analysis and the analysis of the test results from the blood samples taken for ctDNA will 
be performed and reported separately outside of the CSR. 
Hematoxylin and eosin (H & E) staining and immunohistochemistry (IHC) will be used to 
analyze any available historical tissue biopsy samples obtained prior to a participant’s entry into 
the study (e.g. at the time of diagnosis).  
Test results from the H & E staining and for target genes, phosphatase and tensin homolog 
(PTEN), Ki67 (cellular marker for proliferation in tumors), Gremlin-1, mothers against 
decapentaplegic homolog 4 (SMAD4) and fibroblast activation protein (FAP) will be listed by 
variable and sample analyzed (multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant) for the SS. No summaries of these data will be generated due to the 
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expected small numbers of historical biopsy samples analyzed for each dose level (treatment 
group).  
The following key/component variables will be derived based on H & E staining, PTEN, Ki67, 
Gremlin-1 and FAP test results. No derived variables will be generated for SMAD4; only raw 
test results will be listed. Note that multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant and therefore multiple test results will be presented in the listings. 
H & E: Tissue Integrity (Percentage of Necrosis in Tumor Area) 
In order to assess tissue integrity, percentage of necrosis in the tumor area will be categorized as 
‘<20%’ and ‘>=20%’. If percentage of necrosis data are missing but other H & E staining and 
IHC data are available for a participant (i.e. the participant had historical tumor biopsy sample(s) 
analyzed), then the result will be categorized as ‘Not Done’.  
This categorical variable will be listed together with all other H & E test results. 
PTEN: Tissue Sample Quality Control 
The presence of staining of intrinsic control elements on the slides together with the level of 
staining intensity will be used to determine the tissue sample quality control. 
If staining of intrinsic control elements on stained slides=’YES’ and staining intensity of intrinsic 
control elements on stained slides is 1, 2 or 3 then the tissue sample quality control is ‘Good’, 
otherwise if the staining intensity of intrinsic control elements=0 then the tissue sample quality 
control is ‘Questionable’. If staining of intrinsic control elements on stained slides=’NOT 
PRESENT’ then the tissue sample quality control is ‘No staining present’.  If both variables are 
missing but other IHC results are available (i.e. the participant had historical tumor biopsy 
sample(s) analyzed), then the result will be categorized as ‘Not done’.   
This categorical variable will be listed together with the presence/absence of staining of intrinsic 
control elements on the slides, the level of staining intensity, staining pattern, staining artifacts 
and any assay-specific comments. Since the percent of tumor cells with staining intensity 0/1/2/3 
and the H-score (test results for which will be provided by the laboratory) are less relevant to 
assessing the quality control of the tissue sample, these raw test results will not be listed. 
Ki67 – Proliferative Activity of the Tumor  
In order to assess the proliferative activity of the tumor mass, cellular proliferation reflected by 
the number of Ki67-positive cell objects in the tumor region divided by the total number of cell 
objects in the tumor region will be categorized as ‘<=10%’ or ‘>10%’ with the latter category 
indicating an actively/moderately proliferating tumor. If the test result is ‘NOT EVALUABLE’ 
or missing but IHC results are available (i.e. the participant had historical tumor biopsy 
sample(s) analyzed), then the result will be categorized as ‘Not done’.  
This categorical variable will be listed together with all other Ki67 raw test results. 
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Gremlin-1: Cytoplasmic Histoscore 
The cytoplasmic histoscore will be calculated as a weighted score based on the percentage of 
tumor cells with Gremlin-1 cytoplasmic staining intensity 1, 2 or 3 as follows: 
(1 x percent tumor cells with Gremlin-1 cytoplasmic staining intensity 1) + (2 x percent tumor 
cells with Gremlin-1 cytoplasmic staining intensity 2) + (3 x percent tumor cells with Gremlin-1 
cytoplasmic staining intensity 3). 
The cytoplasmic histoscore will be missing if the participant had a historical biopsy tumor 
sample analyzed but there are no test results for percent tumor cells with Gremlin-1 cytoplasmic 
staining intensity 1, 2 or 3. 
The cytoplasmic histoscore will be listed together with all other Gremlin-1 raw test results. 
FAP 
From the image analysis of FAP-stained slides, the tumor will be classified into 2 regions: the 
cancer (CN) tumor region and the invasive margin (IM) region using a pre-established digital 
automated algorithm.  The IM region is usually a small proportion of the whole tumor and, per 
standard procedures at the analytical laboratory, will be identified first. As a result, there is a risk 
that some parts of the CN tumor region may be inaccurately classified as part of the IM region, 
particularly in cases when the tumor is small. Therefore, instead of using the results for the 
percentage of high, medium and low intensity FAP provided by the laboratory, a decision was 
made to back-calculate the areas of the CN tumor region and the IM region and add these 
together in order to re-calculate the percentage of high, medium and low intensity FAP in the 
whole tumor. 
These back-calculated results and derived variables based on FAP test results are defined in 
Table 9-1. 
Table 9-1: 
FAP Derived Variables 
Variable No. 
FAP Derived Variable 
Description and Calculation 
1[a] 
Total Analyzed Tumor 
Area (um2) 
This is the total tumor area (um2) across the CN tumor region 
and the IM region and will be calculated as the sum of the 
areas of the CN tumor region (um2) and the IM region (um2) 
where a non-missing numeric test result is available for both 
the area of the CN tumor region and the area of the IM 
region. Note that, in cases where no IM region is defined, the 
area of the IM region will be recorded as 0 or ‘NOT 
APPLICABLE’, or may be missing.  If the area of the IM 
region is recorded as ‘NOT APPLICABLE’ or is missing, 
then 0 will be assumed in this calculation and the total 
analyzed tumor area will be equal to the area of the CN tumor 
region. 
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Variable No. 
FAP Derived Variable 
Description and Calculation 
This variable will be missing if both the areas of the CN 
tumor region and IM region are missing, or if one or both are 
‘NOT EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
2  
Measured Area of Weakly 
Stained FAP in the CN 
Tumor Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
CN tumor region (weak positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of weakly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
weakly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
3  
Measured Area of 
Moderately Stained FAP 
in the CN Tumor Region 
(um2)  
This is the back-calculated area of moderately stained FAP in 
the CN tumor region (moderate positive) and will be 
calculated by multiplying the area of the CN tumor region 
(um2) and the relative area of moderately stained FAP in the 
CN tumor region (%) where a non-missing numeric test 
result is available for both the area of the CN tumor region 
and the relative area of moderately stained FAP in the CN 
tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
4  
Measured Area of 
Strongly Stained FAP in 
the CN Tumor Region 
(um2)  
This is the back-calculated area of strongly stained FAP in the 
CN tumor region (strong positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of strongly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
strongly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
5  
Measured Area of Weakly 
Stained FAP in the IM 
Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
IM region (weak FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative 
area of weakly stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area 
of the IM region and the relative area of weakly stained FAP 
in the IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
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Variable No. 
FAP Derived Variable 
Description and Calculation 
6  
Measured Area of 
Moderately Stained FAP 
in the IM Region (um2)  
This is the back-calculated area of moderately stained FAP in 
the IM region (moderate FAP-positive) and will be calculated 
by multiplying the area of the IM region (um2) and the 
relative area of moderately stained FAP in the IM region (%) 
where a non-missing numeric test result is available for both 
the area of the IM region and the relative area of moderately 
stained FAP in the IM region. 
This variable will be set to 0 if one or both are ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
7[a]  
Measured Area of 
Strongly Stained FAP in 
the IM Region (um2)  
This is the back-calculated area of strongly stained FAP in the 
IM region (strong FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative 
area of strongly stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area 
of the IM region and the relative area of strongly stained FAP 
in the IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
8[a] 
Total FAP-Positive 
Tumor Area (um2) 
This is the total FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be 
calculated as the sum of component derived variables 2-7. 
If all 6 component variables are 0 then this derived variable 
will be missing. 
9[a] 
Total Measured Area of 
Weakly Stained FAP 
(um2) 
This is the total weak FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 2 
and 5. 
10[a] 
Total Measured Area of 
Moderately Stained FAP 
(um2) 
This is the total moderate FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 3 
and 6. 
11[a] 
Total Measured Area of 
Strongly Stained FAP 
(um2) 
This is the total strong FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 4 
and 7. 
12[a] 
Total Relative Area of 
Weakly Stained FAP (%) 
This is the percentage of weak FAP expression across the CN 
tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 9 as   
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Variable No. 
FAP Derived Variable 
Description and Calculation 
(Total Measured Area Of Weakly Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
13[a] 
Total Relative Area of 
Moderately Stained FAP 
(%) 
This is the percentage of moderate FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 10 
as   
(Total Measured Area Of Moderately Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
14[a] 
Total Relative Area of 
Strongly Stained FAP (%) 
This is the percentage of strong FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 11 
as   
(Total Measured Area Of Strongly Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
15[a] 
Total Relative FAP-
Positive Tumor Area 
(TPS) (%) 
This is the total proportion score which is the percentage of 
FAP-positive area across the CN tumor region and the IM 
region (whole tumor) and will be calculated using component 
derived variables 1 and 8 as  
(Total FAP-Positive Tumor Area / Total Analyzed Tumor 
Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
16[a] 
Total FAP Histoscore 
This is a histoscore for the combined CN tumor region and 
IM region (whole tumor) and will be calculated as a weighted 
score based on component derived variables 12, 13 and 14 as  
(1 x Total Relative Area of Weakly Stained FAP) + (2 x Total 
Relative Area of Moderately Stained FAP) + (3 x Total 
Relative Area of Strongly Stained FAP). 
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CN=cancer; FAP=fibroblast activation protein, IM=invasive margin, TPS=total proportion score. 
[a] Included in the listing of FAP test results. 
The derived variables containing the [a] flag in Table 9-1 above will be listed together with 
information on staining artifacts and any assay-specific comments provided by the laboratory. 
Further informal analyses may be performed to explore the relationship between the PD and 
biomarker endpoints with antitumor activity, ADA status, and also with key PK parameters. The 
PK-PD effects of UCB6114 may be assessed using a population analysis approach. These 
analyses will also be performed separately outside of the CSR and the details of analysis 
methods will be included in a separate analysis plan. 
The incidence of available historical tumor biopsies will be summarized by treatment group.  
The incidence of PD samples taken from blood and urine will be summarized by cycle and 
treatment group.      
9.3 
Immunogenicity 
Anti-drug (UCB6114) antibody status and classification, changes from Baseline in titer over time 
(Cycles 1, 2 and even cycles thereafter) and the incidence of treatment-emergent ADA positivity 
are exploratory immunogenicity endpoints in Part B of this study.  Potential relationships 
between ADA and PK, PD, antitumor activity and safety will also be explored but this will be 
reported separately outside of the CSR. 
Serum samples will be collected from all study participants for the measurement of ADA and the 
evaluation of immunogenicity according to the Schedule of Activities in the protocol.  
All listings of ADA will be presented for the SS and summaries of the ADA data will be 
presented by treatment group for the ADAS. 
Anti-drug (UCB6114) antibodies will be measured using a three-tiered assay approach: 
Screening assay, confirmatory assay and titration assay.  
Samples will first be evaluated in the Screening assay using a false positivity rate of 5% 
(reported as ‘negative screen’ or ‘positive screen’), followed by analysis of screened positive 
samples in the confirmatory assay (which is a drug depletion assay) to confirm the positivity of 
the samples (reported as ‘negative immunodepletion’ or ‘positive immunodepletion’). Samples 
that are confirmed as positive in the confirmatory assay will be evaluated in a titration assay to 
assess the ADA level and this will be reported as titer (reciprocal dilution factor including 
minimum required dilution). 
Anti-drug (UCB6114) antibody sample status will be determined as follows from the pre-
treatment sample taken on Day 1 of Cycle 1 (Baseline) and all post-treatment (post-Baseline) 
samples.  
• Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
• Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
Anti-drug (UCB6114) antibody sample status will be listed for each participant at each visit by 
treatment group.  This listing will include sampling dates and times, the Screening assay result, 
the confirmatory assay result and the derived ADA sample status.  In addition, the titer from the 
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titration assay (if applicable) will be listed together with the change from Baseline in titer. The 
number and percentage of participants with a positive or negative sample at each visit will be 
summarized by treatment group.  Percentages will be calculated based on the number of 
participants with a non-missing/sufficient sample at the visit. 
Based on the ADA status of the samples, study participants will be categorized according to the 
following 6 ADA classifications in Table 9-2: 
Table 9-2: 
ADA Classifications 
Classification Classification Label 
Definition 
1 
Pre-ADA negative – treatment 
induced ADA negative 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA negative status at all sampling 
timepoints post-Baseline (including SFU).  
Participants with missing post-Baseline samples are 
included as long as the missing samples do not 
result in an unmonitored period greater than 16 
weeks. 
2 
Pre-ADA negative – treatment 
induced ADA positive 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA positive status at any sampling 
timepoint post-Baseline (including SFU).  
3 
Pre-ADA positive – treatment 
reduced ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA negative status at all 
sampling timepoints post-Baseline (including SFU)  
4 
Pre-ADA positive – treatment 
unaffected ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with titer values of the same magnitude as Baseline 
(≤1.80 fold difference from the Baseline value) or 
with decreased titer values compared to Baseline 
(>1.80 fold decrease from the Baseline value). 
5 
Pre-ADA positive – treatment 
boosted ADA positive 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with increased titer values compared to Baseline 
(>1.80 fold increase from the Baseline value). 
6 
Inconclusive 
Includes participants who do not satisfy the criteria 
for classifications 1-5. 
ADA=anti-drug (UCB6114) antibody; SFU=Safety Follow-up. 
Note: The terminology ‘treatment unaffected’ is ambiguous as the criteria refers to ADA responses that are not increased upon 
dosing compared to Baseline level whereas titers may reduce. 
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A study participant will be classified as having treatment-emergent ADA positivity if they 
satisfy one of the following criteria: 
• The Baseline result is ADA negative and at least one post-Baseline result is ADA 
positive (pre-ADA negative – treatment induced ADA positive) – ADA classification 2 in 
Table 9-2; 
• The Baseline result is ADA positive and at least one post-Baseline result shows a pre-
defined fold increase in titer from the Baseline value (the fold increase from Baseline 
required to meet this criterion will be defined with the development of the assay and will 
be included in the TFLs) (pre-ADA positive – treatment boosted ADA positive) – ADA 
classification 5 in Table 9-2. 
Total anti-drug (UCB6114) antibody incidence will be determined by the number and 
percentage of participants with treatment-emergent ADA positivity (as defined above).  The 
denominator for the percentage calculation will be the number of participants with at least one 
available/reported post-Baseline result. 
Total prevalence of pre-anti-drug (UCB6114) antibody will be determined by the number and 
percentage of participants who are pre-ADA positive (i.e. participants who have a positive ADA 
status at Baseline).  The denominator for the percentage calculation will be the number of 
participants with an available/reported Baseline sample result. 
Total anti-drug (UCB6114) antibody prevalence will be determined by the number and 
percentage of participants with ADA classifications 2, 3 or 5 in Table 9-2 (i.e. an ADA positive 
status at any post-Baseline sampling timepoint). The denominator for the percentage calculation 
will be the number of participants with at least one available/reported sample result (either at 
Baseline and/or post-Baseline). 
The ADA classification for each participant will be listed by treatment group.  This listing will 
also include whether or not the participant achieved treatment-emergent ADA positivity (ADA 
incidence), whether the participant was pre-ADA positive (pre-ADA prevalence) and whether 
the participant had an ADA positive status at any post-Baseline sampling timepoint (ADA 
prevalence).  In addition, the visit at which the participant first achieved treatment-emergent 
ADA positivity will be included.  
The number and percentage of participants in each of the 6 ADA classifications defined above in 
Table 9-2 will be presented by treatment group. Also, in this tabulation, ADA incidence and 
prevalence (as defined above) will be summarized. 
The first occurrence of treatment-emergent ADA positivity (based on the criteria above) will be 
summarized using frequency counts and percentages at each post-Baseline visit by treatment 
group. This tabulation will include a count of the number of participants at each post-Baseline 
visit who fulfill at least one of the above defined criteria for treatment-emergent ADA positivity; 
participants will be counted in the numerator based on the earliest visit at which one of these 
criteria is fulfilled. At other visits, participants will be counted in the denominator (assuming an 
assessment of treatment-emergent positivity is available) and this will be used in the percentage 
calculations. 
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Individual study participant ADA titer profiles over actual time will be presented graphically on 
the linear and the semi-logarithmic scale. The linear scale plots will be repeated for the subset of 
participants who achieve treatment-emergent ADA positivity during Part B.   
Mean (±standard deviation) Cmin will be plotted by ADA sample status over nominal (scheduled) 
time with treatment groups overlaid on the same plot. On this plot, mean Cmin at Cycle 1 Day 15 
will be the mean of the derived Cmin following the first dose of UCB6114 (as described in 
Section 9.1.2) and, thereafter from Cycle 2 Day 1, mean Cmin will be the mean of the predose 
concentrations at the subsequent dosing visits.  
10. 
EFFICACY ANALYSES 
10.1 
Antitumor activity 
The analysis of antitumor activity is exploratory in Part B of this study. 
10.1.1 
Definitions of the antitumor activity endpoints 
The following endpoints are defined based on RECIST (Version 1.1) which standardizes solid 
tumor measurements and provides guidelines for the objective assessment of changes in tumor 
size during anti-cancer treatment.   
Appendix 9 (Section 11.9) of the protocol contains the RECIST 1.1 guidelines to be used in this 
study, adapted from Eisenhauer (2009), and includes the definitions of target and non-target 
lesions, the definitions of target and non-target lesion responses at each tumor assessment, the 
criteria for determining overall response at each tumor assessment based on target lesion 
response, non-target lesion response and the presence/absence of new lesions, and a participant’s 
best overall response (BOR).  Further details on the rules to apply in the derivation of BOR are 
included in the Derivation of Efficacy Endpoints document which has been developed to support 
this SAP. 
At each post-Baseline tumor assessment, the investigator will record responses for target lesions 
and non-target lesions, whether or not there has been an appearance of any new lesions, and the 
participant’s overall response based on their target lesion response, non-target lesion response 
and the presence/absence of new lesions.  Note that target lesion response and non-target lesion 
response assessments will be based on the changes in the pre-existing lesions at Baseline and the 
appearance of new lesions will only factor in the determination of an overall response of PD at 
that tumor assessment visit (i.e. per Tables A and B in Section 11.9.2 of Appendix 9 of the 
protocol). 
Objective response rate (ORR) is defined as the percentage of participants with a BOR of 
complete response (CR) or partial response (PR) during Part B.   
Disease Control Rate (DCR) is defined as the percentage of participants with a BOR of CR, 
PR, or stable disease (SD) during Part B.   
Best overall response (BOR) is defined for each study participant as the best overall tumor 
response from each tumor assessment performed every 8 weeks from Day 1 of Cycle 1 (±7 
days)) according to the RECIST criteria for changes in target and non-target lesions and the 
appearance of new lesions. Best overall response is determined from the start of study treatment 
(first dose of UCB6114) until documented objective disease progression or the date of 
subsequent anti-cancer therapy (systemic therapy, surgery or radiotherapy for cancer), whichever 
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occurs first. If anti-cancer therapy is started on the same day as a tumor assessment, then the 
overall response from that assessment will be used in the derivation of BOR. If a participant does 
not have objective disease progression or does not start a subsequent anti-cancer therapy, then all 
tumor assessments up to the SFU visit will be included in the derivation of BOR. For a BOR of 
SD, a participant’s tumor measurements must have met the SD criteria at least once after the start 
of study treatment at a minimum interval of no less than 49 days. 
For this study, BOR determination requires confirmation of CR or PR responses at a subsequent 
assessment ≥4 weeks (28 days) after the criteria for CR or PR responses are first met, however, 
an unconfirmed BOR will also be derived for each participant for the purpose of reporting (as 
described below in Section 10.1.2). Table C in Appendix 11.9 of the protocol and Table 1 and 
subsequent text in the Derivation of Efficacy Endpoints document provides the derivation of 
BOR when confirmation of CR and PR responses are required. The definition of an unconfirmed 
BOR is also included in this document. Although the derivation of unconfirmed BOR does not 
include the requirement for a CR or PR response to be confirmed ≥4 weeks (28 days) after the 
initial response, a participant's CR or PR response may, in fact, be confirmed at a subsequent 
assessment ≥4 weeks (28 days) after the criteria for the CR or PR response are first met. 
Unconfirmed BOR will be referred to as BOR (confirmed or unconfirmed) throughout the rest of 
this document. 
 
Confirmed BOR and BOR (confirmed or unconfirmed) will be derived programmatically based 
on the overall tumor assessment data recorded on the eCRF by the investigator.   
Duration of response (DOR) will be calculated for participants with a BOR of confirmed CR or 
PR as the time in days from the start date of the confirmed CR or PR (e.g. the date of the first 
overall response of CR or PR, which is at least 4 weeks before a second overall response of CR 
or PR) to the first date that recurrent or progressive disease is objectively documented (i.e. 
according to the RECIST guidelines).  This will be referred to as the duration of confirmed 
response and the following calculation will be performed: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
Duration of response will also be calculated for participants with a BOR of CR or PR which is 
either confirmed or unconfirmed [DOR (confirmed or unconfirmed)] as the time in days from the 
start date of the CR or PR to the date of the first documented objective disease progression (i.e. 
according to the RECIST guidelines).  The following calculation will be performed: 
𝐷𝑂𝑅 (𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑜𝑟 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑)
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For the purpose of a sensitivity analysis of both duration of confirmed response and DOR 
(confirmed or unconfirmed), the above calculations will take into consideration the occurrence of 
both objective disease progression (per RECIST 1.1) and clinical disease progression (as 
described in Appendix 11.9 of the protocol and as determined by the investigator and recorded as 
a reason for study treatment discontinuation on the eCRF), whichever occurs first.  If clinical 
disease progression occurs on the same date that a participant’s objective disease progression is 
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determined, then the participant will be included in the sensitivity analyses as having objective 
disease progression. 
The following calculations will therefore be performed for the sensitivity analyses: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
𝐷𝑂𝑅 (𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑜𝑟 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑)
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For participants who die without objective disease progression, DOR will be censored on the 
date of death, regardless of cause. For a participant who discontinues early from Part B of the 
study with no objective disease progression, DOR will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who discontinue study treatment but who do not have 
documented objective disease progression (i.e. according to the RECIST guidelines), DOR will 
be censored at the date of their last available (scheduled or unscheduled) tumor assessment at 
which a lack of objective disease progression was determined. Such participants might include 
those that are ongoing in Part B at the time of any defined data cut-off.   Likewise, participants 
who have not discontinued early and do not have disease progression after a confirmed or 
unconfirmed response, DOR will be censored at the date of their last available (scheduled or 
unscheduled) tumor assessment. 
In the sensitivity analyses of duration of confirmed response and duration of unconfirmed 
response, the same censoring rules will apply except that the date of last contact will be used for 
the censoring of participants who discontinue early from Part B or complete Part B without 
objective disease progression, clinical disease progression or death.  
Date of last contact will be the latest of the dates of premature study termination and of last 
contact recorded on Study Termination eCRF page, the date of death, the date of last dose of 
study treatment, the dates of all visits, AE start and end dates (with partial dates imputed as 
earliest possible) and the date of contact recorded on the Survival Safety Follow-up and Survival 
Final Follow-up eCRF forms. 
Further details on the rules to apply in the derivation of DOR are included in the Derivation of 
Efficacy Endpoints document which has been developed to support this SAP. 
Progression-free survival (PFS) will be calculated as the time in days from the first dose of 
UCB6114 to the date of the first documented objective disease progression (i.e. according to the 
RECIST guidelines), or death due to any cause, whichever occurs first. The following calculation 
will be performed: 
𝑃𝐹𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑣𝑒𝐷𝑖𝑠𝑒𝑎𝑠𝑒
𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114 ) + 1  
Participants who die due to any cause without a documented objective disease progression will 
be considered to have progressed on the date of their death.  Participants who do not have any 
post-Baseline tumor assessments will be censored on the date of their first dose of UCB6114.  
Participants who discontinue early from Part B or discontinue study treatment without 
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documented objective disease progression or death, will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who start anti-cancer therapy during Part B without a 
prior documented objective disease progression will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment prior to the initiation of the subsequent 
anti-cancer therapy.  If anti-cancer therapy starts on the same date as the participant’s tumor 
assessment and determination of objective disease progression, or the participant’s death (due to 
any cause), then the participant will not be censored and the participant will be included as 
having an uncensored event on this date. This censoring rule will also be applied to participants 
who are ongoing at any data cut-off for an analysis of Part B data who have no documented 
objective disease progression. The use of anti-cancer therapy during Part B will be identified via 
ongoing medical review of the concomitant medications together with the start dates of further 
anti-cancer therapy information recorded on the survival follow-up pages of the eCRF. 
As a sensitivity analysis, PFS will also be calculated as the time in days from the first dose of 
UCB6114 to the date of the first documented objective disease progression (per RECIST 1.1), 
the date of clinical disease progression, as determined by the investigator, or the date of death 
due to any cause, whichever occurs first.  Last contact date will be used for the censoring of 
participants still alive with no reported disease progression (objective or clinical). The same rules 
described above for the censoring of participants who start anti-cancer therapy will be applied in 
this sensitivity analysis. 
Further details on the rules to apply in the derivation of PFS are included in the Derivation of 
Efficacy Endpoints document which has been developed to support this SAP. 
Overall survival (OS) will be calculated as the time in days from the date of first dose of 
UCB6114 to the date of death from any cause.  Participants will be followed up to ascertain their 
survival status at the SFU visit (within 30 days after their last dose of UCB6114) and at the Final 
Visit (3 months after their last dose of UCB6114); they will not be followed up beyond this 
timepoint. 
The following calculation will be performed: 
𝑂𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114 ) + 1 
OS will be censored on the date of their last contact for participants who discontinue early from 
Part B of the study or who discontinue study treatment due to disease progression but continue in 
the study, and are not known to have died.   
 
Further details on the rules to apply in the derivation of OS are included in the Derivation of 
Efficacy Endpoints document which has been developed to support this SAP. 
 
10.1.2 
Analysis of the antitumor activity endpoints 
The analyses of the antitumor activity endpoints in Part B will be performed for the PPS.  As a 
sensitivity analysis, all analyses will be repeated for the SS.  All listings will be presented for the 
SS.  Summaries and listings will be presented by treatment group. 
All lesion assessment data recorded at Baseline (Screening) and during the Treatment Period 
(every 8 weeks from Day 1 of Cycle 1 [±7 days]) will be listed separately for target lesions, non-
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target lesions and new lesions.  Each post-Baseline tumor assessment will be labelled as ‘Tumor 
Assessment 1, Tumor Assessment 2 etc. – see further details below). These listings will include 
lesion number and lesion type (nodal/non-nodal), location, method of assessment, dimension (or 
an indication that the lesion is too small to measure, for target lesions only) and lesion response 
evaluation (for non-target lesions at post-Baseline assessments). The listing for target lesions will 
also include the derived eCRF component data used for the determination of the overall target 
lesion response at each post-Baseline assessment (e.g. sum of all dimensions across target lesions 
and percentage change from Baseline in the sum).  In addition, the overall response assessment 
for target lesions and non-target lesions, as determined by the investigator, will be listed for each 
post-Baseline tumor assessment (Tumor Assessment 1, Tumor Assessment 2 etc.) together with 
the presence of new lesions and the overall response assessment.    
The investigator's overall tumor response assessment will be summarized using frequency counts 
and percentages over time (tumor assessment). Post-Baseline tumor assessments are scheduled to 
be performed per protocol every 8 weeks from Day 1 (±7 days). For the purpose of this 
summary, the first post-Baseline tumor assessment (scheduled or unscheduled) will be assigned 
to ‘Tumor Assessment 1’ using the protocol-defined window of Day 50 to 64 (Day 57 ± 7 days) 
relative to Day 1 (first dose of UCB6114). For all subsequent post-Baseline tumor assessments 
(scheduled or unscheduled, but excluding tumor assessments performed at the SFU visit), these 
will be assigned to ‘Tumor Assessment 2’, ‘Tumor Assessment 3’ etc. using the protocol-defined 
window of Day 50-64 relative to the previous post-Baseline tumor assessment. If a post-Baseline 
tumor assessment is missed, then the scheduled day of the missed assessment will be used to 
window the next tumor assessment. In cases where a scheduled and unscheduled tumor 
assessment occurs in the same window, the investigator’s overall tumor response at both 
assessments will be considered. If the overall tumor response is NE at one of the assessments, 
then the overall tumor response from the other assessment will be included in the summary table. 
If the overall tumor response is not NE at both assessments, then the tumor assessment that is 
closest to the target day of the tumor assessment will be included in the summary table. In the 
event that the two tumor assessments are equidistant from the target day of the tumor assessment 
and neither have an overall tumor response of NE, then the worst case overall tumor response 
will be included in the summary table. Otherwise, if the post-Baseline tumor assessment falls 
outside of the protocol-defined window, it will be classified as an unscheduled assessment and 
not included in the summary of overall tumor response. 
Bar charts will also be produced for overall tumor response rate by treatment group for each 
visit. In addition, waterfall plots of participants’ percentage change from Baseline in the sum of 
dimensions for all target lesions will be presented by treatment group and visit. The individual 
participants’ bars will be colored by overall tumor response at the visit. 
Confirmed and unconfirmed BOR for each participant will be derived programmatically using 
the investigator's overall tumor response assessments (scheduled and unscheduled) performed 
every 8 weeks from Day 1 of Cycle 1 (or at unscheduled timepoints) and the RECIST criteria. 
Whether a BOR of CR or PR is confirmed or unconfirmed will be indicated on this listing.  
Using a participant’s confirmed BOR and unconfirmed BOR, whether the participant achieves an 
objective tumor response (i.e. a BOR of CR or PR) and/or disease control (i.e. a BOR of CR, PR 
or SD) during study treatment will be determined.  These derived data will be listed for the SS. 
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Confirmed and unconfirmed BOR will be summarized using frequency counts and percentages. 
Bar charts will also be produced for confirmed BOR and unconfirmed BOR by treatment group.  
The number and percentage of participants achieving objective tumor response and disease 
control (ORR and DCR) based on confirmed BOR and BOR (confirmed or unconfirmed) will be 
presented and, if data allow, exact 95% CIs for binomial proportions will be calculated using the 
Clopper-Pearson method and presented for the response rates. In the calculation of ORR and 
DCR, the denominator will include all participants in the analysis set. Objective response rate 
and DCR (based on confirmed BOR and unconfirmed BOR) will also be summarized in bar 
charts by treatment group overall and by tumor type and ECOG performance status at Baseline. 
In addition, waterfall plots of each participant’s best percentage change from Baseline in the sum 
of the dimensions for all target lesions will be presented by treatment group overall and by tumor 
type and ECOG performance status at Baseline with the individual participants’ bars colored by 
confirmed BOR and unconfirmed BOR. 
The summaries and analyses of DOR, PFS and OS will be carried out as described below, if the 
data allow. 
Duration of confirmed response, DOR (confirmed or unconfirmed) and PFS will be listed and 
summarized descriptively using Kaplan-Meier estimation.  These summaries will be repeated for 
the sensitivity analyses of these endpoints (defined in Section 10.1.1 above) and will include the 
number and percentage of participants with the event, the number and percentage of participants 
censored, minimum and maximum values and Kaplan-Meier estimates of the 25th percentile, 
median, 75th percentile and corresponding 95% CIs calculated using Greenwood’s formula. In 
addition, DOR and PFS rates at 3 months, 6 months and 9 months will be derived from the 
Kaplan-Meier estimation and presented together with associated 95% CIs. 
Kaplan-Meier curves will be presented for duration of confirmed response and DOR (confirmed 
or unconfirmed) and PFS.  Treatment groups will be overlaid on each plot.   
Survival status collected on the eCRF at the SFU visit and at the Final Visit will be listed for 
each participant by treatment group.  This listing will include the participant’s survival status, 
date and cause of death, whether an autopsy was performed and date of autopsy, whether the 
participant had received any further antitumor treatment after the last dose of study treatment and 
the type of treatment, and whether the participant’s disease had been assessed since the end of 
study treatment including method of assessment and the overall response.  
Overall survival times will be listed and summarized descriptively using Kaplan-Meier 
estimation.  Note that since participants are only followed up for survival until the Final Visit in 
Part B of the study, a summary of OS may not be meaningful (i.e. if no participants die then OS 
cannot be assessed).   
Exploratory analyses of selected antitumor activity endpoints may be performed based on 
subgroups of participants in the SS. Data permitting, the subgroups will be defined based on 
participant, disease, and treatment history information (e.g. extent of prior anti-cancer therapy). 
Additionally, the relationship of the antitumor activity variables with key PK parameters may be 
explored but this will be reported separately. 
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10.2 
ECOG performance status 
ECOG performance status is an additional efficacy assessment performed in Part B of this study 
and is defined in Table 10-1. 
Table 10-1: ECOG Performance Status Scale 
Grade 
ECOG performance status scale 
0 
Fully active, able to carry on all pre-disease performance 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 for more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group. 
ECOG performance status will be listed by treatment group at each visit for the SS. 
ECOG performance status will be summarized as an ordinal categorical variable using frequency 
counts and percentages.  Shift tables for the change from Baseline in each grade will be 
summarized by visit. 
 
11. 
OTHER ANALYSES  
Not applicable. 
 
12. 
REFERENCES 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-center 
clinical trials. Drug Information Journal. Vol 26, 77-84, 1992. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
European Medicines Agency, Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronovirus) Pandemic, accessed 29-March-2020.  
(https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf) 
International Council for Harmonization/Food and Drug Administration E9 Guidance (ICH-E9). 
US Food and Drug Administration FDA Guidance on Conduct of Clinical Trials of Medical 
Products During COVID-19 Public Health Emergency Guidance for Industry, Investigators and 
Institutional Review Boards, accessed 29-March-2020. 
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(https://www.fda.gov/media/136238/download) 
 
13. 
APPENDICES 
13.1 
SMQ algorithm for identification of anaphylactic reactions 
Based on MedDRA® Version 25.1, the SMQ=‘Anaphylactic reaction’ consists of 3 parts: 
1) A narrow search containing PTs that represent core anaphylactic reaction terms:  
Category A 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Circulatory collapse 
Dialysis membrane reaction 
Kounis syndrome 
Procedural shock 
Shock 
Shock symptom 
Type I hypersensitivity 
2) A broad search:  
Category B 
Acute respiratory failure 
Asthma 
Bronchial oedema 
Bronchospasm 
Cardio-respiratory distress 
Chest discomfort 
Choking 
Choking sensation 
Circumoral oedema 
Cough 
Cough variant asthma 
Cyanosis 
Dyspnoea 
Hyperventilation 
Irregular breathing 
Laryngeal dyspnoea 
Laryngeal oedema 
Laryngospasm 
Laryngotracheal oedema  
Mouth swelling 
Nasal obstruction 
Oedema mouth 
Oropharyngeal oedema 
Oropharyngeal spasm 
Oropharyngeal swelling 
Pharyngeal oedema 
Pharyngeal swelling 
Respiratory arrest 
Respiratory distress 
Respiratory failure 
Reversible airways obstruction 
Sensation of foreign body 
Sneezing 
Stridor 
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Swollen tongue 
Tachypnoea 
Throat tightness 
Tongue oedema  
Tracheal obstruction 
Tracheal oedema 
Upper airway obstruction 
Vaccine associated enhanced respiratory 
disease 
Wheezing 
Category C 
Allergic oedema 
Angioedema 
Circumoral swelling 
Erythema 
Eye oedema 
Eye pruritis 
Eye swelling 
Eyelid oedema 
Face oedema 
Flushing 
Injection site urticaria 
Lip oedema 
Lip swelling 
Nodular rash 
Ocular hyperaemia 
Oedema 
Oedema blister 
Periorbital oedema 
Periorbital swelling 
Pruritis 
Pruritis allergic 
Rash 
Rash erythematous 
Rash pruritic 
Skin swelling 
Swelling 
Swelling face 
Swelling of eyelid 
Urticaria 
Urticaria papular 
Category D 
Blood pressure decreased 
Blood pressure diastolic decreased  
Blood pressure systolic decreased 
Cardiac arrest 
Cardio-respiratory arrest 
Cardiovascular insufficiency 
Diastolic hypotension 
Hypotension 
Hypotensive crisis 
Post procedural hypotension 
 
Note that if the MedDRA® version is increased from 25.1 during the study, any changes to the 
terms in the above categories should be applied. 
The following algorithmic approach will be applied: A or (B and C) or [D and (B or C)], i.e.  
If a participant has a TEAE which codes to a PT included in Category A, then the event will be 
flagged as an anaphylactic reaction.  Note that participants with a TEAE coded to a PT=’Type 1 
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hypersensitivity’ will also be flagged as having a hypersensitivity reaction as this PT is also 
included in the Category A narrow search for the ‘Hypersensitivity’ SMQ. 
OR 
If a participant has a TEAE which codes to a PT included in Category B AND has a TEAE 
which codes to a PT included in Category C, and both TEAEs have the same start date, then 
both events will be flagged as anaphylactic reactions. 
OR 
If a participant has a TEAE which codes to a PT included in Category D AND has (either a 
TEAE which codes to a PT included in Category B OR a TEAE which codes to a PT included in 
Category C), and both TEAEs have the same start date, then both events will be flagged as 
anaphylactic reactions. 
13.2 
SAP Amendment 1 Changes 
The main rationale for SAP Amendment 1 is to include details on the additional key derived and 
component exploratory variables required based on the results from the analyses of historical 
tumor biopsy samples in Part B.  It was decided that these additional variables were needed to 
improve the interpretability of the test results received from the laboratory. This SAP amendment 
also provides some clarifications relating to the handling of data for the purpose of summarizing 
safety and exploratory anti-tumor activity endpoints. 
The key changes are summarized in the table below (note that additional minor corrections and 
clarifications were also applied in this amendment but are not included in this table). 
Section  
Description of Change 
1 
The versions and dates of supporting study documentation were 
updated. 
5.1 
An update was made to the example illustrating the definition of a 
complete cycle of UCB6114. 
7 
TFD/TPI compliance calculation and corresponding definitions 
were updated. 
8.1 
The additional summary of the total number of doses of study 
treatment received was included. 
8.2 
Rules for handling missing relationship to study treatment for an 
adverse event were updated. 
8.4.2 
Clarification on the handling of triplicate ECG measurements was 
included. 
9.1.2 
Updates were added for more clarification on how Cmin and Cmax is 
to be derived. 
9.2 
Details on the analysis of the historical tumor biopsy samples was 
included together with rules for defining key and component 
derived variables based on the test results received from the 
laboratory. These variables were considered important for clearer 
interpretation of these results from data listings. 
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Section  
Description of Change 
9.3 
A predefined fold-increase of 1.80 was included. 
10.1.2 
Rules for applying the protocol-defined window around the post-
Baseline tumor assessments (scheduled and unscheduled) for the 
purpose of summarizing the investigator’s overall tumor response 
assessment were included. 
General 
MedDRA® version number was updated to the latest version (25.1) 
throughout the document. 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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STATISTICAL ANALYSIS PLAN 
PART C  
DOSE ESCALATION (COMBINATION THERAPY) 
Study: ONC001 
Product: UCB6114 
A PHASE 1/2 OPEN-LABEL, MULTICENTER STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND 
ANTITUMOR ACTIVITY OF UCB6114 ADMINISTERED 
INTRAVENOUSLY TO PARTICIPANTS WITH ADVANCED 
SOLID TUMORS 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
SAP/Amendment Number Date 
Version 1.0 
20 August 2021 
Amendment 1 Version 1.0 
13 October 2023 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
INTRODUCTION ..................................................................................................................... 8 
PROTOCOL SUMMARY ......................................................................................................... 8 
2.1 
Study objectives ....................................................................................................... 8 
2.1.1 
Primary objective ........................................................................................... 8 
2.1.2 
Secondary objective ....................................................................................... 9 
2.1.3 
Exploratory/Tertiary objectives ..................................................................... 9 
2.2 
Study endpoints ........................................................................................................ 9 
2.2.1 
Safety endpoints ............................................................................................. 9 
2.2.1.1 Primary safety endpoints.................................................................................... 9 
2.2.1.2 Other safety endpoints ....................................................................................... 9 
2.2.2 
Pharmacokinetic and pharmacodynamic endpoints ..................................... 10 
2.2.2.1 Secondary pharmacokinetic endpoint .............................................................. 10 
2.2.2.2 Exploratory pharmacokinetic endpoints .......................................................... 10 
2.2.2.3 Exploratory pharmacodynamic endpoints ....................................................... 10 
2.2.2.4 Exploratory immunogenicity endpoints ........................................................... 10 
2.2.3 
Efficacy endpoints ....................................................................................... 10 
2.2.3.1 Exploratory antitumor activity endpoints ........................................................ 10 
2.2.3.2 Other exploratory efficacy endpoint ................................................................ 10 
2.3 
Study design and conduct ...................................................................................... 10 
2.4 
Determination of sample size ................................................................................. 13 
DATA ANALYSIS CONSIDERATIONS .............................................................................. 14 
3.1 
General presentation of summaries and analyses .................................................. 14 
3.2 
General study level definitions .............................................................................. 16 
3.2.1 
First and last dose of study treatment .......................................................... 16 
3.2.2 
Relative day and time .................................................................................. 16 
3.2.3 
Study periods ............................................................................................... 17 
3.2.4 
Visits ............................................................................................................ 18 
3.3 
Definition of Baseline values ................................................................................. 18 
3.4 
Protocol deviations................................................................................................. 18 
3.5 
Analysis sets........................................................................................................... 19 
3.5.1 
Enrolled Set (ES) ......................................................................................... 19 
3.5.2 
Safety Analysis Set (SS) .............................................................................. 19 
3.5.3 
Per-protocol Set (PPS) ................................................................................. 20 
3.5.4 
Pharmacokinetic Set (PKS) ......................................................................... 20 
3.5.5 
Anti-drug Antibody Set (ADAS) ................................................................. 20 
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3.5.6 
Pharmacodynamic Set (PDS) ....................................................................... 20 
3.5.7 
DLT Evaluable Set (DES) ........................................................................... 20 
3.6 
Treatment assignment and treatment groups ......................................................... 20 
3.7 
Center pooling strategy .......................................................................................... 21 
3.8 
Coding dictionaries ................................................................................................ 21 
3.9 
Changes to protocol-defined analyses ................................................................... 21 
STATISTICAL/ANALYTICAL ISSUES ............................................................................... 22 
4.1 
Adjustments for covariates .................................................................................... 22 
4.2 
Handling of dropouts or missing data .................................................................... 22 
4.2.1 
Pharmacokinetics and pharmacodynamics .................................................. 22 
4.2.2 
Safety laboratory data .................................................................................. 22 
4.2.3 
Dates and times ............................................................................................ 22 
4.2.4 
Impact of COVID-19 ................................................................................... 24 
4.3 
Handling of repeated and unscheduled measurements .......................................... 24 
4.4 
Handling of measurements obtained for early withdrawals .................................. 25 
4.5 
Interim analyses and data monitoring .................................................................... 25 
4.6 
Multicenter studies ................................................................................................. 26 
4.7 
Multiple comparisons/multiplicity ......................................................................... 26 
4.8 
Use of an efficacy subset of participants ............................................................... 26 
4.9 
Active-control studies intended to show equivalence ............................................ 26 
4.10 
Examination of subgroups ..................................................................................... 26 
STUDY POPULATION CHARACTERISTICS ..................................................................... 26 
5.1 
Study participant disposition.................................................................................. 26 
5.2 
Protocol deviations................................................................................................. 29 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................................ 29 
6.1 
Demographics ........................................................................................................ 29 
6.2 
Cancer history ........................................................................................................ 30 
6.3 
Prior anti-cancer therapy ........................................................................................ 30 
6.4 
Cancer status at Screening ..................................................................................... 31 
6.5 
Medical history and concomitant diseases ............................................................. 32 
6.6 
Prior and concomitant medications ........................................................................ 32 
MEASUREMENTS OF TREATMENT COMPLIANCE....................................................... 33 
SAFETY ANALYSES............................................................................................................. 33 
8.1 
Extent of exposure ................................................................................................. 33 
8.2 
Adverse events ....................................................................................................... 34 
8.2.1 
Adverse events of special interest ................................................................ 39 
8.2.2 
Infusion-related reactions ............................................................................ 39 
8.3 
Clinical laboratory evaluations .............................................................................. 39 
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8.4 
Vital signs, physical findings, and other observations related to safety ................ 43 
8.4.1 
Vital signs .................................................................................................... 43 
8.4.2 
12-Lead Electrocardiograms ........................................................................ 44 
8.4.3 
Echocardiogram ........................................................................................... 46 
8.4.4 
ECOG performance status ........................................................................... 46 
8.4.5 
Physical examination ................................................................................... 47 
PHARMACOKINETICS AND PHARMACODYNAMICS .................................................. 47 
9.1 
Pharmacokinetics ................................................................................................... 47 
9.1.1 
Secondary pharmacokinetic endpoint .......................................................... 47 
9.1.2 
Exploratory pharmacokinetic endpoints ...................................................... 47 
9.2 
Pharmacodynamics ................................................................................................ 48 
9.3 
Immunogenicity ..................................................................................................... 54 
EFFICACY ANALYSES ........................................................................................................ 57 
10.1 
Antitumor activity .................................................................................................. 57 
10.1.1 
Definitions of the antitumor activity endpoints ........................................... 57 
10.1.2 
Analysis of the antitumor activity endpoints ............................................... 60 
10.2 
ECOG performance status ..................................................................................... 62 
OTHER ANALYSES .............................................................................................................. 63 
REFERENCES ........................................................................................................................ 63 
APPENDICES ......................................................................................................................... 64 
13.1 
SMQ algorithm for identification of anaphylactic reactions ................................. 64 
13.2 
SAP Amendment 1 Changes .................................................................................. 66 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 67 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ADA 
anti-drug (UCB6114) antibody 
ADaM 
Analysis Data Model 
ALP 
alkaline phosphatase 
ALQ 
above limit of quantification 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BLQ 
below limit of quantification 
BMI 
body mass index 
BOR 
best overall response 
CA 
cancer 
CDISC 
Clinical Data Interchange Standards Consortium 
CDMS 
clinical data management system 
cGremlin-1 
circulating gremlin-1 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CPPC 
CDMS postproduction change 
CR 
complete response 
CS 
clinically significant 
CRC 
colorectal adenocarcinoma  
CSR 
clinical study report 
ctDNA 
circulating tumor DNA 
CTMS 
clinical trial management system 
DCR 
disease control rate 
DEM 
data evaluation meeting 
DES 
DLT Evaluable Set 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ES 
enrolled set 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAP 
fibroblast activation protein 
FDA 
Food and Drug Administration 
Gastric cancer 
gastric adenocarcinoma 
GEJ cancer 
adenocarcinoma of the gastroesophageal junction 
geoCV 
geometric coefficient of variation 
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Statistical Analysis Plan Amendment 1.0 
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geoMean 
geometric mean 
hh:mm 
hours:minutes 
H & E 
hematoxylin and eosin 
HLT 
high level term 
IHC 
immunohistochemistry 
ICH 
International Council for Harmonization 
IM 
invasive margin 
iv 
intravenous 
IPD 
important protocol deviations 
LLOQ 
lower limit of quantification 
LLT 
low level term 
LVEF 
left ventricular ejection fraction 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mFOLFOX6 
modified FOLFOX 6 regimen (leucovorin 400mg/m2 on Day 1, 5-
fluorouracil 400mg/m2 on Day 1 + 1200mg/m2/day on Day 1 and  
Day 2, and oxaliplatin 85mg/m2 on Day 1) 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
n 
number of study participants 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for AEs  
NC 
not calculable 
NCS 
not clinically significant  
NEst 
not estimable 
NV 
no value 
ORR 
objective tumor response rate 
OS 
overall survival 
PCS 
potentially clinically significant 
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PDS 
pharmacodynamic set 
PK 
pharmacokinetic(s) 
PKS 
pharmacokinetic set 
PFS 
progression-free survival 
PPS 
per-protocol set 
PR 
partial response 
PT 
preferred term 
PTEN 
phosphatase and tensin homolog 
Q2W 
every 2 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D-F 
recommended Phase 2 dose of UCB6114 when used in combination 
with mFOLFOX6 
SAE 
serious adverse event 
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ONC001 – Part C 
 
 
 
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SAP 
statistical analysis plan 
SD 
stable disease 
SDTM 
Study Data Tabulation Model 
SFU 
safety follow-up 
SI 
International System of Units 
SMAD4 
mothers against decapentaplegic homolog 4 
SMC 
Safety Monitoring Committee 
SoC 
standard of care 
SOC 
system organ class 
SS 
safety analysis set 
SSC 
Study Steering Committee 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
TFL 
Table, Figure and Listing 
TNM 
TNM Classification of Malignant Tumors  
TPS 
tumor proportion score 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 
 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of the dose escalation (combination therapy) module 
(Part C) of study ONC001. It also describes the summary tables, figures and listings (TFLs) to be 
generated for Part C according to  
Protocol amendment 6, dated 26 June 2023;  
Electronic case report form (eCRF) (Clinical Data Management System [CDMS] 
postproduction change [CPPC] #14, version 23.0, dated 14 April 2023); 
UCB’s standards for TFL shells version 2023Q1; 
Part A TFL shells, final version 2.4, dated 04 July 2023 (under development); 
Part B and C Mocks draft version 1.3, dated 13 March 2023 (under development); 
Part A, B and C List of TFLs (LoT) draft version 1.2, dated 04 July 2023 (under 
development); 
UCB’s Derivation of Efficacy Endpoints document, version 0.6, dated 21 January 2022. 
Unless specified in the sections below, Part C of the study will be analyzed as described in the 
most recent version of the protocol. If a future protocol amendment necessitates a substantial 
change to the analysis of the Part C study data, this SAP will be amended accordingly. In 
addition, if the methodology for the analysis of key study endpoints must be modified or updated 
prior to the final database lock for Part C of this study, a SAP amendment will be required. 
Protocol amendments that do not affect the statistical analysis will not necessitate an amendment 
to the SAP.  If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the clinical study report (CSR) 
together with the associated rationale.  
Note that there may be a number of data cut-offs defined prior to the final database lock for Part 
C due to the regulatory safety reporting requirements for this study.  
The content of this SAP is compatible with the International Council for Harmonization 
(ICH)/Food and Drug Administration (FDA) E9 Guidance (ICH-E9). 
UCB is the Sponsor and ICON PLC is the contract research organization (CRO) for this study. 
 
2. 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective of Part C (dose escalation module) of this study is to characterize the 
safety profile of UCB6114 administered in combination with oxaliplatin, leucovorin, and 5-
fluorouracil (administered as mFOLFOX6 regimen) as standard of care (SoC) therapy in 
participants with locally advanced or metastatic colorectal adenocarcinoma, gastric 
adenocarcinoma, and adenocarcinoma of the gastroesophageal junction. 
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2.1.2 
Secondary objective 
The secondary objective of Part C of this study is to characterize the pharmacokinetics (PK) of 
UCB6114 administered in combination with mFOLFOX6 SoC regimen in participants with 
locally advanced or metastatic colorectal adenocarcinoma, gastric adenocarcinoma, and 
adenocarcinoma of the gastroesophageal junction. 
2.1.3 
Exploratory/Tertiary objectives 
The exploratory/tertiary objectives of Part C of this study are: 
• To document any antitumor activity observed with UCB6114 administered in 
combination with mFOLFOX6 SoC regimen according to relevant Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria; 
• To explore pharmacodynamics (PD) biomarkers of UCB6114 administered in 
combination with mFOLFOX6 SoC regimen; 
• To evaluate the immunogenicity of UCB6114 administered in combination with 
mFOLFOX6 SoC regimen. 
2.2 
Study endpoints 
2.2.1 
Safety endpoints 
2.2.1.1 Primary safety endpoints 
The primary safety endpoints for Part C of this study are the incidence and severity of treatment-
emergent adverse events (TEAEs) (including serious adverse events [SAEs]) from the first dose 
of UCB6114 on Day 1 of Cycle 1 to the Safety Follow-up (SFU) visit, and the incidence of dose 
limiting toxicities (DLTs) from the first dose of UCB6114 on Day 1 of Cycle 1 to the end of the 
DLT Observation Period (Day 28 of Cycle 1). 
2.2.1.2 Other safety endpoints 
The following other safety data will be assessed during Part C of the study to further support the 
characterization of the safety profile of UCB6114 administered in combination with 
mFOLFOX6 regimen: 
• Clinical laboratory data (hematology, serum chemistry, coagulation and urinalysis); 
• Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature); 
• 12-lead electrocardiogram (ECG); 
• Echocardiogram (left ventricular ejection fraction [LVEF]); 
• Eastern Cooperative Oncology Group (ECOG) performance status;  
• Physical examination. 
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2.2.2 
Pharmacokinetic and pharmacodynamic endpoints 
2.2.2.1 Secondary pharmacokinetic endpoint 
The secondary PK endpoint in Part C is the UCB6114 concentration by scheduled assessment for 
each UCB6114 dose level. 
2.2.2.2 Exploratory pharmacokinetic endpoints 
 will be exploratory PK endpoints in Part C.  
2.2.2.3 Exploratory pharmacodynamic endpoints 
The following PD endpoints will be assessed in Part C and reported separately outside of the 
CSR: 
• Change in protein marker levels in blood by scheduled assessment and UCB6114 dose 
level; 
• Change in circulating tumor deoxyribonucleic acid (ctDNA) levels in blood by 
scheduled assessment and UCB6114 dose level. 
2.2.2.4 Exploratory immunogenicity endpoints 
Immunogenicity in Part C will be explored using anti-drug (UCB6114) antibody (ADA) sample 
status and participant classification, and changes in titer over time.  Potential relationships 
between ADA and PK, PD, anti-tumor activity and safety may also be explored but these 
analyses will be reported separately outside of the CSR. 
2.2.3 
Efficacy endpoints 
2.2.3.1 Exploratory antitumor activity endpoints 
Antitumor activity in Part C will be explored using the following endpoints: 
• Objective tumor response rate (ORR); 
• Disease control rate (DCR); 
• Duration of antitumor response (DOR); 
• Progression-free survival (PFS); 
• Overall survival (OS). 
2.2.3.2 Other exploratory efficacy endpoint 
To further explore efficacy in Part C of the study, changes from Baseline in the ECOG 
performance status scale will be assessed. 
2.3 
Study design and conduct 
Study ONC001 is a multicenter, nonrandomized, open-label, Phase 1/2 study evaluating the 
safety, PK, efficacy (as assessed by antitumor activity), PD, biomarkers, and immunogenicity 
(ADA activity) of intravenous (iv) UCB6114 as monotherapy and in combination with selected 
SoC regimens in study participants with advanced solid tumors. 
The study has a modular design including up to 3 dose escalation modules (Parts A, B, and C), 
1 dose adaptation module (Part A1), and up to 4 dose expansion modules (Parts D, E, F, and G). 
Depending on emerging data, not all modules may open. This SAP is focused only on the 
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Statistical Analysis Plan Amendment 1.0 
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ascending dose escalation module of the study evaluating UCB6114 in combination with 
mFOLFOX6 SoC regimen (Part C). 
Part C consists of a Screening Period (28 days), a Treatment Period (consisting of 28-day 
cycles), a SFU visit (approximately 30 days after the last dose of UCB6114), and a Final Visit 
(approximately 3 months after the last dose of UCB6114).  
In Part C, eligible participants with unresectable locally advanced or metastatic colorectal 
adenocarcinoma, gastric adenocarcinoma, or adenocarcinoma of the gastroesophageal junction 
will receive UCB6114 as an iv infusion in combination with mFOLFOX6 chemotherapy. During 
the Treatment Period, UCB6114 will be administered as an iv infusion every 2 weeks (Q2W) 
followed by iv oxaliplatin, leucovorin, and 5-fluorouracil Q2W on a 28-day cycle. Modified 
FOLFOX 6 (mFOLFOX6) will be administered at the recommended SoC dose: oxaliplatin 
85mg/m2 iv infusion on Day 1, leucovorin 400mg/m2 iv infusion on Day 1, 5-fluorouracil 
400mg/m2 iv bolus on Day 1, followed by 5-fluorouracil 1200mg/m2/day continuous infusion on 
Days 1 and 2 (2400mg/m2 over 46 hours). The starting dose and schedule of UCB6114 will 
depend on the dose level evaluated in Cohort 3 of Part A (anticipated to be 500mg Q2W iv), the 
emerging safety profile of UCB6114 monotherapy, and any predicted overlapping toxicities with 
mFOLFOX6. Up to 3 dose levels (anticipated to be 500mg, 1000mg, and 2000mg administered 
Q2W iv) will be explored and up to 27 participants may be enrolled. Dose escalation decisions in 
this module will be guided by a model-based estimation of the probability of DLT in Cycle 1. 
Part C will be undertaken using the modified toxicity probability interval (mTPI) method. The 
mTPI design uses a Bayesian decision framework to inform dose-escalation and dose de-
escalation decisions.  A target DLT rate of 25% with an equivalence interval (20% to 30%) will 
be used to estimate the maximum tolerated dose (MTD) of combined regimen during dose 
escalation. For all UCB6114 dose levels, enrolled participants will be treated in cohorts of 2 to 4 
participants (target of 3), who can be treated in parallel. Each UCB6114 dose level may have 
more than one cohort and will have a minimum of 3 and maximum of 9 evaluable participants. 
For further detail on the mTPI method, the calculated model-based dose-escalation/dose de-
escalation decisions to help inform the Safety Monitoring Committee (SMC)'s decision, and the 
determination of the MTD, please refer to Section 4.1.3.2.2 of the protocol.  Detail on the 
operating characteristics for the mTPI design is included in Section 2.4 below. 
The planned duration of UCB6114 in Part C is 2 cycles. Participants may remain on study for 
additional cycles if they are receiving therapeutic benefit or until they fulfill one of the criteria 
for study discontinuation. Participants will continue treatment until disease progression, 
unmanageable toxicity, or withdrawal of consent. Upon discontinuation of treatment, participants 
will be referred to appropriate follow-up care per the investigator’s judgement. 
From Part C, a recommended Phase 2 dose for UCB6114 in combination with mFOLFOX6 
(RP2D-F) will be determined based upon the totality of information, including the safety profile, 
PK data, PD biomarker data, and available antitumor activity. 
Part C of the study is planned to be conducted at study sites in the United Kingdom (UK) and 
United States (US). 
A schematic diagram of Part C of the study is provided in Figure 2-1. 
 
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Figure 2-1: Study Schematic for Part C 
D=Day; DLT=dose-limiting toxicity; mFOLFOX6=leucovorin 400mg/m2 on Day 1, 5-fluorouracil 400mg/m2 on 
Day 1 + 1200mg/m2/day on Day 1 and Day 2, and oxaliplatin 85mg/m2 on Day 1; iv=intravenous; Q2W=every 2 
weeks. mTPI= modified toxicity probability interval  
Notes: A dose level may be given in more than 1 cohort 
Escalation to the next dose level or de-escalation to the previous dose level will be guided by the mTPI algorithm. 
 
A Study Steering Committee (SSC) will be implemented prior to the start of Part C. Part C of 
ONC001 is planned to be initiated after all participants in Cohort 3 of Part A have completed the 
28-day DLT assessment period and after consultation with the SMC , the when the SCC 
provided a recommendation to dose escalate to the next protocol-defined level in Part A of the 
study. The SSC members will include the coordinating investigator, supporting co-investigators, 
and clinical experts not involved in the study. The medical, scientific, and clinical study 
expertise of the SSC will assist the Sponsor in identifying and resolving any study related issues, 
such as study design, study implementation and conduct, and data analysis and reporting. 
During the Treatment Period, UCB6114 will be administered as an iv infusion Q2W followed by 
iv oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) Q2W on a 28-day cycle. Modified 
FOLFOX 6 (mFOLFOX6) will be administered at the recommended standard of care dose: 
oxaliplatin 85mg/m2 iv infusion on Day 1, leucovorin 400mg/m2 iv infusion on Day 1, 5-
fluorouracil 400mg/m2 iv bolus on Day 1, followed by 5-fluorouracil 1200mg/m2/day 
continuous infusion on Days 1 and 2 (2400mg/m2 over 46 hours). The starting dose of UCB6114 
in Part C will depend on the dose level evaluated in Cohort 3 of Part A (anticipated to be 500mg 
Q2W iv), and the emerging safety profile of UCB6114 monotherapy, including any overlapping 
toxicity with the mFOLFOX6 regimen. 
It is expected that up to 3 dose levels of UCB6114 will be explored in combination with the 
mFOLFOX6 SoC regimen. However, additional dose levels may be added based on emerging 
data and recommendations of the SMC. Dose escalation steps are currently planned at a 
maximum of 2-fold. Escalating dose levels in Part C will not exceed a dose level tested and 
considered safe by the SMC to allow dose escalation in monotherapy (Part A). 
Eligible participants who withdraw from the study before receiving study treatment will be 
replaced. Participants who fail to receive the second planned dose of UCB6114 within 7 days of 
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the scheduled administration day during the 28-day DLT Observation Period for reasons not 
related to toxicity will be replaced by a new participant in that cohort. Safety data for replaced 
participants will be included in the data listings and in the summary tables, as applicable. 
2.4 
Determination of sample size 
No formal statistical sample size calculation has been performed for the dose escalation modules 
in study ONC001.  
The number of participants likely to be enrolled in Part C depends on how many dose levels are 
needed to define the RP2D-F for combination therapy. In Part C, up to 27 eligible participants 
will be enrolled.   It is expected that up to 3 dose levels of UCB6114 will be explored in 
combination with the mFOLFOX6 dosing regimen, respectively. However, additional dose 
levels may be added based on emerging data and recommendations of the SMC.  
Between 3 and 9 participants are expected to be enrolled for each dose level of UCB6114 
depending on the observed toxicity/observation of DLTs. An administrative decision to stop 
enrolling into Part C may be made by the Sponsor at any time. “Dose level” refers to a particular 
UCB6114 dose, that can be given to one or more cohorts, not necessarily consecutive.  
The operating characteristics of the mTPI design were evaluated using a simulation approach 
under four scenarios (see Table 2-1) and based on no DLTs observed in the first 2 cohorts in Part 
A monotherapy treatment (UCB6114 100mg and 250mg). The results of this evaluation can be 
seen in Table 2-2.  
 
Table 2‒1: 
Scenarios used for evaluating the operating characteristics of the 
mTPI design. Orange cells indicate the correct decision assuming 
a maximum tolerated toxicity of 25% (equivalence limits 20%, 30%) 
 
Probability of a DLT 
UCB6114 Dose 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Dose 1 (500 mg) 
0.05 
0.05 
0.15 
0.25 
Dose 2 (1000 mg) 
0.05 
0.15 
0.25 
0.35 
Dose 3 (2000 mg) 
0.05 
0.25 
0.35 
0.50 
 
Table 2‒2: Evaluation of the operating characteristics of the mTPI design with a 
target maximum tolerated toxicity of 25%, using 5000 simulated 
trials for each scenario. Orange cells indicate the correct decision. 
Final UCB6114 Dose Selected 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
% of Simulations (Number of Simulations) 
 
 Dose 1 (500 mg) 
3.9% (196) 
5.2% (262) 
31.6% (1580) 
53.3% (2666) 
 
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 Dose 2 (1000 mg) 
3.9% (195) 
35.1% (1755) 
40% (1999) 
26.7% (1337) 
 
 Dose 3 (2000 mg) 
91.4% (4571) 
58.9% (2947) 
21.6% (1080) 
3.8% (191) 
 
 Overly Toxic at First Cohort 
0.8% (38) 
0.7% (36) 
6.7% (336) 
15.2% (758) 
 
 Overly Toxic after First Cohort 
0 
0 
0.1% (5) 
1% (48) 
 
 
3. 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
All TFLs will be produced by ICON PLC using SAS® Version 9.4 or higher (SAS Institute, Cary, 
North Carolina, USA). ICON PLC will also produce the analysis datasets which will adhere to 
the Clinical Data Interchange Standards Consortium (CDISC) guidance documents for Analysis 
Data Model (ADaM) and follow the Sponsor’s interpretation. General statistical and reporting 
conventions will follow the current UCB Global Conventions Document Version 1.1.  
Data will be summarized by UCB6114 dose level (treatment group), visit and timepoint, as 
applicable. All relevant reported and derived data will be listed and will be presented by 
treatment group, study participant and visit, as applicable. 
Categorical variables will be summarized using frequency counts and percentages. Unless 
otherwise stated, the denominator for the percentages will be based on the number of participants 
in the respective analysis set, treatment group, visit and timepoint (as applicable) with non-
missing data. 
When reporting frequency counts and percentages, the following rules apply: 
• For categories where all participants fulfill certain criteria, the percentage value will be 
displayed as 100; 
• For categories where zero participants fulfill certain criteria, there will be no percentage 
displayed; 
• All other percentage displays will use 1 decimal place. 
Summary statistics will be presented for continuous variables including number of participants 
(n), arithmetic mean, standard deviation, median, minimum and maximum. 95% confidence 
intervals (CIs) for the arithmetic mean may also be included depending on the variable and 
where stated in the SAP. Geometric mean (geoMean), geometric coefficient of variation (geoCV) 
and 95% CI for the geoMean will also be presented in the summaries of UCB6114 concentration 
data.  In all relevant outputs the 95% confidence limits will be restricted to the possible values 
that the variable can take.  
 
When reporting descriptive statistics for data other than UCB6114 concentration data, the 
following rules will apply: 
• n will be an integer; 
• Mean (arithmetic and geometric), standard deviation, median and quartiles will use 1 
decimal place more, or 1 significant figure more – depending on the reporting format of 
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the original data – than the original data.  Original data may be data as reported directly 
onto the eCRF or summary data based on data reported onto the eCRF (e.g. mean of 
triplicates or percentage change from Baseline); 
• Confidence intervals will be presented to the same number of decimal places as the value 
around which the CI is constructed; 
• Minimum and maximum will be reported using the same number of decimal places or 
significant figures as the original value; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “);  
• If no participants have data at a given timepoint, then only n=0 will be presented; 
• Percentage change from Baseline values will be calculated and displayed to 1 decimal 
place in the listings.  In the summaries, where applicable, the mean, standard deviation 
and median percentage change from Baseline values will be presented to 2 decimal places 
and the minimum and maximum values presented to 1 decimal place. 
When reporting individual UCB6114 concentration data in listings and figures, and presenting 
summary statistics in tables, the following rules will apply: 
• UCB6114 concentration data should be reported in the listings to the same level of 
precision as received from the bioanalytical laboratory; 
• Missing data should be reported as ‘NV’ (no value) in the listings; 
• Concentrations below the lower limit of quantification (LLOQ) should be reported as 
BLQ (below the limit of quantification) in the listings; 
• BLQ values prior to Cmax should be set to 0 for purposes of plotting a figure (to capture 
lag-time);  
• Actual sampling times will be used in the spaghetti plots of individual PK concentrations 
over time, and nominal sampling times will be used in the summaries of geoMean 
concentrations over time; 
• UCB6114 concentration data should be plotted on both linear and semi-logarithmic 
scales;  
• To calculate summary statistics, BLQ values should be set to half the LLOQ value and 
missing values should be excluded; 
• When the total number of BLQ and missing values exceeds one third of the total then 
only minimum and maximum should be reported for this timepoint. Other summary 
statistics should be reported as missing (“-“). The minimum should be reported as BLQ; 
• When the mean value includes one or more replaced BLQ values then a footnote should 
be included to say “contains one or more BLQ values replaced by half the LLOQ value”; 
• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these should be presented as the minimum and maximum with other 
summary statistics reported as missing (“- “); 
• If no participants have data at a given timepoint, then only n=0 will be presented; 
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• Summary statistics for UCB6114 concentration data will be reported to the same level of 
precision as the individual data for the minimum and maximum, and to 1 additional 
decimal place or 1 additional significant figure – depending on the reporting format of the 
original data with a maximum of 3 significant figures - for the mean (arithmetic and 
geometric), median and standard deviation. The 95% CI for the geoMean will use the 
same number of decimal places or significant figures as the geoMean. It will be left blank 
if the geoCV is 0; 
• Geometric coefficient of variation will be reported as a percentage to 1 decimal place. 
The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed da data: 
𝐺𝑒𝑜𝐶𝑉(%) = √exp 𝑆𝐷2 −1 × 100 
When reporting PK parameters in listings and figures, and presenting summary statistics in 
tables, the following rules will apply: 
3.2 
General study level definitions 
3.2.1 
First and last dose of study treatment  
For each participant the start of study treatment is defined as the date and time of the first dose of 
UCB6114.  This will be considered as the starting point of the combination therapy. 
Similarly, for each participant, the last dose of study treatment will be the date of the last dose of 
UCB6114. 
3.2.2 
Relative day and time 
For each participant, the relative day of an event or assessment will be derived using the earliest 
date of their first dose of UCB6114 as reference.  
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Relative days for an event or assessment occurring before the date of first dose are calculated as 
follows: 
Relative Day = Event/Assessment Date - Date of First Dose of UCB6114 
The relative day for an event or assessment occurring on the date of first dose is 1. The relative 
day for an event or assessment occurring on or after the first dose to the date of the last dose of 
UCB6114 will be calculated as follows: 
Relative Day = (Event/Assessment Date - Date of First Dose of UCB6114) + 1 
For events or assessments occurring after the date of the last dose of UCB6114, relative day will 
be prefixed with ‘+’ in the data listings and will be calculated as follows: 
Relative Day = Event/Assessment Date – Date of Last Dose of UCB6114 
There is no relative Day 0. Relative day will not be calculated in cases where dates are partial 
and should be presented as “--” in the relevant data listing. 
Relative time of TEAEs recorded on, but not limited to, the day of UCB6114 infusion (Days 1 
and 15 of each cycle) will be derived in minutes as follows using the infusion start time as 
reference: 
Relative Time of TEAE = Onset Time of TEAE – Start Time of UCB6114 Infusion 
Relative times of PK and PD sampling will be derived in hours using the end of infusion times 
on the day of UCB6114 dosing as reference, i.e. on Days 1 and 15 of each cycle: 
Relative Sampling Time = Sampling Time – End Time of UCB6114 Infusion 
3.2.3 
Study periods 
Part C of the study will consist of the following study periods: 
• Screening Period – up to 28 days; 
• Treatment Period – Successive 28-day cycles of study treatment (UCB6114 will be 
administered as an iv Q2W dose on Day 1 and Day 15 of each cycle followed by iv 
oxaliplatin, leucovorin, and 5-fluorouracil (mFOLFOX6) Q2W on a 28-day cycle. 
Modified FOLFOX 6 will be administered at the recommended SoC dose: oxaliplatin 
85mg/m2 iv infusion on Day 1, leucovorin 400mg/m2 iv infusion on Day 1, 5-fluorouracil 
400mg/m2 iv bolus on Day 1, followed by 5-fluorouracil 1200mg/m2/day continuous 
infusion on Days 1 and 2 (2400mg/m2 over 46 hours), continuing until disease 
progression, unmanageable toxicity, or participant withdrawal. Within the first cycle of 
the Treatment Period, a 28-day DLT Observation Period is defined to determine safety 
events for dose escalation decisions using mTPI;   
• Safety Follow-up Period – up to 30 days after the last dose of UCB6114. 
There will be a further extended follow-up period, up to 3 months after the last dose of 
UCB6114, at which time the Final Visit will be performed.   
For each participant, the end of the Treatment Period is defined by the date of their last dose of 
UCB6114.   
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The end of Part C of the study is defined by the date of the Final Visit for the last participant (3 
months after the last participant’s last dose of UCB6114), or the date of the SFU visit, if they 
discontinue prior to attending the Final Visit, or their last contact date if they discontinue early 
from the study without attending the SFU visit. 
3.2.4 
Visits 
Unless otherwise specified, in the TFLs, visits will be labelled as follows (as applicable) using 
timepoints as recorded in the database: 
Screening 
Baseline 
Cycle 1, Day X 
Cycle 2, Day X  
Cycle 3, Day X 
Cycle 4, Day X 
Cycle X, Day X 
Etc. 
SFU 
Final Visit 
3.3 
Definition of Baseline values 
Baseline in Part C will be the last available value prior to the first dose of UCB6114. Both 
scheduled and unscheduled values, as well as any repeated values, should be used when defining 
Baseline.  
Measurement-specific Baseline definitions are presented in Table 3-1. 
Table 3-1: 
Definition of Baseline 
Measurement 
Definition of Baseline 
Echocardiogram (LVEF) 
Tumor assessments (antitumor activity) 
Screening value 
12-lead ECG 
Physical examination and weight 
Vital signs 
Clinical laboratory data 
ECOG performance status 
Predose value obtained on Cycle 1, Day 1, or, if 
missing, Screening value  
Serum and urinary markers of bone turnover  
Circulating gremlin-1 (cGremlin-1) 
Immunogenicity (ADA) 
Predose sample value obtained on Cycle 1, Day 1 
ADA=anti-drug (UCB6114) antibody; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
LVEF=left ventricular ejection fraction. 
3.4 
Protocol deviations 
Per ICH definition, important protocol deviations (IPDs) are a subset of protocol deviations that 
may significantly impact the completeness, accuracy, and/or reliability of the study data or that 
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may significantly affect a participant’s rights, safety, or well-being. The criteria for identifying 
potentially important protocol deviations will be defined within the IPD specifications 
document.  
 
For Part C of this study, IPDs will be categorized as follows:   
• 
Inclusion/exclusion criteria deviations  
• 
Incorrect treatment or dose administered  
• 
Procedural non-compliance  
• 
Prohibited concomitant medication use (see Section 6.5.6 of the protocol) 
• 
Withdrawal criteria deviation   
All protocol deviations will be reviewed as part of the ongoing data cleaning process and Data 
Evaluation Meetings (DEMs), and decisions made on whether they should be considered 
important or not, and whether they warrant a participant’s exclusion from an analysis set, or 
partial exclusion from an analysis due to being an IPD (e.g. prohibited concomitant medication 
use).  Multiple DEMs will be scheduled prior to the final database lock for Part C, in line with 
regulatory safety reporting requirements, with the final one held after all data have been 
verified/coded/entered into the database.  
More specifically, participants who have IPDs relating to dosing of UCB6114 (e.g. interrupted, 
discontinued and missed infusion, incomplete/incorrect dose administered, additional dose 
received, or infusions administered outside of the defined visit window) will be reviewed at the 
DEM for potential exclusion of UCB6114 concentration data from the by-visit summaries at an 
individual visit or from the visit at which the dosing deviation was observed onwards. 
Any protocol deviations that are considered related to coronavirus disease 2019 (COVID-19) 
will be reviewed on an ongoing basis in case they collectively or individually give reason to 
consider a protocol amendment (e.g. study design changes or changes to primary analysis 
methods etc.).  To facilitate this ongoing review, protocol deviations will be categorized as 
‘related to COVID-19’ within the Clinical Trial Management System (CTMS) (ICOTrial).  The 
COVID-19-related IPDs will then be listed separately for review and discussion at the DEMs. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set (ES) 
The Enrolled Set (ES) consists of all study participants who sign the Informed Consent Form. 
This analysis set includes screening failures and will be used for the summary of disposition of 
study participants and for selected data listings (which will include all available data for the 
screening failures).  
3.5.2 
Safety Analysis Set (SS) 
The Safety Analysis Set (SS) consists of all study participants who receive at least 1 full or 
partial dose of UCB6114.    
This analysis set will be used for the reporting of demographic, baseline characteristics, safety 
and immunogenicity data. All summaries of the exploratory antitumor activity endpoints will be 
repeated for the SS as a sensitivity analysis.    
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3.5.3 
Per-protocol Set (PPS) 
The Per-protocol Set (PPS) consists of all study participants in the SS who do not have IPDs that 
may substantially affect antitumor activity. Potential exclusions will be reviewed at the DEMs 
and a final determination of the composition of this analysis set will be made prior to the final 
database lock for Part C.  
The PPS will be the primary analysis set for the analysis of the exploratory antitumor activity 
endpoints.  
3.5.4 
Pharmacokinetic Set (PKS) 
The Pharmacokinetic Set (PKS) consists of all study participants in the SS who have at least 
1 evaluable postdose UCB6114 concentration sample (i.e. a sample which is above the lower 
limit of quantitation and for which the date and time of the sample and prior date and time of 
dosing are known). Additional participants or specific samples may be excluded from the PKS at 
the discretion of the Advanced Modeling and Simulation scientist/Quantitative Clinical 
Pharmacologist at UCB. 
Pharmacokinetic analysis will be performed for the PKS. 
3.5.5 
Anti-drug Antibody Set (ADAS) 
The Anti-drug Antibody Set (ADAS) consists of all study participants in the SS who have at 
least 1 evaluable ADA assessment.  
Immunogenicity analyses will be performed for the ADAS. 
3.5.6 
Pharmacodynamic Set (PDS) 
The Pharmacodynamic Set (PDS) consists of all study participants in the SS who have at least 
1 evaluable PD assessment (where appropriate, the sample should be above the lower limit of 
quantitation and the date and time of the sample should be known). 
Pharmacodynamic analysis will be performed for the PDS. 
3.5.7 
DLT Evaluable Set (DES) 
The DLT Evaluable Set (DES) will include all study participants who, during the DLT 
assessment period receive the planned dose of UCB6114 and at least 80% of the planned dose of 
mFOLFOX6 or stopped treatment because of a DLT. 
The DES will be used by the SMC for all dose escalation/de-escalation decision making. 
3.6 
Treatment assignment and treatment groups 
In Part C, it is planned that study participants will be dosed with UCB6114 Q2W at ascending 
dose levels in combination with mFOLFOX6 SoC regimen.  Treatment groups will be defined by 
each UCB6114 dose level and will be presented in ascending order and labelled in the TFLs as 
illustrated in Table 3-2. 
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Table 3-2: 
Treatment Group Labels 
Cohort/UCB6114 Dose Level 
Planned Treatment Group Label 
Dose Level 1 (any cohort) 
UCB6114 500mg + mFOLFOX6 
Dose Level 2 (any cohort)  
UCB6114 1000mg + mFOLFOX6 
Dose Level 3 (any cohort) 
UCB6114 2000mg + mFOLFOX6 
UCB6114 dose level will be referred to as ‘treatment group’ from this point onwards in the SAP 
and in the TFLs. 
 
Note that the actual dose levels and treatment group labels may change depending on whether 
MTD condition is met.  Further, additional dose levels may be included based on emerging data.  
3.7 
Center pooling strategy 
Each study site will contribute to the summaries of data from Part C according to the number of 
evaluable participants recruited; no separate summaries for each site will be presented. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded by UCB, using the latest available version of 
the Medical Dictionary for Regulatory Activities (MedDRA®) (Version 25.1 or higher).  The 
National Cancer Institute Common Terminology Criteria for AEs (Version 5.0) (NCI CTCAE) 
dictionary will also be used by the investigator to assign CTCAE severity grades to each adverse 
event (AE) and will be merged with the clinical database to define a CTCAE code and term to be 
used in the summaries of TEAEs by maximum CTCAE severity grade. 
Medications (including prior anti-cancer systemic therapies) will be coded according to the 
World Health Organization Drug Dictionary (WHODD) (Version SEP/2020). Medical 
procedures will not be coded. 
The versions of the coding dictionaries used will be displayed in the relevant TFLs. 
3.9 
Changes to protocol-defined analyses 
The following changes to the protocol have been incorporated into the SAP: 
• Other safety data have not been defined as safety endpoints in the protocol, e.g. clinical 
laboratory data, vital signs, ECG, echocardiogram, ECOG performance status and 
physical examination.  These have been listed in Section 2.2.1 of the SAP as ‘other safety 
endpoints’ to support the characterization of the safety profile of UCB6114 and to 
provide supporting evidence of any measurements that are deemed abnormal and 
clinically significant and reported as an AE. 
• ECOG performance status is defined as an efficacy assessment in Section 9.6.2 of the 
protocol, however, it will also be assessed from a safety perspective in Part C.  The SAP 
therefore includes ECOG performance status as both a safety endpoint (Section 2.2.1) 
and an exploratory efficacy endpoint (changes from Baseline during Part C in Section 
2.2.3). 
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• Section 9.4.2.1 of the protocol does not explicitly define the analysis set to be used for 
the antitumor activity endpoints but defines the denominator as the number of treated 
participants, which matches the protocol definition for the SS in Section 9.1 of the 
protocol. The SAP has been written to clarify that the PPS will be the primary analysis 
set for the analysis of the antitumor activity endpoints (Section 3.5.3) and that the SS will 
be used for the sensitivity analysis (Section 3.5.2). 
 
4. 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
There will be no imputation of missing data unless otherwise stated in the sections below. 
4.2.1 
Pharmacokinetics and pharmacodynamics 
The reporting and handling of missing values and values that are BLQ in the TFLs is described 
in Section 3.1.  Zero values will be assumed at the predose timepoint on Day 1 of Cycle 1. 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ in the safety laboratory data will be the same as those 
described for PK data in Section 3.1. Any values above the limit of quantification (ALQ) will be 
assigned as the value of upper limit of quantification. 
4.2.3 
Dates and times 
Partial dates may be imputed for the following reasons: 
• Classification of adverse events (AEs) as treatment-emergent; 
• Classification of medications recorded on the concomitant medications log as prior or 
concomitant; 
• Calculation of time since initial diagnosis, time since completion of most recent line of 
anti-cancer therapy and time since progression/relapse on most recent line of anti-cancer 
therapy. 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial onset/start dates: 
• If only the month and year are specified and the month and year of the first dose of 
UCB6114 is not the same as the month and year of the start date then the 1st of the month 
will be used, or the date of the Screening visit if this is later (if the latter imputation 
results in an end date that is earlier than the start date, then the 1st of the month will be 
used); 
• If only the month and year are specified and the month and year of the first dose of 
UCB6114 is the same as the month and year of the start date, then the date of the first 
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dose of UCB6114 will be used. If this results in an imputed start date that is after the 
specified end date, then the 1st of the month will be used, or the date of Screening if this 
is later (if the latter imputation results in an end date that is earlier than the start date, then 
the 1st of the month will be used). If the imputed date is the same date as the date of the 
first dose of UCB6114 then, for AEs, the event will be regarded as treatment-emergent. 
For medications, the medication will be classified as concomitant; 
• If only the year is specified, and the year of the first dose of UCB6114 is not the same as 
the year of the start date then January 01 will be used; 
• If only the year is specified, and the year of the first dose of UCB6114 is the same as the 
year of the start date, then the date of the first dose of UCB6114 will be used. If this 
results in an imputed start date that is after the specified end date, then January 01, or the 
date of the Screening visit if this is later will be used (if the latter imputation results in an 
end date that is earlier than the start date, then January 01 will be used). If the imputed 
date is the date of the first dose of UCB6114 then, for AEs, the event will be regarded as 
treatment-emergent.  For medications, the medication will be classified as concomitant; 
• If the onset/start date is completely missing then the onset/start date will be imputed to 
the date of first dose of UCB6114 and therefore, for AEs, the event will be regarded as 
treatment-emergent and, for medications, the medication will be classified as 
concomitant. 
The following rules will be applied to partial end/stop dates: 
• If only the month and year are specified, then the last day of the month will be used; 
• If only the year is specified, then December 31 of the known year will be used; 
• If the stop date is completely unknown, the stop date will not be imputed. 
Note that the start date or stop date of a prior medication (partial or otherwise) should not be 
imputed past the Screening date - 1.  
In addition to onset and stop dates, the onset and end times of AEs occurring on the day of 
UCB6114 infusion will be collected on the eCRF. Onset and end times may also be recorded for 
other AEs that do not occur on the same day as the UCB6114 infusion.  The duration of AEs 
with onset and end times will be calculated in days and hours:minutes (hh:mm) as: 
Duration of AE = End Date and Time – Onset Date and Time 
In cases where only the onset and stop dates are recorded for an AE, the duration of an AE will 
be calculated in days as:  
Duration of AE = (Stop Date – Onset Date) + 1 
Note that for participants who have an AE which starts and stops on the same day, but with only 
a start time or only a stop time recorded, it will be assumed that their AE started from 00:00 (if 
no start time is recorded) and ended at 23:59 (if no stop time is recorded) on that day. 
If the date of a participant’s initial diagnosis is incomplete, it will be imputed to the most recent 
feasible date for the calculation of time since initial diagnosis as follows: 
 
• If only the day is missing, it will be imputed to the last day of the known month; 
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• If the day and month are missing, it will be imputed to December 31 in the known year; 
• If the date of initial diagnosis is completely missing, then time since initial diagnosis will 
not be calculated. 
 
 
The above date imputation rules will be applied to partially missing stop dates of a participant’s 
last prior anti-cancer systemic therapy as well as partially and completely missing dates of 
progression/relapse on last prior anti-cancer systemic therapy. 
 
In cases where the stop date of a participant’s last prior anti-cancer systemic therapy and/or a 
participant’s date of progression on last line of prior anti-cancer systemic therapy is completely 
missing, the participant’s Screening date - 1 will be used in the calculation of the time since 
completion of most recent line of prior anti-cancer systemic therapy and the time since 
progression/relapse on most recent line of prior anti-cancer systemic therapy, respectively.  
Note that partial dates will not be imputed as a participant’s first dose of UCB6114 in the 
calculation of time since initial diagnosis, time since completion of most recent line of prior anti-
cancer systemic therapy and time since progression/relapse on most recent line of prior anti-
cancer systemic therapy. 
4.2.4 
Impact of COVID-19 
The FDA and European Medicines Agency (EMA) have provided guidance (see references listed 
in Section 12) to help assure the safety of all trial participants, maintaining compliance with good 
clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.  
At the time of writing this SAP, the impact of the pandemic is still evolving and regulators 
continue to clarify their position, and how to handle missing or delayed assessments resulting 
from the pandemic is part of the risk assessment of the impact of COVID-19 on trial integrity.  
For this purpose, the impact at a visit level will be assessed by data collected on a specific 
COVID-19 impact eCRF form and protocol deviations related to COVID-19.  Due to the timing 
of the start-up of recruitment of participants into this study, the consequences for Part C are not 
expected to be significant and, as a result, no details on strategies for handling missing data are 
included in this version of the SAP.  However, should the ongoing review of COVID-19-related 
protocol deviations suggest that the impact is more significant than expected, e.g. in the case of a 
new wave, the SAP may be updated to include further details of handling missing data and/or 
any sensitivity analyses required.  Note that there are no guidelines regarding how much missing 
data is too much, and there is no proportion of missing data under which valid results and 
preservation of study power can be guaranteed. In accordance with the EMA guidance, an 
independent Data Monitoring Committee (DMC) may be convened to make an assessment 
regarding the scientific integrity of the study.  
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. Repeated measurements are defined as more than 1 measurement at the same 
timepoint. For example, the same laboratory parameters assessed twice using the same batch of 
blood samples due to issues with the first assessment. The following general rules will apply to 
all repeated and unscheduled measurements: 
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• Unscheduled and repeated measurements prior to the first dose of UCB6114 will be used 
in the determination of Baseline and hence in the calculation of summary statistics at 
Baseline; 
• Unscheduled and repeated measurements performed after the first dose of UCB6114 will 
not be included in the calculation of change from Baseline, summary measures such as 
minimum, maximum, average and last post-Baseline value calculated for the summaries 
of laboratory data (see Section 8.3), vital signs (see Section 8.4.1) and 12-lead ECG (see 
Section 8.4.2), or summary statistics, i.e. only the scheduled measurements will be used 
and summarized. Similarly, only scheduled visits will be used in the summaries of shifts 
from Baseline to the worst post-Baseline CTCAE severity grade for laboratory data (see 
Section 8.3).  
• For the summaries of the investigator’s overall tumor response assessment, protocol-
defined windows will be applied to all post-Baseline tumor assessments (scheduled or 
unscheduled, but excluding tumor assessments performed at the SFU visit), as detailed in 
Section 10.1.2. Those tumor assessments which fall outside of the window will be 
considered as unscheduled assessments and not included in the summaries. 
• Best overall response, DOR and PFS derivations will use data from all scheduled and 
unscheduled tumor assessments.  
• All data from unscheduled visits will, however, be included on the relevant data listings. 
4.4 
Handling of measurements obtained for early withdrawals 
Participants who withdraw early from the study for any reason will be asked to return to the 
clinic to complete the SFU visit.  The SFU procedures performed at this visit are as shown in the 
Schedule of Activities in the protocol and will be summarized together with all other SFU visit 
data in the tables. 
4.5 
Interim analyses and data monitoring 
No formal interim analyses are planned during Part C of this study. 
A SSC will be implemented prior to the start of Part C. In consultation with the SMC, the SSC 
will recommend to the Sponsor the dose and dosing regimen to be taken forward for Part C. The 
SSC members will include the coordinating investigator, supporting co-investigators, and clinical 
experts not involved in the study. The medical, scientific, and clinical study expertise of the SSC 
will assist the Sponsor in identifying and resolving any study related issues, such as study design, 
study implementation and conduct, and data analysis and reporting.  
The SMC already established for Part A of the study comprising investigators from UK sites 
participating in Part A and key Sponsor personnel, will continue as the SMC for Part B as long 
as they are actively enrolling study participants into the study.  In addition, investigators from 
US sites who are actively enrolling participants into Part C of the study will also become 
members of the SMC for Part C. 
Responsibilities of the SMC for Part C include: 
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• Review of safety data for study participants including review and provision of 
adjudication of individual DLTs, if needed; 
• Review of available PK and PD biomarker data; 
• Make dose escalation recommendations; 
• Determination of the MTD, if applicable. 
The SMC will convene after the last participant in a given cohort has completed the required 28-
day DLT Observation Period. The SMC will decide whether to halt dose escalation, further 
expand the dose level to gain additional safety data, or determine the next dose level to be tested.  
All data presented to the SMC will be cumulative in order that the members can review and 
discuss the data in its totality at the end of all completed cohorts, i.e. all safety information 
beyond Cycle 1 for all previous cohorts will be presented cumulatively for review during each 
subsequent SMC meeting. 
In addition to the planned SMC data review meetings, the Sponsor and the SMC will have the 
ability to hold/request ad hoc meetings should they be deemed necessary (e.g. if safety concerns 
arise during Part C of the study and/or during other ongoing nonclinical and clinical studies). 
4.6 
Multicenter studies 
Part C of this study is planned to be conducted at study sites in the UK and US. With the 
exception of participant disposition, no summaries will be presented by site. 
4.7 
Multiple comparisons/multiplicity 
Not applicable. 
4.8 
Use of an efficacy subset of participants 
The PPS will be used as the primary analysis set for the summaries of the exploratory antitumor 
activity endpoints in Part C. 
4.9 
Active-control studies intended to show equivalence 
Not applicable. 
4.10 
Examination of subgroups 
Not applicable. 
 
5. 
STUDY POPULATION CHARACTERISTICS 
5.1 
Study participant disposition 
The number of study participants who were screened for Part C of this study, the number and 
percentage of screen failures and the primary reasons for screen failure will be summarized for 
the ES.  A listing of participants who did not meet the eligibility criteria for Part C will also be 
presented for the ES. In addition, the disposition of study participants screened and who received 
study treatment will be summarized by site.  This table will include, for each site and overall, site 
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number, principal investigator name, the dates of the first participant in and the last participant 
out, the number of participants screened (ES), the number of screen failures, the number of 
participants who were treated (SS) and included in the PPS, PKS, ADAS and PDS.  Disposition 
in each analysis set across all study sites will be summarized by treatment group.  
The number of study participants who received study treatment and the primary reason for 
discontinuation of study treatment during Part C will be summarized by treatment group, 
together with the number and percentage of participants who continued participation in the study 
after discontinuation of study treatment (at subsequent scheduled visits and/or SFU visit and 
Final Visit). This summary will be based on the SS. 
The number of study participants enrolled into Part C, who were screen failures as well as the 
number of eligible participants who were assigned to a study cohort but not treated will be 
presented for the ES.  For those participants who did not receive study treatment, the reasons for 
early discontinuation from the study will be summarized.   
Of those participants who received UCB6114, the number and percentage of participants who 
completed the study (i.e. participants who received at least 2 complete cycles of UCB6114 and 
attended the SFU visit), who received at least 2 complete cycles of UCB6114 but who did not 
attend the SFU visit and who discontinued early from Part C, together with the primary reasons 
for study discontinuation will be presented for all participants.  
The number and percentage of participants who discontinued due to AEs will be summarized 
separately for all participants, based on the SS. This will be used for European Union Drug 
Regulating Authorities Clinical Trials (EudraCT) reporting.  
The following study disposition tables will also be presented by gastric adenocarcinoma, 
adenocarcinoma of the gastroesophageal junction (Gastric/GEJ-Cancer) and colorectal 
adenocarcinoma (CRC) tumor type depending on the number of participants with specific tumor 
types. 
• Disposition and Reasons for Discontinuation of Study Treatment; 
• Disposition and Reasons for Discontinuation of Study Treatment; 
• Discontinuation of the Study Due to AEs. 
Visits impacted by COVID-19 will be listed for the ES.  This listing will include, visit, visit date, 
relative day, impact category (e.g. visit performed out of window, visit performed by telephone, 
visit not done, missed study drug administration/dispensation, termination of study 
participation), relationship to COVID-19 (confirmed COVID-19 infection, suspected COVID-19 
infection, general circumstances around COVID-19 or other) and a narrative for the event.  The 
number and percentage of participants with visits impacted by COVID-19 will be presented by 
treatment group and by impact category.  This summary will be presented for the different 
relationships to COVID-19.  The denominator for the percentage calculations will be the number 
of participants in the SS. 
In addition, the following listings will be presented: 
• Study participant disposition (ES); 
• Study treatment discontinuation (SS); 
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• Study discontinuation (ES); 
• Visit dates (ES); 
• Participant analysis sets and exclusions from analysis sets (ES)*. 
*DES is not included in this listing as it is only relevant for the SMC, and not required for the 
CSR. 
The listing of study participant disposition will include the date of informed consent, date and 
time of first and last dose of study treatments (UCB6114, mFOLFOX6 SoC regimen), date of 
early study discontinuation (if applicable) and primary reason for discontinuation.   
Separate listings of UCB6114 and mFOLFOX6 study treatment discontinuation will include date 
and time of first and last dose of UBC6114 and individual oxaliplatin, leucovorin and 5-
fluorouracil treatments, date of decision to discontinue study treatments and primary reason for 
discontinuation of each study treatment, date of clinical progression (if applicable), number of 
doses of study treatment received (based on 2 doses per cycle for UCB6114 and mFOLFOX6 
SoC regimen), total dose of study treatment received across all cycles for UCB6114 and 
mFOLFOX6 SoC regimen, number of complete cycles of study treatment received, and whether 
or not the participant had continued participation in the study (at subsequent visits, the SFU visit 
or the Final Visit). 
Note that a participant is deemed to have completed a full cycle of study treatment if they 
received the planned dose of UCB6114 on Days 1 and 15 of the cycle (i.e. the infusion was not 
permanently discontinued due to an AE or other reason such that less than the planned dose was 
received) and a decision was not made to discontinue UCB6114 up to and including Day 28 
relative to Day 1 of the cycle. This will be derived based on a participant’s last dose of UCB6114 
and whether or not the participant attended the visit at which they were scheduled to receive their 
next dose of UCB6114.  For example, if a participant received UCB6114 on Day 1 and Day 15 
of Cycle 1 and attended the clinic for their UCB6114 infusion on Day 1 of Cycle 2 then the 
participant will be counted as having completed Cycle 1.  If the participant did not attend Day 1 
of a subsequent cycle, then it is likely that a decision was made to discontinue their UCB6114 
treatment and/or the study. Therefore, the date that the decision was made to discontinue 
UCB6114 will be used to determine whether the participant completed a cycle of study 
treatment.  If a decision was made to discontinue UCB6114 on >Day 28 relative to Day 1 of the 
particular cycle then the participant will be counted as having completed the cycle. For any 
interim deliveries at a data cut-off, if the participant did not attend Day 1 of their next cycle and 
there was no decision to discontinue UCB6114, then the latest date available for that participant 
should be used to determine whether they have completed a 28-day cycle. 
Whether or not a participant has completed the study is defined as having received at least 2 
complete cycles of UCB6114 and attended the SFU visit. The investigator will record a study 
participant’s disposition status at study termination according to this definition of a  ‘completed’ 
participant, however, a study completion flag will also be programmatically derived based on the 
relevant data on the database and the above rules for defining completion of a full cycle of 
UCB6114. 
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The listing of study discontinuation will include the primary reason for early study 
discontinuation, the number of cycles of UCB6114 received, and the total number of days on 
UCB6114. 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types defined in 
the IPD specification document, as per Section 3.4. 
A listing of all IPDs identified at the DEM will be presented for all study participants based on 
the SS and will include the deviation type and description. In addition, a listing of all protocol 
deviations related to COVID-19 (whether considered important or not) will be presented for the 
SS. The number and percentage of participants in the SS with IPDs will be summarized by 
treatment group and for all participants for each deviation type. The number and percentage of 
participants who were excluded from the PPS will also be presented. The denominator for the 
percentage calculations will be the number of participants in the SS. A summary will also be 
presented for all protocol deviations related to COVID-19, all IPDs related to COVID-19 and all 
IPDs related to COVID-19 leading to exclusion from the PPS. 
 
6. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographics 
A by-participant listing of demographics will be presented based on the ES. This will include the 
year of birth, age (as entered by investigator in the eCRF in years), sex, race, ethnicity, height (in 
cm), weight (in kg) and body mass index (BMI, in kg/m2). Height will be the measurement 
obtained at the Screening visit and weight will be the last non-missing value prior to the first 
dose of study treatment. 
The BMI will be derived in the database using the height and weight measurements recorded at 
the Screening visit and will be automatically reported to 1 decimal place on the eCRF. 
All demographic characteristics (except for date of birth) will be summarized by treatment group 
and for all study participants based on the SS. The summary of age will include descriptive 
statistics and categorical summaries, the latter based on requirements for EudraCT and 
clinicaltrials.gov reporting. In addition, summaries will be presented by Gastric/GEJ-Cancer and 
CRC tumor type depending on the number of participants with specific tumor types. 
For the EudraCT reporting, the categories will include: 
• 18 to <65 years; 
• 65 to <85 years. 
For clinicaltrials.gov reporting, the categories will include: 
• ≤18 years; 
• 19 to <65 years; 
• ≥65 years. 
Childbearing potential and method of birth control will be listed for the ES. 
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6.2 
Cancer history 
All cancer history data for Part C participants will be listed for the ES.  This listing will include 
date of initial diagnosis, tumor type, TNM Classification of Malignant Tumors (TNM) 
classifications and stage, Duke’s score (participants with colorectal adenocarcinoma only), 
histological and cytological diagnosis details (as relevant), whether the participant had any 
metastases and associated anatomical location, and whether the participant had received any 
prior anti-cancer therapies (including the number of lines of any prior systemic therapies, prior 
radiation therapies and prior anti-cancer surgeries). 
Time since initial diagnosis (calculated in months using date of Screening visit and date of initial 
diagnosis and multiplying the duration in days by 12/365.25), tumor type, T, N, and M 
classifications and TNM stage, Duke’s score (participants with colorectal adenocarcinoma only), 
presence of metastases and anatomical location of metastases will be summarized by treatment 
group and for all study participants based on the SS. In the summaries of categorical variables, 
percentages will be calculated based on the number of study participants with non-missing data. 
Further, for the Duke’s score, the denominator for the percentage calculation will be the number 
of study participants with colorectal adenocarcinoma. 
Cancer history will be presented by Gastric/GEJ-Cancer and CRC tumor type depending on the 
number of participants with specific tumor types. 
6.3 
Prior anti-cancer therapy 
Details recorded for each line of prior anti-cancer systemic therapy received by a study 
participant will be listed for the ES.  This listing will include the line and type of systemic 
therapy, intent, drug name and dose, formulation, indication (current/ultimate), start and end 
dates, number of cycles received and the number of days per cycle, the participant’s best 
response and the date of that best response, reason for discontinuation and whether the 
participant had disease progression prior to the next line of systemic therapy.  If there was 
progression, then the date of progression will also be listed.  In addition, time from completion of 
the last prior anti-cancer systemic therapy to the start of UCB6114, whether the participant had 
progression after the last line of systemic therapy and, if so, the time from progression to the start 
of UCB6114 will be derived and listed. 
For those participants in the ES who received prior radiotherapy, the following data will be 
listed: treatment site, type of radiotherapy, intent, settings (concurrent with other anti-cancer 
systemic therapy or stand-alone radiation therapy), and, if concurrent radiotherapy, the anti-
cancer systemic therapy line that the radiotherapy was given with and the drug name.  In 
addition, the start and stop dates, total cumulative dose (if known), number of fractions (if 
known), the participant’s best response to radiotherapy and whether the tumor at the treatment 
site had progressed since radiotherapy will be included in this listing. 
A further listing of prior anti-cancer radiotherapy with systemic therapy regimens will be 
presented for participants in the ES who had concurrent prior systemic therapy and radiotherapy 
as their prior anti-cancer therapy.  This listing will include the relevant data described above 
together with the participant’s best response to that regimen. 
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Date of surgery/procedure, anatomical location, description of the surgical procedure and 
whether the tumor was completely removed will be listed for those study participants in the ES 
who had prior anti-cancer surgeries or procedures. 
The following summaries of prior anti-cancer therapy regimens and surgeries will be presented 
by treatment group and for all participants for the SS: 
• Number of prior anti-cancer therapy regimens (0, 1, 2, 3, >3) (including all anti-cancer 
systemic therapy lines given alone and concurrently with radiotherapy)  
• Best response to the most recent prior anti-cancer therapy regimen 
• Number of prior anti-cancer systemic therapy + radiotherapy regimens (0, 1, 2, 3, >3) 
• Best response to the most recent anti-cancer systemic therapy + radiotherapy regimen 
• Reasons for discontinuation of the most recent line[a]   
• Time from completion of most recent line[a] to the start of UCB6114 (<1 month, 1-<3 
months, 3-6 months, >6 months)[b] 
• For participants that progressed after their most recent line[a], the time from progression 
to the start of UCB6114 (<1 month, 1-<3 months, 3-6 months, >6 months)[b] 
• Number of prior anti-cancer radiotherapies (including radiotherapies given alone and 
concurrently with anti-cancer systemic therapy) (0, 1, 2, >2) 
• Number of prior anti-cancer surgeries and procedures (0, 1, 2, >2) 
[a] Most recent line is the last prior anti-cancer therapy regimen received which may be a prior 
anti-cancer systemic therapy given alone or concurrently with radiotherapy. 
[b] 1 month = 30 days. 
Time from completion and time from progression relative to the last line of anti-cancer systemic 
therapy will also be summarized using frequency counts and percentages as well as summary 
statistics. 
The number and percentage of participants with any prior anti-cancer systemic therapy, and any 
prior anti-cancer systemic therapy given concurrently with radiotherapy will be summarized for 
the SS by treatment group and for all participants, and by WHODD Anatomical Main Group 
[Level 1 term text], Pharmacological Subgroup [Level 3 term text] and PT. 
Prior anti-cancer therapy will be presented by Gastric/GEJ-Cancer and CRC tumor type 
depending on the number of participants with specific tumor types. 
6.4 
Cancer status at Screening 
The current cancer status of study participants at entry into Part C of this study will be assessed 
at the Screening visit and listed for the ES.  This listing will include tumor type, T, N and M 
classifications and TNM stage, Duke’s score (participants with colorectal adenocarcinoma only), 
histological and cytological diagnosis details (as relevant), whether the participant has any 
metastases and associated anatomical location, whether the tumor is recurrent and whether the 
participant had relapsed from their last line of anti-cancer therapy.  
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Tumor type, T, N, and M classifications and TMN stage, Duke’s score (participants with 
colorectal adenocarcinoma only), presence of metastases and anatomical location of metastases, 
and time since relapse on last line of therapy (calculated in days using the date of the Screening 
visit and date of relapse) will be summarized by treatment group and for all study participants 
based on the SS.  In the summaries of categorical variables, percentages will be calculated based 
on the number of study participants with non-missing data.  Further, for Duke’s score, the 
denominator for the percentage calculation will be the number of study participants with 
colorectal adenocarcinoma. 
Cancer status will be presented by Gastric/GEJ-Cancer and CRC tumor type depending on the 
number of participants with specific tumor types. 
6.5 
Medical history and concomitant diseases 
Medical history will be listed for the ES and summarized by MedDRA® system organ class 
(SOC) and preferred term (PT) by treatment group and for all study participants for the SS. The 
reported term will be included in the listing. Previous medical history (any previous medical 
conditions with a stop date prior to the start of UCB6114) and ongoing medical history (any 
ongoing medical conditions with a missing stop date but recorded as ongoing on the eCRF) will 
be summarized separately. These summaries will include the number and percentage of study 
participants and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the incidence in all study participants.  
Non-anti-cancer procedure history will be listed for the ES and concomitant medical procedures 
performed during the study will be listed for the SS. 
Medical history and concomitant disease will be presented by Gastric/GEJ-Cancer and CRC 
tumor type depending on the number of participants with specific tumor types. 
6.6 
Prior and concomitant medications 
Prior medications will include any medications that started prior to the date of the first dose of 
UCB6114. This will include medications that started prior to the first dose of UCB6114 and 
continued after. 
Concomitant medications will include medications with a start date on or after the first dose of 
UCB6114 and prior to the date of the last dose of UCB6114 + 30 days, and whose stop date is 
either missing, or on or after the date of the first dose of UCB6114. Any medications with a start 
date prior to the first dose of UCB6114 and a stop date after, or continued to be ongoing during 
the study, will also be classified as concomitant medications. Medications with a start date > 30 
days after the last dose of UCB6114 will be considered as post-study medications and will not be 
included in the summaries of concomitant medication.  
Any medication that started prior to, and stopped after the first dose of UCB6114 or continued to 
be ongoing during the study, will be classified as both prior and concomitant.  
Any medications with missing start dates will be classified as both prior and concomitant. 
Any medications with partially missing dates will be handled as described in Section 4.2.3 to 
classify them as prior or concomitant provided that a stop date is not present or a stop date is 
present but prior to the first dose of UCB6114. 
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All medications (prior, concomitant and post-study) will be listed for the ES.  Any prohibited 
concomitant medications, rescue medications or steroid use will be identified via a medical 
review and flagged in this listing.   
Prior and concomitant medications (per the definitions above) will be summarized for the SS by 
treatment group and by WHODD Anatomical Main Group [Level 1 term text], Pharmacological 
Subgroup [Level 3 term text] and PT. The reported term will be included in the listing. Separate 
summaries will be presented for prior medications and concomitant medications. As per the 
definitions above, prior medications which continued into the Treatment Period will also be 
classified as concomitant and will be included in both summaries. 
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in all study participants. 
A glossary of all prior and concomitant medications will be presented for the SS including the 
Anatomical Main Group (Level 1), Pharmacological Subgroup (Level 3), PT and reported term.  
Prior and concomitant medications will be presented by Gastric/GEJ-Cancer and CRC tumor 
type depending on the number of participants with specific tumor types. 
 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
During Part C of this study, administration of study treatment will be performed via iv 
infusion/bolus at the study site under the supervision of the designated site personnel and in 
compliance with the Guideline for First in Human clinical studies 
(EMEA/CHMP/SWP/28367/07Rev. 1). Compliance will be monitored at the site through a 
review of accountability logs which will be used to record study treatment dispensing and return 
information to ensure that each study participant received the correct dose level of all 
components of the combination therapy, i.e. UCB6114 and each component of mFOLFOX6. 
Any dosing deviations will be reviewed as IPDs at the DEMs and assessed for possible impact 
on the PPS and PKS.  If considered important, these deviations will be included in the summary 
and listing of IPDs. 
 
8. 
SAFETY ANALYSES 
All safety summaries and listings will be presented by treatment group based on the SS, unless 
otherwise stated. 
All safety summaries may be presented by Gastric/GEJ-Cancer and CRC tumor type depending 
on the number of participants with specific tumor types. 
8.1 
Extent of exposure 
A combination of study treatments is administered in Part C, and exposure to UCB6114, 
oxaliplatin, leucovorin and 5-fluorouracil will be summarized and listed separately.  
Details on UCB6114 administration on Day 1 and Day 15, oxaliplatin+leucovorin infusion on 
Day 1 and Day 15, 5-fluorouracil bolus on Day 1 and Day 15 and 5-fluorouracil infusion on Day 
2 and Day 16 of each cycle will be listed. This listing will be split into two parts.  The first part 
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will include the start and stop dates and times of infusion, duration of infusion, infusion rate, 
whether the infusion was temporarily stopped/interrupted, whether the infusion was permanently 
discontinued and, if this was the case, whether the interruption or permanent discontinuation was 
due to an AE or other reason.  The second part of this listing will include, for each visit, and for 
each study treatment, infusion site, total volume delivered, volume infused, planned total dose 
and total dose actually administered at infusion. In addition, the percentage of planned dose 
received, total dose administered across all cycles, number of complete cycles of UCB6114 
received and the total number of doses of UCB6114 received will be listed.  
The percentage of planned dose received will be calculated for UCB6114 and each component of 
mFOLFOX6 for each study participant at each dosing visit within each cycle as follows: 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑜𝑓 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑= 100 × 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒
 
 
Actual duration of infusion will be calculated in minutes for UCB6114 and each component of 
mFOLFOX6 only for those study participants who did not have any temporary interruption(s) of 
their infusion using the infusion start and stop times and included on this listing. Length of 
interruption(s) will be calculated for those study participants who had temporary interruption(s) 
of their infusion. 
Extent or duration of exposure will be calculated and summarized separately for UCB6114 and 
the components of mFOLFOX6.  Frequency counts and percentages for the number of complete 
cycles of UCB6114 received (0, 1, 2, 3, 4, >4) and summary statistics for the total dose of 
UCB6114 and the components of mFOLFOX6 received across all cycles, the total number of 
doses of UCB6114 and the components of mFOLFOX6 received, and the total duration of 
exposure to each will be presented.  
Total duration of exposure will be calculated in days as follows: 
𝑇𝑜𝑡𝑎𝑙 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒) + 30  
Note that 30 days is added to this calculation to account for a participant’s continued exposure to 
UCB6114 and the components of mFOLFOX6 following their last dose of study treatment.  
Note that a participant is deemed to have completed a full cycle of UCB6114 if they receive the 
planned dose of UCB6114 on Day 1 and Day 15 of each cycle and a decision was not made to 
discontinue UCB6114 up to and including Day 28 relative to Day 1 of a cycle.   
8.2 
Adverse events 
The primary safety endpoints for Part C of this study are the incidence and severity of TEAEs 
(including SAEs) from the first dose of UCB6114 treatment on Day 1 of Cycle 1 until the end of 
the SFU Period (up to 30 days following the last dose of UCB6114), and the incidence of DLTs 
from the first dose of UCB6114 on Day 1 of Cycle 1 until the end of the DLT Observation 
Period (Day 28 of Cycle 1). 
All AEs in Part C of the study will be coded using MedDRA® and classified as pre-treatment and 
treatment-emergent relative to the first infusion of UCB6114.  Adverse events with a start date 
prior to the first dose of UCB6114 will be defined as pre-treatment AEs. A TEAE is defined as 
any AE with a start date on or after the first dose of UCB6114 up until the last dose of UCB6114 
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+ 30 days.  A pre-treatment AE which increases in severity on or after the first dose of UCB6114 
will also be counted as a TEAE. Note that in this case, the pre-existing AE will have a stop date 
and an outcome of ‘worsened’ and a new AE (with the same verbatim) will be entered with the 
same start date and the increased severity recorded on the eCRF. Any AE (including SAEs) with 
an onset date later than the last dose of UCB6114 + 30 days will not be considered as treatment-
emergent and therefore will not be included in the tabulations of TEAEs.  These AEs will be 
considered as post-study AEs and will be listed only. Where onset dates are missing or partially 
missing, AEs will be assumed to be treatment-emergent, unless there is clear evidence to suggest 
that the AE started prior to the first dose of UCB6114 and it has not increased in severity. 
Missing or partially missing dates for AEs will be handled as described in Section 4.2.3. All AEs 
for a participant will be recorded in the eCRF from the time of informed consent until 
completion or early discontinuation of Part C of this study. Serious adverse events are to be 
reported up to 30 days after the Final Visit (i.e. up to 150 days after the last dose of UCB6114). 
Adverse events will be assigned an NCI CTCAE severity grade (Grade 1/Grade 2/Grade 3/Grade 
4/Grade 5), where possible.  If a CTCAE toxicity grading is not possible, then the intensity of the 
AE (mild/moderate/severe) will be recorded on the eCRF. If the AE is not gradable, is serious, 
and is considered as life threatening, then the intensity for this AE will be missing and one of the 
reasons for seriousness will be recorded as life threatening. Adverse events will also be 
categorized according to their relationship to UCB6114 and/or individual components of 
mFOLFOX6 treatment (related/not related), and whether the event is a DLT, as judged by the 
investigator. A DLT is defined as a TEAE at least possibly related to UCB6114 that occurs 
during Cycle 1 and fulfills any of the criteria listed in Section 4.1.4.2.1 of the protocol.  The 
investigator is expected to record whether an AE is a DLT on the eCRF. 
An overview of the number and percentage of participants who experience TEAEs will be 
presented.  This summary will include the number and percentage of participants with any 
TEAEs, serious TEAEs, related TEAEs (related to UCB6114 only, related to UCB6114 and/or 
mFOLFOX6, and related to each of oxaliplatin, leucovorin or 5-fluorouracil), discontinuations 
from study treatment (UCB6114 and mFOLFOX6, mFOLFOX6 only, oxaliplatin, leucovorin or 
5-fluorouracil) due to TEAE(s), discontinuations from the study due to TEAE(s), CTCAE Grade 
≥ 3 TEAEs, CTCAE Grade ≥3 related TEAEs (related to UCB6114 only, related to UCB6114 
and/or mFOLFOX6, and related to each of oxaliplatin, leucovorin or 5-fluorouracil), DLTs, AEs 
leading to death and TEAEs leading to death; event counts will also be included against each of 
these categories. The overview of TEAEs will be presented by Gastric/GEJ-Cancer and CRC 
tumor type depending on the number of participants with specific tumor types. 
In addition, the following summaries will be presented by SOC, high level term (HLT) and PT, 
and where indicated also by Gastric/GEJ-Cancer and CRC tumor type depending on the number 
of participants with specific tumor types: 
• Incidence of TEAEs (overall and by tumor type); 
• Incidence of serious TEAEs (overall and by tumor type); 
• Incidence of non-serious TEAEs (overall and by tumor type); 
• Incidence of TEAEs leading to a temporary interruption of UCB6114 infusion and/or 
dose reduction (overall and by tumor type); 
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• Incidence of TEAEs leading to a temporary interruption of oxaliplatin infusion and/or 
dose reduction (overall and by tumor type); 
• Incidence of TEAEs leading to a temporary interruption of leucovorin infusion and/or 
dose reduction (overall and by tumor type); 
• Incidence of TEAEs leading to a temporary interruption of 5-fluorouracil bolus or 
infusion and/or dose reduction (overall and by tumor type); 
• Incidence of TEAEs leading to discontinuation of UCB6114 and mFOLFOX6 (overall 
and by tumor type); 
• Incidence of TEAEs leading to discontinuation of mFOLFOX6 only (overall and by 
tumor type); 
• Incidence of TEAEs leading to discontinuation of oxaliplatin (overall and by tumor type); 
• Incidence of TEAEs leading to discontinuation of leucovorin (overall and by tumor type); 
• Incidence of TEAEs leading to discontinuation of 5-fluorouracil (overall and by tumor 
type); 
• Incidence of TEAEs leading to discontinuation of study (overall and by tumor type); 
• Incidence of DLTs (separately for during the 28-day DLT Observation Period and after 
the 28-day DLT Observation Period) (overall and by tumor type); 
• Incidence of adverse events of special interest (AESIs) (Hy’s Law – see Section 8.2.1 
below) (overall and by tumor type); 
• Incidence of UCB6114 infusion-related reactions (defined as any TEAE with a PT from 
both a narrow and broad scope search of category A terms of the ‘Hypersensitivity’ 
Standardized MedDRA® Query (SMQ) – see Section 8.2.2) (overall and by tumor type); 
• Incidence of TEAEs by maximum CTCAE severity grade (overall and by tumor type); 
• Incidence of TEAEs related to UCB6114 only by maximum CTCAE severity grade 
(overall and by tumor type); 
• Incidence of TEAEs related to UCB6114 and/or mFOLFOX6 by maximum CTCAE 
severity grade (overall and by tumor type); 
• Incidence of TEAEs by maximum relationship to UCB6114 only (overall and by tumor 
type); 
• Incidence of TEAEs by maximum relationship to UCB6114 and/or mFOLFOX6 (overall 
and by tumor type); 
• Incidence of TEAEs by relationship to UCB6114 only; 
• Incidence of TEAEs by relationship to UCB6114 and/or mFOLFOX6; 
• Incidence of serious TEAEs by relationship to UCB6114 only; 
• Incidence of serious TEAEs by relationship to UCB6114 and/or mFOLFOX6; 
• Incidence of non-serious TEAEs by relationship to UCB6114 only; 
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• Incidence of non-serious TEAEs by relationship to UCB6114 and/or mFOLFOX6; 
• Incidence of fatal TEAEs by relationship to UCB6114 only; 
• Incidence of fatal TEAEs by relationship to UCB6114 and/or mFOLFOX6; 
• Incidence and event rate of TEAEs by treatment-emergent ADA positivity. 
The following summary will be presented by SOC and PT for EudraCT reporting: 
• Incidence of non-serious TEAEs above the threshold of 5% of participants in any 
treatment group. 
The above summaries of TEAEs will be ordered alphabetically by SOC, alphabetically by HLT 
within SOC and decreasing incidence of PT events within SOC /HLT in all study participants.  
For tables including only the number and percentage of participants, summaries will be ordered 
alphabetically by SOC, alphabetically by HLT within SOC and decreasing incidence of 
participants with each PT within SOC /HLT in all study participants. 
The incidence of TEAEs by maximum CTCAE severity grade will be presented by CTCAE 
term.  CTCAE term will be obtained from the NCI CTCAE Version 5.0 via a mapping of 
MedDRA® lower level terms.  This summary will be ordered by decreasing incidence of 
participants with each CTCAE term in all study participants. 
Summary tables will contain frequency counts and percentages, and the number of events, where 
applicable. A study participant who experiences the same event multiple times will be counted 
only once in the frequency counts for the PT, but all events will be included. 
In the summaries of TEAEs by relationship, participants will be counted in “Not related” and 
“Related” categories (or “Missing” in the case where an event has a missing relationship). A 
study participant who experiences the same event multiple times will be included in the most 
related category for the summaries by maximum relationship. 
In the overview summary of TEAEs, participants will be counted as having at least one TEAE 
with CTCAE severity grade ≥3, and in the summary of TEAEs by maximum CTCAE severity 
grade, participants will be counted as having at least one TEAE in the following categories: 
‘Grade 1’, ‘Grade 2’, ‘Grade 3’, ‘Grade 4’, ‘Grade 5’, ‘Grade 3 or 4’ and ‘Grade >=3’.  Events 
for which no CTCAE severity grade is recorded by the investigator but an intensity is recorded 
instead, the intensity of this event will be assigned to a CTCAE severity grade for the purpose of 
these summaries, i.e. ‘Mild’ will be included as ‘Grade 1’, ‘Moderate’ will be included as ‘Grade 
2’, ‘Severe’ will be included as ‘Grade 3’, ‘Life Threatening’ will be included as ‘Grade 4’ and, 
if the participant dies due to the event, it will be included as ‘Grade 5’. The determination of 
whether the event is life threatening or results in death will be based on the reason for 
seriousness recorded as life-threatening or death on the eCRF, or on the event having a fatal 
outcome. Otherwise, if both the CTCAE severity grade and intensity is missing then the CTCAE 
severity grade in these summaries will be missing. A study participant who experiences the same 
event multiple times will be included in the highest severity grade category in the summary of 
TEAEs by maximum CTCAE severity grade.  
A glossary of all AEs will be presented including the MedDRA® SOC, HLT, PT, reported term 
and low level term (LLT).  
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A listing of all AEs will be presented by study participant for the ES. The listing will include the 
onset date and stop date of the event (including relative days) and also the onset times and stop 
times of events where available.  Period of onset of AEs will also be presented on this listing. 
Period of onset of AEs will be defined as follows for the purpose of the listing: 
• If the AE has an onset date prior to the date of the Screening visit, then Period=Pre-study; 
• If the AE has an onset date on or after the date of the Screening visit and has an onset 
date and time prior to the start time of UCB6114 infusion on Day 1 of Cycle 1 then 
Period=Screening; 
• If the AE has an onset date and time on or after the start time of UCB6114 infusion on 
Day 1 of Cycle 1 and up to the date and time of the start of Cycle 2 (i.e. prior to the start 
time of the UCB6114 infusion on Day 1 of Cycle 2) then Period=Cycle 1 
• If the AE has an onset date and time on or after the start time of UCB6114infusion on 
Day 1 of Cycle 2 and up to the date and time of the start of Cycle 3 (i.e. prior to the start 
time of the UCB6114 infusion on Day 1 of Cycle 3) then Period=Cycle 2; 
• Same as above for subsequent cycles (Cycle 3 etc.); 
• If the AE has an onset date after the last dose of UCB6114up to and including 30 days 
after the last dose of UCB6114, then Period=SFU; 
• If the event has an onset date after the 30-day period following the last dose of UCB6114, 
then Period=Post-study. 
The listing of all AEs will also include the AE duration (derived in days, hh:mm for AEs with 
onset and stop times recorded and derived in days for all other AEs with only onset and stop 
dates recorded), days since start of UCB6114 infusion (time if an onset time is recorded, days 
otherwise), seriousness and reason for seriousness, CTCAE severity grade, intensity (where a 
CTCAE severity grade is not recorded), pattern of event, relationship to UCB6114 and 
mFOLFOX6 and action taken with UCB6114 and mFOLFOX6 (including other action taken), 
the outcome of the AE, whether an autopsy was performed and cause of death. In addition, the 
listing will flag AEs that led to discontinuation from the study, TEAEs, AESIs, SAEs, led to 
UCB6114 infusion-related reactions, and DLTs. Whether an AE is related to a concomitant 
medication, (and separately whether it is related to the COVID-19 vaccination), the names of any 
co-suspect medications will also be listed. 
Separate listings of all SAEs, TEAEs leading to discontinuation of UCB6114 and mFOLFOX6, 
TEAEs leading to discontinuation of mFOLFOX6 only, TEAEs leading to discontinuation of 
each component of mFOLFOX6 and TEAEs leading to discontinuation of the study will also be 
presented.  
All deaths that occur on study (defined as during study treatment or within 30 days of the latest 
dose of UCB6114) will be listed separately.  This listing will include the primary cause of death 
and the number of days between the date of the last dose of UCB6114 and death, defined as 
𝐷𝑎𝑦𝑠 𝑠𝑖𝑛𝑐𝑒 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑡𝑒𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114 )  
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8.2.1 
Adverse events of special interest  
An AESI is any AE that a regulatory authority has mandated be reported on an expedited basis, 
regardless of the seriousness, expectedness, or relatedness of the AE to the administration of a 
UCB product/compound.  
For ONC001, potential Hy’s Law is used to identify AESIs and is defined using the laboratory 
data and the following potential drug-induced liver injury (PDILI) criteria: 
• ≥3x upper limit of normal (ULN) alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of 
≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the biochemical 
abnormality; 
• Study participants who have evidence of liver metastases may be considered to have an 
alternate etiology for the described laboratory abnormalities. 
All AESIs will be flagged on the listing of AEs. 
8.2.2 
Infusion-related reactions  
Infusion-related reactions are defined as hypersensitivity reactions, anaphylactic reactions and 
cytokine release syndrome with onset within 24 hours after the start of the UCB6114 infusion.   
All potential infusion-related reactions will be identified programmatically and will then undergo 
medical review for confirmation based on participant characteristics and other signs and 
symptoms.  The final assessment from the medical review will be used in the programming to 
ensure that all infusion-related reactions are flagged correctly in the listings and included in the 
relevant summaries. 
Hypersensitivity reactions will be programmatically identified as any TEAE with a PT from both 
a narrow and broad scope search of category A terms of the ‘Hypersensitivity’ SMQ. 
Anaphylactic reactions will be programmatically identified using an algorithmic approach based 
on the ‘Anaphylactic Reaction’ SMQ.  Further details on this algorithm are given in Section 11.  
Note that if the MedDRA® version is increased from 25.1 during the study, any changes to the 
terms included in the ‘Anaphylactic Reaction’ SMQ should be applied. 
Cytokine release syndrome will be programmatically identified as any TEAE with a PT of 
‘Cytokine release syndrome’ from the broad scope search of category A terms of the 
‘Hypersensitivity’ SMQ.  Since this disorder is characterized by fever, headache, tachycardia, 
hypotension, rash, tachypnoea and/or hypoxia, a further medical review of participants with 
these events occurring within 24 hours after infusion of UCB6114 will be performed to confirm 
any further infusion-related reactions. 
Note that any other AEs (i.e. not identified as infusion-related reactions using the rules above) 
which result in a temporary interruption or permanent discontinuation of a UCB6114 infusion 
will not be considered as an infusion-related reaction. 
8.3 
Clinical laboratory evaluations 
The use of multiple local laboratories (1 per site in the UK and US) in Part C of this study has 
meant that results have been recorded in different units and with reference to different normal 
ranges, and further, for some laboratory tests, different normal ranges have been applied to males 
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and females and age groups.  As a first step to ensure comparability of laboratory results, results 
and normal ranges will be converted to the same International System of Units (SI) units using 
UCB’s standard conversion factors.  This will be programmed at the Study Data Tabulation 
Model (SDTM) level.  Note though that the simple conversion to SI units does not represent a 
full homogenization of results from different local laboratories using different methods.  To 
ensure full comparability, the observed laboratory results will be normalized to a unique set of 
standard reference ranges using the location-scale normalization formula (Chuang-Stein, 1992) 
which normalizes all results in relation to a standard set of reference ranges (for hematology, 
clinical chemistry and coagulation parameters): 
𝑠= 𝐿𝑆+ (𝑥− 𝐿𝑋) (𝑈𝑆−𝐿𝑆)
(𝑈𝑋− 𝐿𝑋) 
and when the standard lower limit is 0: 𝑠= 𝑥
𝑈𝑆
𝑈𝑋 where: 
s = normalized observed value 
x = original observed value in SI units 
LS = Lower Limit of the reference range chosen to be the standard reference range 
US = Upper Limit of the reference range chosen to be the standard reference range 
LX = Lower Limit of the reference range associated with the original observed value in SI 
units (local laboratory reference range) 
UX = Upper Limit of the reference range associated with the original observed value in SI 
units (local laboratory reference range) 
 
This transformation preserves the distance of the original laboratory result from the lower limit 
of normal as a multiple of the specified standard reference range. 
 
Note that the choice of the standard reference range is arbitrary, however, the most recent 
reference ranges used by ICON Central Laboratories (including the age and gender specific 
reference ranges for parameters, where available) will be used to normalize the results in this 
study. 
 
Normalization of the laboratory results will be performed in the ADaM programming by ICON. 
All laboratory data (hematology, serum chemistry and coagulation) and changes from Baseline 
for numeric variables will be listed for participants who have at least one value outside of the 
reference range. All urinalysis data will be listed for all participants.  Data will be listed by study 
participant, laboratory panel, laboratory parameter and visit within each treatment group. Any 
laboratory measurements that are BLQ or ALQ will be handled as described in Section 4.2.2.   
For the relevant numeric laboratory parameters, the reference ranges supplied by the local 
analytical laboratory will be used to flag values outside the reference range as low or high in this 
listing. For the parameters for which the local laboratory cannot supply the reference ranges, the 
reference ranges provided by ICON Central Laboratories will be used instead. A listing of all 
laboratory results outside of the reference range will also be presented.  The reference ranges will 
also be reported in the listings. 
In addition, for the relevant hematology, clinical chemistry and coagulation laboratory tests, 
CTCAE severity grades (Grade 1, Grade 2, Grade 3, Grade 4) will be applied (where possible) in 
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the ADaM programming according to NCI CTCAE Version 5.0, and these grades will also be 
listed for the relevant laboratory parameters.  Note that Grade 0 will be applied in cases where a 
result is normal for the relevant laboratory test and Grade 5 is not applicable in the grading of 
laboratory data. 
Observed values and changes from Baseline in the hematology, serum chemistry and coagulation 
parameters presented below in Table 8-1 will be summarized at each visit.  In addition, for each 
of these parameters, the Baseline value, the minimum, maximum, average and last post-Baseline 
value for each participant will be summarized by cycle using descriptive statistics.  These post-
Baseline summary measures will be calculated based on all available scheduled postdose values 
within each cycle, i.e. from Day 8 of the current cycle up to Day 1 (pre-UCB6114) of the 
subsequent cycle. The last value in a cycle will be the predose value of the subsequent cycle 
where a subsequent cycle occurs, otherwise it will be the value at the last scheduled assessment.  
If only one value is available then the average will not be calculated and presented but this value 
will be used for the minimum, maximum and last post-Baseline summary measures. These 
summary measures for each cycle will also be listed.  
The summaries of normalized hematology, serum chemistry and coagulation values and changes 
from Baseline will also be presented by Gastric/GEJ-Cancer and CRC tumor type depending on 
the number of participants with specific tumor types. 
For those laboratory parameters with a CTCAE toxicity assigned, shift tables for the change 
from Baseline in CTCAE severity grade at each visit and to the worst post-Baseline CTCAE 
severity grade during the Treatment Period will be presented.  
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Table 8-1: 
Clinical Laboratory Assessments 
Laboratory Assessment 
Laboratory Parameters 
Hematology 
Platelet Count, RBC Count, Hemoglobin, Hematocrit, RBC 
Indices (MCV, MCH, MCHC), WBC Count with Differential 
(Absolute Neutrophils, Absolute Lymphocytes, Absolute 
Monocytes, Absolute Eosinophils, Absolute Basophils) 
Clinical Chemistry 
ALT, AST, ALPa , Bicarbonate, Sodium, Potassium, 
Magnesium, Chloride, Calcium, Total Bilirubin, BUN or 
Urea, Serum Creatinine, Glucose (non-fasted), Phosphorus or 
Phosphate, Albumin, Total Protein, Uric Acid, Amylase, 
GGT, Cholesterol, Creatine Kinase, CRP, LDH, Lipase, 
Triglycerides 
Coagulation 
aPTT and either prothrombin time or INR  
Routine Urinalysis 
Specific Gravity, pH, Glucose, Protein, Blood, Ketones, 
Bilirubin, Urobilinogen, Nitrite, Leukocyte Esterase by 
Dipstick 
Microscopic Examination (if blood or protein is abnormal, 
including crystals) 
Screening Tests 
Pregnancy tests: FSH and estradiol (for women of 
non-childbearing potential only); serum or urine hCG 
pregnancy test (for women of childbearing potential)  
Bone turnover markers: blood BAP, blood CTx, urinary NTx 
and urinary CTxII  
Tumor markers: e.g. PSA, CA125, CA19-9 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPPT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; BAP=bone alkaline phosphatase; BUN=blood urea nitrogen; CA=cancer antigen; CRP=C-reactive protein; 
CTx=C-terminal telopeptide; FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; hCG=human chorionic 
gonadotropin; INR=international normalized ratio; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; NTx=N-terminal telopeptide; 
PSA=prostate specific antigen; RBC=red blood cell; WBC=white blood cell.  
a including liver-specific ALP for use in assessing participants with bone metastases at Screening. In the case of bone metastases 
liver function abnormalities considered potential Hy’s law cases, the liver-specific ALP must be separated from the total in 
participants with bone metastases and used to assess the liver function instead of the total ALP 
 
The screening laboratory tests included above in Table 8-1 will be listed only. 
Liver function abnormalities will be defined using the following criteria: 
• ALT or AST ≥2xULN 
• ALT or AST ≥3xULN 
• Total bilirubin ≥2xULN 
• Total bilirubin ≥3xULN 
• ALT or AST ≥5xULN 
• ALT or AST ≥8xULN 
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• ALT or AST ≥3xULN AND total bilirubin ≥2xULN (>35% direct bilirubin) 
For the subgroups of participants with liver metastases and without liver metastases at Baseline, 
the number and percentage of participants in each liver function abnormality category will be 
summarized at each visit. 
In addition, participants with PDILI criteria are those that fulfill the following laboratory data 
(based on liver function tests) criteria at a visit: 
• AST or ALT and total bilirubin within the normal range at Baseline and AST or ALT 
≥3xULN concurrent with total bilirubin ≥2xULN; 
• AST, ALT or total bilirubin above ULN at Baseline and AST or ALT ≥2 times Baseline 
values AND AST or ALT ≥3xULN (participants without liver metastases at 
Baseline)/AST or ALT ≥8xULN (participants with liver metastases at Baseline) 
concurrent with total bilirubin above ULN at Baseline and total bilirubin ≥2 times 
Baseline value or ≥3xULN (whichever is lower). 
All relevant laboratory data collected for participants with a PDILI event (i.e. liver function tests) 
will be listed at the visits at which at least one of the above criteria was fulfilled.  
The number and percentage of participants meeting different combinations of the ALT, AST and 
total bilirubin criteria defined above will be summarized by treatment group.  This summary will 
be presented for all participants as well as for the subgroups of participants who had liver 
metastases at Baseline and participants without liver metastases at Baseline. 
A separate listing will also be produced containing drug-induced liver injury -relevant family 
medical history, lifestyle data (alcohol consumption or drug abuse in the previous 6 months), 
hepatic event supplemental medical history and any hepato-toxic medications taken for 
participants in the SS with a PDILI event. 
8.4 
Vital signs, physical findings, and other observations related to 
safety 
8.4.1 
Vital signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include:  
• Systolic and diastolic blood pressure; 
• Pulse rate; 
• Oral body temperature; 
• Respiratory rate. 
On UCB6114 dosing visits (Days 1 and 15 of each cycle), vital signs will be assessed at multiple 
timepoints relative to the UCB6114 infusion: predose, 10 minutes (±5 minutes) and 30 minutes 
(±10 minutes) after the start of the infusion, at the end of the infusion (+15 minutes); and at 1 
hour (+15 minutes) after the end of the infusion. In addition, on Cycle 1 Day 1, vital signs will 
also be assessed at 2 hours (+1 hour) and 5 hours (+1 hours) after the end of the infusion. All 
vital signs measurements will be performed prior to the collection of PK samples. 
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At all other scheduled visits (Day 8, and 22 of Cycle 1 and Days 1), vital signs will be measured 
prior to UCB6114 dosing on dosing days. At the SFU visit, vital signs measurements will be 
taken prior to PK sampling. 
Observed vital sign measurements and changes from Baseline will be listed by visit and 
timepoint and summarized using descriptive statistics. In addition, for each of the vital signs, the 
Baseline value, the minimum, maximum, average and last post-Baseline value for each 
participant will be calculated based on all available scheduled postdose values during each cycle 
up to the predose value on Day 1 of the subsequent cycle and will be summarized by cycle using 
descriptive statistics. The last value in a cycle will be the predose value of the subsequent cycle 
where a subsequent cycle occurs, otherwise it will be the value at the last scheduled assessment.  
If only 1 value is available then the average will not be calculated and presented but this value 
will be used for the minimum, maximum and last post-Baseline summary measures. These 
summary measures for each cycle will also be listed.   
For the multiple vital signs measurements on treatment days (i.e. on Days 1 and 15 of each 
cycle), changes from the predose value will be calculated at each postdose timepoint and 
summarized using descriptive statistics.   
For each vital signs parameter, the mean (±standard deviation) change from Baseline value will 
be plotted over scheduled visit and timepoint with treatment group overlaid on the same plot. 
The incidence of treatment-emergent markedly abnormal (TEMA)/ potentially clinically 
significant (PCS) vital signs based on blood pressure and pulse rate measurements will be 
summarized by visit and timepoint using frequency counts and percentages. The criteria for 
identifying a TEMA/PCS are included in Table 8-2. 
Table 8-2: 
TEMA/PCS Criteria for Vital Signs 
Variable (unit) 
Lowa 
Higha 
Systolic Blood Pressure (mmHg)  
 
Value <90 and ≥20 decrease 
from Baseline 
Value >140 and ≥20 increase from 
Baseline 
Diastolic Blood Pressure 
(mmHg)  
Value <50 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
Pulse Rate (bpm) 
Value <45 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase from 
Baseline 
 
bpm=beats per minute; PCS=potentially clinically significant; mmHg=millimeter of mercury; TEMA=treatment-emergent 
markedly abnormal. 
a Both conditions must be satisfied for a measurement to be considered PCS. 
8.4.2 
12-Lead Electrocardiograms  
Electrocardiograms will be performed at each visit and timepoint in triplicate with the participant 
in a supine position after a minimum of 5 minutes rest.   
On Days 1 and 15 of Cycle 1 only, ECGs will be performed in triplicate at multiple timepoints 
relative to UCB6114 dosing (predose, end of infusion, and 2 hours after the end of infusion).  
When ECG measurements coincide with blood sampling for PK (and PD), ECG will be 
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performed first.  On Days 1 and 15 of Cycle 2 and on Day 1 of all subsequent cycles, ECGs will 
be performed in triplicate prior to UCB6114 dosing.  At the SFU visit, ECGs will be performed 
once in triplicate prior to PK sampling. 
All ECGs will be evaluated for any clinically relevant changes by the investigator.  
Electrocardiograms will also be collected for central reading, the data from which will be 
analyzed separately.   
All summaries and listings of ECG data will be based on the local (site) 12-lead ECG 
measurements. 
The following ECG parameters will be reported: 
• PR interval;  
• QT interval; 
• QRS interval; 
• QTcF interval (QT corrected for heart rate using Fridericia’s formula [QTcF]); 
• Heart rate.  
Observed values and changes from Baseline in these ECG parameters will be listed and 
summarized by visit using descriptive statistics.  The mean of the triplicate measurements taken 
for each parameter will be used in the summary at each visit and timepoint. If less than 3 of the 
triplicate measurements are taken then the mean of the available measurements will be used (if 
only 1 of the 3 triplicate measurements is available, then this value will be used in the 
summaries).  The Baseline value will be the mean of the last scheduled or unscheduled triplicate 
measurements taken prior to first dose of UCB6114 on Day 1 of Cycle 1. If no predose triplicate 
measurements are taken then the mean of the triplicate measurements taken at Screening will be 
used. The mean of only the scheduled triplicate measurements at each Post-Baseline visit and 
timepoint will be included in the summary. In addition, for each of the ECG parameters, the 
minimum, maximum, average and last post-Baseline value for each participant will be calculated 
based on the mean of the triplicate of all available scheduled postdose measurements during each 
cycle up to the predose value on Day 1 of the subsequent cycle, and will be summarized by cycle 
using descriptive statistics. The last value in a cycle will be the predose mean triplicate value of 
the subsequent cycle where a subsequent cycle occurs, otherwise it will be the mean triplicate 
value at the last scheduled assessment. If only 1 mean triplicate value is available then the 
average will not be calculated and presented but this value will be used for the minimum, 
maximum and last post-Baseline value summary measures. These summary measures for each 
cycle will also be listed.   
For the multiple ECGs performed on Days 1 and 15 of Cycle 1, changes from the predose value 
will be calculated at each postdose timepoint and summarized using descriptive statistics.   
Mean (±standard deviation) change from Baseline in QTcF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot.  Individual observed values of QTcF will be 
presented over actual time in a spaghetti plot. 
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The following cut-points in QTcF will be applied for observed data and changes from Baseline:  
For observed QTcF data: 
• <450 msec; 
• ≥450 to <480 msec; 
• ≥480 to <500 msec; 
• ≥500 msec. 
For changes from Baseline in QTcF: 
• <30 msec; 
• ≥30 to <60 msec; 
• ≥60 msec. 
The incidence of participants in each of these categories will be summarized using frequency 
counts and percentages by visit. 
A listing of 12-lead ECG abnormal findings will be presented. 
Electrocardiograms will also be collected for central reading; however, these data will be 
reported in an addendum to the CSR. 
8.4.3 
Echocardiogram 
Echocardiograms will be performed at the Screening visit, at Cycle 3 Day 1 (+/- 7 days), as 
clinically indicated afterwards, and at the SFU Visit. 
All details on the echocardiogram assessments performed at each visit will be listed including the 
observed LVEF measurements and changes from Baseline, as well as information on whether the 
result was normal, abnormal not clinically significant (NCS) or abnormal clinically significant 
(CS). 
Observed values and changes from Baseline in LVEF will be summarized by visit using 
descriptive statistics.  In addition, shift tables for the change from Baseline in normal, abnormal 
NCS, abnormal CS LVEF results will be summarized by visit. 
Mean (±standard deviation) change from Baseline in LVEF will be plotted over scheduled visit 
with treatment groups overlaid on the same plot.  Individual observed LVEF results will be 
presented over actual time in a spaghetti plot. 
8.4.4 
ECOG performance status 
ECOG performance status will be listed by participant and visit and will be summarized using 
frequency counts and percentages. A shift table summarizing the changes from Baseline to each 
post-Baseline visit will also be presented.   Further detail on the ECOG performance scale, the 
listings and summaries are included in Section 10.2.  
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8.4.5 
Physical examination 
Physical examination abnormalities from the complete physical examination performed at 
Screening and predose on Day 1 of Cycle 1, and from the symptom-directed physical 
examinations performed at other visits (predose on dosing visits), will be listed. 
 
9. 
PHARMACOKINETICS AND PHARMACODYNAMICS  
9.1 
Pharmacokinetics 
9.1.1 
Secondary pharmacokinetic endpoint 
9.1.2 
Exploratory pharmacokinetic endpoints 
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9.2 
Pharmacodynamics 
The following exploratory PD and biomarker endpoints will be obtained from blood and urine 
samples which will be analyzed at a number of external laboratory vendors: 
• Serum markers of bone turnover;  
• Urinary markers of bone turnover;  
• cGremlin-1; 
• Genetic analysis; 
• ctDNA. 
The impact of UCB6114 on bone turnover will be explored using the serum and urinary markers 
provided by the analytical laboratory. These markers will be listed for the SS and summarized 
descriptively over time for the PDS by dose level (treatment group), as described for the clinical 
laboratory parameters in Section 8.3. For each marker of bone turnover, the mean (±standard 
deviation) value and the mean (±standard deviation) change from Baseline value will be plotted 
over scheduled visit with treatment group overlaid on the same plot. 
cGremlin-1 will be reported as concentration in blood by nominal (scheduled) assessment and 
dose level. Concentrations of cGremlin-1 will be listed for the SS and summarized for the PDS 
using descriptive statistics by dose level (treatment group) and nominal (scheduled) sampling 
timepoints (n, arithmetic mean, standard deviation, median, minimum, maximum, geoMean, 
geoCV and 95% CI for the geoMean [assuming lognormally distributed data]). Changes from 
Baseline will also be summarized. Individual study participant cGremlin-1 concentration-time 
profiles will be displayed graphically in spaghetti plots and geoMean cGremlin-1 concentration 
and 95% CI will be plotted at each nominal (scheduled) timepoint with treatment group overlaid 
on the same plot. 
Serum protein analysis, genetic analysis and the analysis of the test results from the blood 
samples taken for ctDNA will be performed and reported separately outside of the CSR. 
Hematoxylin and eosin (H & E) staining and immunohistochemistry (IHC) will be used to 
analyze any available historical tissue biopsy samples obtained prior to a participant’s entry into 
the study (e.g. at the time of diagnosis).  
Test results from the H & E staining and for target genes, phosphatase and tensin homolog 
(PTEN), Ki67 (cellular marker for proliferation in tumors), Gremlin-1, mothers against 
decapentaplegic homolog 4 (SMAD4) and fibroblast activation protein (FAP) will be listed by 
variable and sample analyzed (multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant) for the SS. No summaries of these data will be generated due to the 
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expected small numbers of historical biopsy samples analyzed for each dose level (treatment 
group). 
The following key/component variables will be derived based on H & E staining, PTEN, Ki67, 
Gremlin-1 and FAP test results. No derived variables will be generated for SMAD4; only raw 
test results will be listed. Note that multiple tissue samples from a tumor biopsy may have been 
analyzed for a participant and therefore multiple test results will be presented in the listings. 
H & E: Tissue Integrity (Percentage of Necrosis in Tumor Area) 
In order to assess tissue integrity, percentage of necrosis in the tumor area will be categorized as 
‘<20%’ and ‘>=20%’. If percentage of necrosis data are missing but other H & E staining and 
IHC data are available for a participant (i.e. the participant had historical tumor biopsy sample(s) 
analyzed), then the result will be categorized as ‘Not Done’.  
This categorical variable will be listed together with all other H & E test results. 
PTEN: Tissue Sample Quality Control 
The presence of staining of intrinsic control elements on the slides together with the level of 
staining intensity will be used to determine the tissue sample quality control. 
If staining of intrinsic control elements on stained slides=’YES’ and staining intensity of intrinsic 
control elements on stained slides is 1, 2 or 3 then the tissue sample quality control is ‘Good’, 
otherwise if the staining intensity of intrinsic control elements=0 then the tissue sample quality 
control is ‘Questionable’. If staining of intrinsic control elements on stained slides=’NOT 
PRESENT’ then the tissue sample quality control is ‘No staining present’.  If both variables are 
missing but other IHC results are available (i.e. the participant had historical tumor biopsy 
sample(s) analyzed), then the result will be categorized as ‘Not done’.   
This categorical variable will be listed together with the presence/absence of staining of intrinsic 
control elements on the slides, the level of staining intensity, staining pattern, staining artifacts 
and any assay-specific comments. Since the percent of tumor cells with staining intensity 0/1/2/3 
and the H-score (test results for which will be provided by the laboratory) are less relevant to 
assessing the quality control of the tissue sample, these raw test results will not be listed. 
Ki67 – Proliferative Activity of the Tumor  
In order to assess the proliferative activity of the tumor mass, cellular proliferation reflected by 
the number of Ki67-positive cell objects in the tumor region divided by the total number of cell 
objects in the tumor region will be categorized as ‘<=10%’ or ‘>10%’ with the latter category 
indicating an actively/moderately proliferating tumor. If the test result is ‘NOT EVALUABLE’ 
or missing but IHC results are available (i.e. the participant had historical tumor biopsy 
sample(s) analyzed), then the result will be categorized as ‘Not done’.  
This categorical variable will be listed together with all other Ki67 raw test results. 
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Gremlin-1: Cytoplasmic Histoscore 
The cytoplasmic histoscore will be calculated as a weighted score based on the percentage of 
tumor cells with Gremlin-1 cytoplasmic staining intensity 1, 2 or 3 as follows: 
(1 x percent tumor cells with Gremlin-1 cytoplasmic staining intensity 1) + (2 x percent tumor 
cells with Gremlin-1 cytoplasmic staining intensity 2) + (3 x percent tumor cells with Gremlin-1 
cytoplasmic staining intensity 3). 
The cytoplasmic histoscore will be missing if the participant had a historical biopsy tumor 
sample analyzed but there are no test results for percent tumor cells with Gremlin-1 cytoplasmic 
staining intensity 1, 2 or 3. 
The cytoplasmic histoscore will be listed together with all other Gremlin-1 raw test results. 
FAP 
From the image analysis of FAP-stained slides, the tumor will be classified into 2 regions: the 
cancer (CN) tumor region and the invasive margin (IM) region using a pre-established digital 
automated algorithm.  The IM region is usually a small proportion of the whole tumor and, per 
standard procedures at the analytical laboratory, will be identified first. As a result, there is a risk 
that some parts of the CN tumor region may be inaccurately classified as part of the IM region, 
particularly in cases when the tumor is small. Therefore, instead of using the results for the 
percentage of high, medium and low intensity FAP provided by the laboratory, a decision was 
made to back-calculate the areas of the CN tumor region and the IM region and add these 
together in order to re-calculate the percentage of high, medium and low intensity FAP in the 
whole tumor. 
These back-calculated results and derived variables based on FAP test results are defined in 
Table 9-1. 
Table 9-1: 
FAP Derived Variables 
Variable No. 
FAP Derived Variable 
Description and Calculation 
1[a] 
Total Analyzed Tumor 
Area (um2) 
This is the total tumor area (um2) across the CN tumor region 
and the IM region and will be calculated as the sum of the 
areas of the CN tumor region (um2) and the IM region (um2) 
where a non-missing numeric test result is available for both 
the area of the CN tumor region and the area of the IM 
region. Note that, in cases where no IM region is defined, the 
area of the IM region will be recorded as 0 or ‘NOT 
APPLICABLE’, or may be missing.  If the area of the IM 
region is recorded as ‘NOT APPLICABLE’ or is missing, 
then 0 will be assumed in this calculation and the total 
analyzed tumor area will be equal to the area of the CN tumor 
region. 
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Variable No. 
FAP Derived Variable 
Description and Calculation 
This variable will be missing if both the areas of the CN 
tumor region and IM region are missing, or if one or both are 
‘NOT EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
2  
Measured Area of Weakly 
Stained FAP in the CN 
Tumor Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
CN tumor region (weak positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of weakly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
weakly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
3  
Measured Area of 
Moderately Stained FAP 
in the CN Tumor Region 
(um2)  
This is the back-calculated area of moderately stained FAP in 
the CN tumor region (moderate positive) and will be 
calculated by multiplying the area of the CN tumor region 
(um2) and the relative area of moderately stained FAP in the 
CN tumor region (%) where a non-missing numeric test 
result is available for both the area of the CN tumor region 
and the relative area of moderately stained FAP in the CN 
tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
4  
Measured Area of 
Strongly Stained FAP in 
the CN Tumor Region 
(um2)  
This is the back-calculated area of strongly stained FAP in the 
CN tumor region (strong positive) and will be calculated by 
multiplying the area of the CN tumor region (um2) and the 
relative area of strongly stained FAP in the CN tumor region 
(%) where a non-missing numeric test result is available for 
both the area of the CN tumor region and the relative area of 
strongly stained FAP in the CN tumor region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
5  
Measured Area of Weakly 
Stained FAP in the IM 
Region (um2)  
This is the back-calculated area of weakly stained FAP in the 
IM region (weak FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative 
area of weakly stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area 
of the IM region and the relative area of weakly stained FAP 
in the IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
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Variable No. 
FAP Derived Variable 
Description and Calculation 
6  
Measured Area of 
Moderately Stained FAP 
in the IM Region (um2)  
This is the back-calculated area of moderately stained FAP in 
the IM region (moderate FAP-positive) and will be calculated 
by multiplying the area of the IM region (um2) and the 
relative area of moderately stained FAP in the IM region (%) 
where a non-missing numeric test result is available for both 
the area of the IM region and the relative area of moderately 
stained FAP in the IM region. 
This variable will be set to 0 if one or both are ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’. 
7[a]  
Measured Area of 
Strongly Stained FAP in 
the IM Region (um2)  
This is the back-calculated area of strongly stained FAP in the 
IM region (strong FAP-positive) and will be calculated by 
multiplying the area of the IM region (um2) and the relative 
area of strongly stained FAP in the IM region (%) where a 
non-missing numeric test result is available for both the area 
of the IM region and the relative area of strongly stained FAP 
in the IM region. 
This variable will be set to 0 if one or both are missing, ‘NOT 
EVALUABLE’ or ‘NOT DIAGNOSTIC’.  
8[a] 
Total FAP-Positive 
Tumor Area (um2) 
This is the total FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be 
calculated as the sum of component derived variables 2-7. 
If all 6 component variables are 0 then this derived variable 
will be missing. 
9[a] 
Total Measured Area of 
Weakly Stained FAP 
(um2) 
This is the total weak FAP-positive area across the CN tumor 
region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 2 
and 5. 
10[a] 
Total Measured Area of 
Moderately Stained FAP 
(um2) 
This is the total moderate FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 3 
and 6. 
11[a] 
Total Measured Area of 
Strongly Stained FAP 
(um2) 
This is the total strong FAP-positive area across the CN 
tumor region and the IM region (whole tumor) and will be 
calculated as the sum of component FAP derived variables 4 
and 7. 
12[a] 
Total Relative Area of 
Weakly Stained FAP (%) 
This is the percentage of weak FAP expression across the CN 
tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 9 as   
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Variable No. 
FAP Derived Variable 
Description and Calculation 
(Total Measured Area Of Weakly Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
13[a] 
Total Relative Area of 
Moderately Stained FAP 
(%) 
This is the percentage of moderate FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 10 
as   
(Total Measured Area Of Moderately Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
14[a] 
Total Relative Area of 
Strongly Stained FAP (%) 
This is the percentage of strong FAP expression across the 
CN tumor region and IM region (whole tumor) and will be 
calculated using component FAP derived variables 1 and 11 
as   
(Total Measured Area Of Strongly Stained FAP / Total 
Analyzed Tumor Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
15[a] 
Total Relative FAP-
Positive Tumor Area 
(TPS) (%) 
This is the total proportion score which is the percentage of 
FAP-positive area across the CN tumor region and the IM 
region (whole tumor) and will be calculated using component 
derived variables 1 and 8 as  
(Total FAP-Positive Tumor Area / Total Analyzed Tumor 
Area) x 100 
If the total analyzed tumor area is missing then this variable 
cannot be calculated and will be missing. 
16[a] 
Total FAP Histoscore 
This is a histoscore for the combined CN tumor region and 
IM region (whole tumor) and will be calculated as a weighted 
score based on component derived variables 12, 13 and 14 as  
(1 x Total Relative Area of Weakly Stained FAP) + (2 x Total 
Relative Area of Moderately Stained FAP) + (3 x Total 
Relative Area of Strongly Stained FAP). 
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CN=cancer; FAP=fibroblast activation protein, IM=invasive margin, TPS=total proportion score. 
[a] Included in the listing of FAP test results. 
The derived variables containing the [a] flag in Table 9-1 above will be listed together with 
information on staining artifacts and any assay-specific comments provided by the laboratory. 
Further informal analyses may be performed to explore the relationship between the PD and 
biomarker endpoints with antitumor activity, ADA status, and also with key PK parameters. The 
PK-PD effects of UCB6114 may be assessed using a population analysis approach. These 
analyses will also be performed separately outside of the CSR and the details of analysis 
methods will be included in a separate analysis plan. 
The incidence of available historical tumor biopsies will be summarized by treatment group.  
The incidence of PD samples taken from blood and urine will be summarized by cycle and 
treatment group. 
9.3 
Immunogenicity 
Anti-drug (UCB6114) antibody status and classification, changes from Baseline in titer over time 
(Cycles 1, 2 and even cycles thereafter) and the incidence of treatment-emergent ADA positivity 
are exploratory immunogenicity endpoints in Part C of this study.  Potential relationships 
between ADA and PK, PD, antitumor activity and safety will also be explored but this will be 
reported separately outside of the CSR. 
Serum samples will be collected from all study participants for the measurement of ADA and the 
evaluation of immunogenicity according to the Schedule of Activities in the protocol.  
All listings of ADA will be presented for the SS and summaries of the ADA data will be 
presented by treatment group for the ADAS. 
Anti-drug (UCB6114) antibodies will be measured using a three-tiered assay approach: 
Screening assay, confirmatory assay and titration assay.  
Samples will first be evaluated in the Screening assay using a false positivity rate of 5% 
(reported as ‘negative screen’ or ‘positive screen’), followed by analysis of screened positive 
samples in the confirmatory assay (which is a drug depletion assay) to confirm the positivity of 
the samples (reported as ‘negative immunodepletion’ or ‘positive immunodepletion’). Samples 
that are confirmed as positive in the confirmatory assay will be evaluated in a titration assay to 
assess the ADA level and this will be reported as titer (reciprocal dilution factor including 
minimum required dilution). 
Anti-drug (UCB6114) antibody sample status will be determined as follows from the pre-
treatment sample taken on Day 1 of Cycle 1 (Baseline) and all post-treatment (post-Baseline) 
samples.  
• Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
• Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
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Anti-drug (UCB6114) antibody sample status will be listed for each participant at each visit by 
treatment group.  This listing will include sampling dates and times, the Screening assay result, 
the confirmatory assay result and the derived ADA sample status.  In addition, the titer from the 
titration assay (if applicable) will be listed together with the change from Baseline in titer. The 
number and percentage of participants with a positive or negative sample at each visit will be 
summarized by treatment group.  Percentages will be calculated based on the number of 
participants with a non-missing/sufficient sample at the visit. 
Based on the ADA status of the samples, study participants will be categorized according to the 
following 6 ADA classifications in Table 9-2: 
Table 9-2: 
ADA Classifications 
Classification Classification Label 
Definition 
1 
Pre-ADA negative – treatment 
induced ADA negative 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA negative status at all sampling 
timepoints post-Baseline (including SFU).  
Participants with missing post-Baseline samples are 
included as long as the missing samples do not 
result in an unmonitored period greater than 16 
weeks. 
2 
Pre-ADA negative – treatment 
induced ADA positive 
Includes participants who have an ADA negative 
status at Baseline, or missing/insufficient Baseline 
sample, and an ADA positive status at any sampling 
timepoint post-Baseline (including SFU).  
3 
Pre-ADA positive – treatment 
reduced ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA negative status at all 
sampling timepoints post-Baseline (including SFU).  
4 
Pre-ADA positive – treatment 
unaffected ADA 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with titer values of the same magnitude as Baseline 
(≤1.80 fold difference from the Baseline value) or 
with decreased titer values compared to Baseline 
(>1.80 fold decrease from the Baseline value). 
5 
Pre-ADA positive – treatment 
boosted ADA positive 
Includes participants who have an ADA positive 
status at Baseline and an ADA positive status at any 
sampling timepoint post-Baseline (including SFU) 
with increased titer values compared to Baseline 
(>1.80 fold increase from the Baseline value). 
6 
Inconclusive 
Includes participants who do not satisfy the criteria 
for classifications 1-5. 
ADA=anti-drug (UCB6114) antibody; SFU=Safety Follow-up. 
Note: The terminology ‘treatment unaffected’ is ambiguous as the criteria refers to ADA responses that are not increased upon 
dosing compared to Baseline level whereas titers may reduce. 
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A study participant will be classified as having treatment-emergent ADA positivity if they 
satisfy one of the following criteria: 
• The Baseline result is ADA negative and at least one post-Baseline result is ADA 
positive (pre-ADA negative – treatment induced ADA positive) – ADA classification 2 in 
Table 9-2; 
• The Baseline result is ADA positive and at least one post-Baseline result shows a pre-
defined fold increase in titer from the Baseline value (the fold increase from Baseline 
required to meet this criterion will be defined with the development of the assay and will 
be included in the TFLs) (pre-ADA positive – treatment boosted ADA positive) – ADA 
classification 5 in Table 9-2. 
Total anti-drug (UCB6114) antibody incidence will be determined by the number and 
percentage of participants with treatment-emergent ADA positivity (as defined above).  The 
denominator for the percentage calculation will be the number of participants with at least one 
available/reported post-Baseline result. 
Total prevalence of pre-anti-drug (UCB6114) antibody will be determined by the number and 
percentage of participants who are pre-ADA positive (i.e. participants who have a positive ADA 
status at Baseline).  The denominator for the percentage calculation will be the number of 
participants with an available/reported Baseline sample result. 
Total anti-drug (UCB6114) antibody prevalence will be determined by the number and 
percentage of participants with ADA classifications 2, 3 or 5 in Table 9-2 (i.e. an ADA positive 
status at any post-Baseline sampling timepoint. The denominator for the percentage calculation 
will be the number of participants with at least one available/reported sample result (either at 
Baseline and/or post-Baseline). 
The ADA classification for each participant will be listed by treatment group.  This listing will 
also include whether or not the participant achieved treatment-emergent ADA positivity (ADA 
incidence), whether the participant was pre-ADA positive (pre-ADA prevalence) and whether 
the participant had an ADA positive or negative status at any post-Baseline sampling timepoint 
(ADA prevalence). In addition, the visit at which the participant first achieved treatment-
emergent ADA positivity will be included.  
The number and percentage of participants in each of the 6 ADA classifications defined above in 
Table 9-2 will be presented by treatment group. Also, in this tabulation, ADA incidence and 
prevalence (as defined above) will be summarized. 
The first occurrence of treatment-emergent ADA positivity (based on the criteria above) will be 
summarized using frequency counts and percentages at each post-Baseline visit by treatment 
group. This tabulation will include a count of the number of participants at each post-Baseline 
visit who fulfill at least one of the above defined criteria for treatment-emergent ADA positivity; 
participants will be counted in the numerator based on the earliest visit at which one of these 
criteria is fulfilled. At other visits, participants will be counted in the denominator (assuming an 
assessment of treatment-emergent positivity is available) and this will be used in the percentage 
calculations. 
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Individual study participant ADA titer profiles over actual time will be presented graphically on 
the linear and the semi-logarithmic scale. The linear scale plots will be repeated for the subset of 
participants who achieve treatment-emergent ADA positivity during Part C.   
Mean (±standard deviation) Cmin will be plotted by ADA sample status over nominal (scheduled) 
time with treatment groups overlaid on the same plot. On this plot, mean Cmin at Cycle 1 Day 15 
will be the mean of the derived Cmin following the first dose of UCB6114 (as described in 
Section 9.1.2) and, thereafter from Cycle 2 Day 1, mean Cmin will be the mean of the predose 
concentrations at the subsequent dosing visits.  
10. 
EFFICACY ANALYSES 
10.1 
Antitumor activity 
The analysis of antitumor activity is exploratory in Part C of this study. 
10.1.1 
Definitions of the antitumor activity endpoints 
The following endpoints are defined based on RECIST (Version 1.1) which standardizes solid 
tumor measurements and provides guidelines for the objective assessment of changes in tumor 
size during anti-cancer treatment.   
Appendix 9 (Section 11.9) of the protocol contains the RECIST 1.1 guidelines to be used in this 
study, adapted from Eisenhauer (2009), and includes the definitions of target and non-target 
lesions, the definitions of target and non-target lesion responses at each tumor assessment, the 
criteria for determining overall response at each tumor assessment based on target lesion 
response, non-target lesion response and the presence/absence of new lesions, and a participant’s 
best overall response (BOR).  Further details on the rules to apply in the derivation of BOR are 
included in the Derivation of Efficacy Endpoints document which has been developed to support 
this SAP. 
At each post-Baseline tumor assessment, the investigator will record responses for target lesions 
and non-target lesions, whether or not there has been an appearance of any new lesions, and the 
participant’s overall response based on their target lesion response, non-target lesion response 
and the presence/absence of new lesions.  Note that target lesion response and non-target lesion 
response assessments will be based on the changes in the pre-existing lesions at Baseline and the 
appearance of new lesions will only factor in the determination of an overall response of PD at 
that tumor assessment visit (i.e. per Tables A and B in Section 11.9.2 of Appendix 9 of the 
protocol). 
Objective response rate (ORR) is defined as the percentage of participants with a BOR of 
complete response (CR) or partial response (PR) during Part C.   
Disease Control Rate (DCR) is defined as the percentage of participants with a BOR of CR, 
PR, or stable disease (SD) during Part C.   
Best overall response (BOR) is defined for each study participant as the best overall tumor 
response from each tumor assessment (performed every 8 weeks from Day 1 of Cycle 1 (±7 
days)) according to the RECIST criteria for changes in target and non-target lesions and the 
appearance of new lesions. Best overall response is determined from the start of study treatment 
(first dose of UCB6114) until documented objective disease progression or the date of 
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subsequent anti-cancer therapy (systemic therapy, surgery or radiotherapy for cancer), whichever 
occurs first. If anti-cancer therapy is started on the same day as a tumor assessment, then the 
overall response from that assessment will be used in the derivation of BOR. If a participant does 
not have objective disease progression or does not start a subsequent anti-cancer therapy then all 
tumor assessments up to the SFU visit will be included in the derivation of BOR. For a BOR of 
SD, a participant’s tumor measurements must have met the SD criteria at least once after the start 
of study treatment at a minimum interval of no less than 49 days.  
For this study, BOR determination requires confirmation of CR or PR responses at a subsequent 
assessment ≥4 weeks (28 days) after the criteria for CR or PR responses are first met, however, 
an unconfirmed BOR will also be derived for each participant for the purpose of reporting (as 
described below in Section 10.1.2). Table C in Appendix 11.9 of the protocol and Table 1 and 
subsequent text in the Derivation of Efficacy Endpoints document provides the derivation of 
BOR when confirmation of CR and PR responses are required. The definition of an unconfirmed 
BOR is also included in this document. Although the derivation of unconfirmed BOR does not 
include the requirement for a CR or PR response to be confirmed ≥4 weeks (28 days) after the 
initial response, a participant's CR or PR response may, in fact, be confirmed at a subsequent 
assessment ≥4 weeks (28 days) after the criteria for the CR or PR response are first met. 
Unconfirmed BOR will be referred to as BOR (confirmed or unconfirmed) throughout the rest of 
this document. 
Confirmed BOR and BOR (confirmed or unconfirmed) will be derived programmatically based 
on the overall tumor assessment data recorded on the eCRF by the investigator.  
Duration of response (DOR) will be calculated for participants with a BOR of confirmed CR or 
PR as the time in days from the start date of the confirmed CR or PR (e.g. the date of the first 
overall response of CR or PR, which is at least 4 weeks before a second overall response of CR 
or PR) to the first date that recurrent or progressive disease is objectively documented (i.e. 
according to the RECIST guidelines).  This will be referred to as the duration of confirmed 
response and the following calculation will be performed: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
Duration of response will also be calculated for participants with a BOR of CR or PR which is 
either confirmed or unconfirmed [DOR (confirmed or unconfirmed)] as the time in days from the 
start date of the CR or PR to the date of the first documented objective disease progression (i.e. 
according to the RECIST guidelines).  The following calculation will be performed: 
𝐷𝑂𝑅 (𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑜𝑟 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑)
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For the purpose of a sensitivity analysis of both duration of confirmed response and DOR 
(confirmed or unconfirmed), the above calculations will take into consideration the occurrence of 
both objective disease progression (per RECIST 1.1) and clinical disease progression (as 
described in Appendix 11.9 of the protocol and as determined by the investigator and recorded as 
a reason for study treatment discontinuation on the eCRF), whichever occurs first.  If clinical 
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disease progression occurs on the same date that a participant’s objective disease progression is 
determined, then the participant will be included in the sensitivity analyses as having objective 
disease progression. 
The following calculations will therefore be performed for the sensitivity analyses: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
𝐷𝑂𝑅 (𝐶𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑 𝑜𝑟 𝑈𝑛𝑐𝑜𝑛𝑓𝑖𝑟𝑚𝑒𝑑)
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑜𝑟 𝐶𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛
− 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐶𝑅 𝑜𝑟 𝑃𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒) + 1 
For participants who die without objective disease progression, DOR will be censored on the 
date of death, regardless of cause. For a participant who discontinues early from Part C of the 
study with no objective disease progression, DOR will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who discontinue study treatment but who do not have 
documented objective disease progression (i.e. according to the RECIST guidelines), DOR will 
be censored at the date of their last available (scheduled or unscheduled) tumor assessment at 
which a lack of objective disease progression was determined. Such participants might include 
those that are ongoing in Part C at the time of any defined data cut-off.   Likewise, participants 
who have not discontinued early and do not have disease progression after a confirmed or 
unconfirmed response, DOR will be censored at the date of their last available (scheduled or 
unscheduled) tumor assessment. 
In the sensitivity analyses of duration of confirmed response and duration of unconfirmed 
response, the same censoring rules will apply except that the date of last contact will be used for 
the censoring of participants who discontinue early from Part C or complete Part C without 
objective disease progression, clinical disease progression or death.  
Date of last contact will be the latest of the dates of premature study termination and of last 
contact recorded on Study Termination eCRF page, the date of death, the date of last dose of 
study treatment, the dates of all visits, AE start and end dates (with partial dates imputed as 
earliest possible) and the date of contact recorded on the Survival Safety Follow-up and Survival 
Final Follow-up eCRF forms. 
Further details on the rules to apply in the derivation of DOR are included in the Derivation of 
Efficacy Endpoints document which has been developed to support this SAP. 
Progression-free survival (PFS) will be calculated as the time in days from the first dose of 
study treatment to the date of the first documented objective disease progression (i.e. according 
to the RECIST guidelines), or death due to any cause, whichever occurs first. The following 
calculation will be performed: 
𝑃𝐹𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝑂𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑃𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑣𝑒 𝐷𝑖𝑠𝑒𝑎𝑠𝑒/𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒) + 1  
Participants who die due to any cause without a documented objective disease progression will 
be considered to have progressed on the date of their death.  Participants who do not have any 
post-Baseline tumor assessments will be censored on the date of their first dose of study 
treatment.  Participants who discontinue early from Part C or discontinue study treatment without 
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documented objective disease progression or death, will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment at which a lack of objective disease 
progression was determined. Participants who start anti-cancer therapy during Part C without a 
prior documented objective disease progression will be censored on the date of their last 
available (scheduled or unscheduled) tumor assessment prior to the initiation of the subsequent 
anti-cancer therapy.  If anti-cancer therapy starts on the same date as the participant’s tumor 
assessment and determination of objective disease progression, or the participant’s death (due to 
any cause), then the participant will not be censored and the participant will be included as 
having an uncensored event on this date. This censoring rule will also be applied to participants 
who are ongoing at any data cut-off for an analysis of Part C data who have no documented 
objective disease progression. The use of anti-cancer therapy during Part C will be identified via 
ongoing medical review of the concomitant medications together with the start dates of further 
anti-cancer therapy information recorded on the survival follow-up pages of the eCRF. 
As a sensitivity analysis, PFS will also be calculated as the time in days from the first dose of 
study treatment to the date of the first documented objective disease progression (per RECIST 
1.1), the date of clinical disease progression, as determined by the investigator, or the date of 
death due to any cause, whichever occurs first.  Last contact date will be used for the censoring 
of participants still alive with no reported disease progression (objective or clinical). The same 
rules described above for the censoring of participants who start anti-cancer therapy will be 
applied in this sensitivity analysis. 
Further details on the rules to apply in the derivation of PFS are included in the Derivation of 
Efficacy Endpoints document which has been developed to support this SAP. 
Overall survival (OS) will be calculated as the time in days from the date of first dose of 
UCB6114 to the date of death from any cause.  Participants will be followed up to ascertain their 
survival status at the SFU visit (within 30 days after their last dose of UCB6114) and at the Final 
Visit (3 months after their last dose of UCB6114); they will not be followed up beyond this 
timepoint. 
The following calculation will be performed: 
𝑂𝑆= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑒𝑎𝑡ℎ−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝑈𝐶𝐵6114) + 1 
OS will be censored on the date of their last contact for participants who discontinue early from 
Part C of the study or who discontinue study treatment due to disease progression but continue in 
the study, are not known to have died.   
Further details on the rules to apply in the derivation of OS are included in the Derivation of 
Efficacy Endpoints document which has been developed to support this SAP. 
10.1.2 
Analysis of the antitumor activity endpoints 
The analyses of the antitumor activity endpoints in Part C will be performed for the PPS.  As a 
sensitivity analysis, all analyses will be repeated for the SS.  All listings will be presented for the 
SS.  Summaries and listings will be presented by treatment group. 
All lesion assessment data recorded at Baseline (Screening) and during the Treatment Period 
(every 8 weeks from Day 1 of Cycle 1 [±7 days]) will be listed separately for target lesions, non-
target lesions and new lesions.  Each post-Baseline tumor assessment will be labelled as ‘Tumor 
Assessment 1, Tumor Assessment 2 etc. – see further details below). These listings will include 
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lesion number and lesion type (nodal/non-nodal), location, method of assessment, dimension (or 
an indication that the lesion is too small to measure, for target lesions only) and lesion response 
evaluation (for non-target lesions at post-Baseline assessments). The listing for target lesions will 
also include the derived eCRF component data used for the determination of the overall target 
lesion response at each post-Baseline assessment (e.g. sum of all dimensions across target lesions 
and percentage change from Baseline in the sum).  In addition, the overall response assessment 
for target lesions and non-target lesions, as determined by the investigator, will be listed for each 
post-Baseline tumor assessment (Tumor Assessment 1, Tumor Assessment 2 etc.) together with 
the presence of new lesions and the overall response assessment.    
The investigator's overall tumor response assessment will be summarized using frequency counts 
and percentages over time (tumor assessment). Post-Baseline tumor assessments are scheduled to 
be performed per protocol every 8 weeks from Day 1 (±7 days). For the purpose of this 
summary, the first post-Baseline tumor assessment (scheduled or unscheduled) will be assigned 
to ‘Tumor Assessment 1’ using the protocol-defined window of Day 50 to 64 (Day 57 ± 7 days) 
relative to Day 1 (first dose of UCB6114). For all subsequent post-Baseline tumor assessments 
(scheduled or unscheduled, but excluding tumor assessments performed at the SFU visit), these 
will be assigned to ‘Tumor Assessment 2’, ‘Tumor Assessment 3’ etc. using the protocol-defined 
window of Day 50-64 relative to the previous post-Baseline tumor assessment. If a post-Baseline 
tumor assessment is missed, then the scheduled day of the missed assessment will be used to 
window the next tumor assessment. In cases where a scheduled and unscheduled tumor 
assessment occurs in the same window, the investigator’s overall tumor response at both 
assessments will be considered. If the overall tumor response is NE at one of the assessments, 
then the overall tumor response from the other assessment will be included in the summary table. 
If the overall tumor response is not NE at both assessments, then the tumor assessment that is 
closest to the target day of the tumor assessment will be included in the summary table. In the 
event that the two tumor assessments are equidistant from the target day of the tumor assessment 
and neither have an overall tumor response of NE, then the worst case overall tumor response 
will be included in the summary table. Otherwise, if the post-Baseline tumor assessment falls 
outside of the protocol-defined window, it will be classified as an unscheduled assessment and 
not included in the summary of overall tumor response. Bar charts will also be produced for 
overall tumor response rate by treatment group for each visit. In addition, waterfall plots of 
participants’ percentage change from Baseline in the sum of dimensions for all target lesions will 
be presented by treatment group and visit. The individual participants’ bars will be colored by 
overall tumor response at the visit. 
Confirmed and unconfirmed BOR for each participant will be derived programmatically using 
the overall response assessments performed every 8 weeks from Day 1 of Cycle 1 (or at 
unscheduled timepoints) and the RECIST criteria. Whether a BOR of CR or PR is confirmed or 
unconfirmed will be indicated on this listing.  Using a participant’s BOR, whether the participant 
achieves an objective tumor response (i.e. a BOR of CR or PR) and/or disease control (i.e. a 
BOR of CR, PR or SD) during study treatment will be determined.  These derived data will be 
listed for the SS. 
Confirmed BOR and unconfirmed BOR will be summarized using frequency counts and 
percentages.  Bar charts will also be produced for confirmed BOR and unconfirmed BOR by 
treatment group. 
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The number and percentage of participants achieving objective tumor response and disease 
control (ORR and DCR) based on confirmed BOR and BOR (confirmed or unconfirmed) will be 
presented and, if data allow, exact 95% CIs for binomial proportions will be calculated using the 
Clopper-Pearson method and presented for the response rates. In the calculation of ORR and 
DCR, the denominator will include all participants in the analysis set. Objective response rate 
and DCR (based on confirmed BOR and unconfirmed BOR) will also be summarized in bar 
charts by treatment group overall and by tumor type and ECOG performance status at Baseline. 
In addition, waterfall plots of each participant’s best percentage change from Baseline in the sum 
of the dimensions for all target lesions will be presented by treatment group overall and by tumor 
type and ECOG performance status at Baseline with the individual participants’ bars colored by 
confirmed BOR and unconfirmed BOR. 
The summaries and analyses of DOR, PFS and OS will be carried out as described below, if the 
data allow. 
Duration of confirmed response, DOR (confirmed or unconfirmed) and PFS will be listed and 
summarized descriptively using Kaplan-Meier estimation.  These summaries will be repeated for 
the sensitivity analyses of these endpoints (defined in Section 10.1.1 above) and will include the 
number and percentage of participants with the event, the number and percentage of participants 
censored, minimum and maximum values and Kaplan-Meier estimates of the 25th percentile, 
median, 75th percentile and corresponding 95% CIs calculated using Greenwood’s formula. In 
addition, DOR and PFS rates at 3 months, 6 months and 9 months will be derived from the 
Kaplan-Meier estimation and presented together with associated 95% CIs. 
Kaplan-Meier curves will be presented for duration of confirmed response and DOR (confirmed 
or unconfirmed) and PFS.  Treatment groups will be overlaid on each plot.   
Survival status collected on the eCRF at the SFU visit and at the Final Visit will be listed for 
each participant by treatment group.  This listing will include the participant’s survival status, 
date and cause of death, whether an autopsy was performed and date of autopsy, whether the 
participant had received any further antitumor treatment after the last dose of study treatment and 
the type of treatment, and whether the participant’s disease had been assessed since the end of 
study treatment including method of assessment and the overall response.  
Overall survival times will be listed and summarized descriptively using Kaplan-Meier 
estimation.  Note that since participants are only followed up for survival until the Final Visit in 
Part C of the study, a summary of OS may not be meaningful (i.e. if no participants die then OS 
cannot be assessed).   
Exploratory analyses of selected antitumor activity endpoints may be performed based on 
subgroups of participants in the SS. Data permitting, the subgroups will be defined based on 
participant, disease, and treatment history information (e.g. extent of prior anti-cancer therapy). 
Additionally, the relationship of the antitumor activity variables with key PK parameters may be 
explored but this will be reported separately. 
10.2 
ECOG performance status 
ECOG performance status is an additional efficacy assessment performed in Part C of this study 
and is defined in Table 10-1. 
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Table 10-1: ECOG Performance Status Scale 
Grade 
ECOG performance status scale 
0 
Fully active, able to carry on all pre-disease performance 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 for more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group. 
ECOG performance status will be listed by treatment group at each visit for the SS. 
ECOG performance status will be summarized as an ordinal categorical variable using frequency 
counts and percentages.  Shift tables for the change from Baseline in each grade will be 
summarized by visit. 
 
11. 
OTHER ANALYSES  
Not applicable. 
 
12. 
REFERENCES 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-center 
clinical trials. Drug Information Journal. Vol 26, 77-84, 1992. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
European Medicines Agency, Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronovirus) Pandemic, accessed 29-March-2020.  
(https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf) 
International Council for Harmonization/Food and Drug Administration E9 Guidance (ICH-E9). 
US Food and Drug Administration FDA Guidance on Conduct of Clinical Trials of Medical 
Products During COVID-19 Public Health Emergency Guidance for Industry, Investigators and 
Institutional Review Boards, accessed 29-March-2020. 
(https://www.fda.gov/media/136238/download) 
 
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13. 
APPENDICES 
13.1 
SMQ algorithm for identification of anaphylactic reactions 
Based on MedDRA® Version 25.1, the SMQ=‘Anaphylactic reaction’ consists of 3 parts: 
1) A narrow search containing PTs that represent core anaphylactic reaction terms:  
Category A 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Circulatory collapse 
Dialysis membrane reaction 
Kounis syndrome 
Procedural shock 
Shock 
Shock symptom 
Type I hypersensitivity 
2) A broad search:  
Category B 
Acute respiratory failure 
Asthma 
Bronchial oedema 
Bronchospasm 
Cardio-respiratory distress 
Chest discomfort 
Choking 
Choking sensation 
Circumoral oedema 
Cough 
Cough variant asthma 
Cyanosis 
Dyspnoea 
Hyperventilation 
Irregular breathing 
Laryngeal dyspnoea 
Laryngeal oedema 
Laryngospasm 
Laryngotracheal oedema  
Mouth swelling 
Nasal obstruction 
Oedema mouth 
Oropharyngeal oedema 
Oropharyngeal spasm 
Oropharyngeal swelling 
Pharyngeal oedema 
Pharyngeal swelling 
Respiratory arrest 
Respiratory distress 
Respiratory failure 
Reversible airways obstruction 
Sensation of foreign body 
Sneezing 
Stridor 
Swollen tongue 
Tachypnoea 
Throat tightness 
Tongue oedema  
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Statistical Analysis Plan Amendment 1.0 
UCB6114 
ONC001 – Part C 
 
 
 
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Tracheal obstruction 
Tracheal oedema 
Upper airway obstruction 
Vaccine associated enhanced respiratory 
disease 
Wheezing 
Category C 
Allergic oedema 
Angioedema 
Circumoral swelling 
Erythema 
Eye oedema 
Eye pruritis 
Eye swelling 
Eyelid oedema 
Face oedema 
Flushing 
 Injection site urticaria 
Lip oedema 
Lip swelling 
Nodular rash 
Ocular hyperaemia 
Oedema 
Oedema blister 
Periorbital oedema 
Periorbital swelling 
Pruritis 
Pruritis allergic 
Rash 
Rash erythematous 
Rash pruritic 
Skin swelling 
Swelling 
Swelling face 
Swelling of eyelid 
Urticaria 
Urticaria papular 
Category D 
Blood pressure decreased 
Blood pressure diastolic decreased  
Blood pressure systolic decreased 
Cardiac arrest 
Cardio-respiratory arrest 
Cardiovascular insufficiency 
Diastolic hypotension 
Hypotension 
Hypotensive crisis 
Post procedural hypotension 
 
Note that if the MedDRA® version is increased from 25.1 during the study, any changes to the 
terms in the above categories should be applied. 
The following algorithmic approach will be applied: A or (B and C) or [D and (B or C)], i.e.  
If a participant has a TEAE which codes to a PT included in Category A, then the event will be 
flagged as an anaphylactic reaction.  Note that participants with a TEAE coded to a PT=’Type 1 
hypersensitivity’ will also be flagged as having a hypersensitivity reaction as this PT is also 
included in the Category A narrow search for the ‘Hypersensitivity’ SMQ. 
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ONC001 – Part C 
 
 
 
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OR 
If a participant has a TEAE which codes to a PT included in Category B AND has a TEAE 
which codes to a PT included in Category C, and both TEAEs have the same start date, then 
both events will be flagged as anaphylactic reactions. 
OR 
If a participant has a TEAE which codes to a PT included in Category D AND has (either a 
TEAE which codes to a PT included in Category B OR a TEAE which codes to a PT included in 
Category C), and both TEAEs have the same start date, then both events will be flagged as 
anaphylactic reactions. 
 
13.2 
SAP Amendment 1 Changes 
The main rationale for SAP Amendment 1 is to include details on the additional key derived and 
component exploratory variables required based on the results from the analyses of historical 
tumor biopsy samples in Part C.  It was decided that these additional variables were needed to 
improve the interpretability of the test results received from the laboratory.. This SAP 
amendment also provides some clarifications relating to the handling of data for the purpose of 
summarizing safety and exploratory anti-tumor activity endpoints. 
The key changes are summarized in the table below (note that additional minor corrections and 
clarifications were also applied in this amendment but are not included in this table). 
Section  
Description of Change 
1 
The versions and dates of supporting study documentation were 
updated. 
5.1 
An update was made to the example illustrating the definition of a 
complete cycle of UCB6114. 
8.1 
The additional summary of the total number of doses of study 
treatment received was included. 
8.2 
Rules for handling missing relationship to study treatment for an 
adverse event were updated. 
8.4.2 
Clarification on the handling of triplicate ECG measurements was 
included. 
9.1.2 
Updates were added for more clarification on how Cmin and Cmax is 
to be derived. 
9.2 
Details on the analysis of the historical tumor biopsy samples was 
included together with rules for defining key and component 
derived variables based on the test results received from the 
laboratory. These variables were considered important for clearer 
interpretation of these results from data listings. 
9.3 
A predefined fold-increase of 1.80 was included. 
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ONC001 – Part C 
 
 
 
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Section  
Description of Change 
10.1.2 
Rules for applying the protocol-defined window around the post-
Baseline tumor assessments (scheduled and unscheduled) for the 
purpose of summarizing the investigator’s overall tumor response 
assessment were included. 
General 
MedDRA® version number was updated to the latest version (25.1) 
throughout the document. 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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