Clinical trial NCT05223673
Conditions: Metastatic Colorectal Cancer
Keywords: Futuximab/modotuximab Trifluridine/tipiracil Phase III Safety Lead-In part S95026 Sym004 Adult Metastatic Colorectal Colorectal Cancer EGFR
Sponsor: Institut de Recherches Internationales Servier
Start date: 2022-04-21; Completion date: 2023-06-21
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized phase III study with a safety lead-in part in patients with KRAS/ NRAS and BRAF Wild Type metastatic colorectal cancer who have previously received treatment with oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF agents and anti-EGFR antibodies. The main objective of the safety lead-in part is to assess safety and tolerability of futuximab/modotuximab in combination with trifluridine/tipiracil. The primary objective of the phase III part is to compare Overall Survival of futuximab/modotuximab in combination with trifluridine/tipiracil vs trifluridine/tipiracil monotherapy in patients with tumours that are KRAS/NRAS and BRAF wild-type (WT).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Futuximab/modotuximab intervention 2: Trifluridine/Tipiracil intervention 3: Trifluridine/Tipiracil
Intervention descriptions: intervention 1: Concentrate for solution for infusion, futuximab/modotuximab will be administered via IV route, once weekly of each cycle at 9 mg/kg/dose at Cycle 1 Day 1 and then at 6 mg/kg/dose. Each cycle is up to 28 days. intervention 2: Film-coated tablets of trifluridine/tipiracil (35 mg/m²/dose) will be administered orally before futuximab/ modotuximab administration, twice a day (BID) within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 14 days, followed by a 14-day rest. This treatment cycle will be repeated every 28 days. intervention 3: Film-coated tablets of trifluridine/tipiracil (35 mg/m²/dose) will be administered orally twice a day (BID) within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 14 days, followed by a 14-day rest. This treatment cycle will be repeated every 28 days.

Protocol documents:
Prot_000.pdf: 
  
STANDARD COVER PAGE 
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
A randomised, open-label, multi-centre, two-arm Phase 3 study 
comparing futuximab/modotuximab in combination with 
trifluridine/tipiracil to trifluridine/tipiracil single agent with a 
Safety Lead-In part in participants with KRAS/NRAS and 
BRAF wild type metastatic colorectal cancer previously treated 
with standard treatment and anti-EGFR therapy (COLSTAR) 
Study brief title 
Phase 3 study of futuximab/modotuximab in combination with 
trifluridine/tipiracil versus trifluridine/tipiracil single agent in 
participants with previously treated metastatic colorectal cancer 
Study public title 
A study of futuximab/modotuximab in combination with 
trifluridine/tipiracil in participants with previously treated 
colorectal cancer that has spread (metastatic)  
Study name 
COLSTAR 
Test drug code 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Indication 
Pre-treated metastatic colorectal cancer  
Development phase 
Phase 3 with Safety Lead-In part  
Protocol code 
CL3-95026-001 
EudraCT Number 
2021-003151-41 
Universal Trial Number 
Not applicable 
Other register number 
CT. gov) 
NCT05223673 
Investigational New Drug 
Application Number 
IND 105953 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) 
International coordinator Prof. Fortunato Ciardiello 
University of Campania, Napoli 
Italy 
Date of the document 
26 July 2022 
Version of the document 
Final version 
Version number 
3.0  
Substantial 
Amendment(s) integrated 
No 
Final version date 
Countries concerned 
1 
24 January 2022 
All 
2 
26 July 2022  
All 
 
 
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VERSION LIST 
Protocol 
No 
Substantial 
amendment 
Final version 
date 
Countries 
concerned 
Nature of key modifications 
1.0 
NA 
28 July 2021 
All 
Original protocol 
1.1 
NA 
5 January 2022 
DNK 
-
See Appendix 13
2.0 
1 
24 January 
2022 
All 
-
Typos and formatting changes were made throughout the protocol.
-
Synopsis and investigational schedule were revised to reflect changes made in the protocol body.
-
Blood volume was revised in Section 4.1.2 (Investigation schedule) and Appendix 12; text was added “For
men and post-menopausal women the total volume of blood collected will be slightly lower (since
pregnancy tests don’t apply)”. 
-
In Table (4.1.3.2) 1: Dose-limiting Toxicity Criteria, other adverse events was revised to specify that
“Grade 3 nausea and/or vomiting controlled by anti-emetic therapy that lasts less than 72h” as stipulated
by the FDA (incorporated non-substantial amendment 1). 
-
Screening Criterion 5 was revised to specify that “patients with known MSI-H/dMMR tumours are
eligible if they have received previous treatment with immune checkpoint inhibitors according to
approved indication” to align with FDA requirements. 
-
Screening Criteria 8, 9, 13, 14, 16-25, 29, 32, 33, 35, 36, 39, and 40 were revised to clarify that the
inclusion visit “(Safety Lead-in part) or randomisation visit (Phase 3 part)”.
-
Inclusion Criterion 17 was revised to specify that “Creatinine clearance ≥ 30 mL/min assessed using the
Cockcroft & Gault formula” to align with FDA requirements.
-
Inclusion Criterion 21 was revised to specify that “In addition, highly effective contraception should be
considered for their female partners.” as stipulated by health authority request (Belgium).
-
Exclusion Criterion 26 was removed; patients with MSI-H tumours will be allowed in the study provided
they have received previous treatment with immune check point inhibitors that are approved for this
indication/population. 
-
Exclusion Criterion 32 and corresponding text was revised to include “QTc interval >480 ms” per FDA
feedback. 
-
Exclusion Criterion 35 and corresponding text was revied to specify that participants with skin rash of
Grade > 1 from prior anti-EGFR “at the time of inclusion (Safety Lead-in part) or randomisation (Phase 3
part)” for clarification.
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Protocol 
No 
Substantial 
amendment 
Final version 
date 
Countries 
concerned 
Nature of key modifications 
- 
Exclusion Criterion 36 and corresponding text was revised to specify drainage for ascites, pleural effusion 
or pericardial fluid within 4 weeks prior “to inclusion (Safety Lead-in part) or randomisation (Phase 3 
part)” for clarification. 
- 
Exclusion Criterion 39 and corresponding text was revised to specify that treatment with systemic 
immunosuppressive therapy would occur “within 4 weeks prior to inclusion (Safety Lead-in part) or 
randomisation (Phase 3 part)” for clarification.   
- 
The text describing futuximab/modotuximab administration in Section 6.1.1.2 was revised to remove “an 
indwelling” for consistency.  
- 
Text and references were added regarding the prophylactic use of antibiotics in Section 6.1.2.2. Text 
regarding the recommendation for medical management of EGFR-related skin toxicity was deleted, per 
FDA feedback. 
- 
Section 6.3.2 (Authorised treatments) was modified to specify that “Premedication for dermatologic AEs 
is allowed throughout the study” to align with FDA feedback. 
- 
Table (7.2.4.6) 1 was revised to clarify “Time point response for participants with target, or/and non-
target”disease. 
- 
Section 8.1 (Specification of safety parameters) and corresponding text was revised to specify “total 
calcium” for clarification.  
- 
Section 8.2.5 (Only for futuximab/modotuximab participants (Safety Lead-In part and Arm A of Phase 3 
part) was modified to remove text regarding “trifluridine/tipiracil intake in Arm B of Phase 3 part” as 
dermatologic examination does not apply to Arm B. 
- 
Regarding trifluridine/tipiracil intake in Sections 8.2.7.1 (Haematology) and 8.2.7.2 (Biochemistry) text 
was added: “only for CxD1” for clarification. 
- 
“Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1” 
and “(trifluridine/tipiracil intake in Arm B of Phase 3 part)” was removed in Section 8.2.7.3. 
- 
Text in Section 8.2.7.4 was revised to clarify that “PTT and/or activated PTT” can be included in the 
coagulation assessment. 
- 
“Pregnancy tests should be performed prior to randomisation, at the beginning of each cycle during the 
treatment period (treatment cycle is repeated every 28 days), upon treatment discontinuation and at the 
first follow-up visit, for all relevant patients.” in Section 8.2.7.6 was added as stipulated by health 
authority request (Belgium). 
- 
The following text were added in Section 8.3 as a modification to the template: “Any clinical finding or 
clinically significant abnormal laboratory findings or other abnormal safety assessments, which are 
associated with the studied disease should not be considered as an AE unless judged by the investigator to 
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Protocol 
No 
Substantial 
amendment 
Final version 
date 
Countries 
concerned 
Nature of key modifications 
be more severe than expected for the participant’s condition.” And “A non-fatal studied “disease 
progression” itself should not be considered as an AE.” 
- 
Footnote in Table (8.11.2.3) 1 was corrected to remove “except for management of skin toxicity where a 
third reduction to 1.5 mg/kg is permitted”. 
- 
Codons for KRAS &NRAS mutational analysis were specified in Section 9.1.1.3. 
- 
Table (9.2.1) 1 and Table (9.5) 1 footnotes were revised to “5-60 minutes”. 
- 
Blood volume was corrected in Section 9.2.2, 9.5, and in Appendix 12. 
- 
Text was corrected in Section 9.4: and corresponding table and text: “Peripheral whole blood (20 mL) will 
be collected pre-dose on C1D1 C2D1, C3D1 and then every 2 cycles along with tumour assessment and 
at withdrawal visit, and analysed centrally for ctDNA monitoring.” To align with the investigational 
schedule.  
- 
Footnote in Table (9.5) 1 was added: “**The frequency of futuximab/modotuximab immunogenicity 
assessments will be reduced to every 2 months after the first 6 months in the first year and every 4 months 
after the first year.” per FDA request. 
- 
Text was added in Section 9.5 (Immunogenicity): “. ADA Backup samples will be stored, for a maximum 
of 3 years after the end of the study, to allow additional analyses related to immunogenicity assessment to 
be performed in case of agencies’ request during their review process. All samples will be destroyed at the 
latest at the end of the storage period or at any time on participant’s or sponsor’s request” because storage 
of back-up ADA samples is needed as agencies could request additional analysis until the time of filing. 
- 
Text in Section 10.1.1.1 (Analysis sets) was removed: “Must have measurable or non-measurable lesion 
according to RECIST v1.1 [Screening criterion #4].” Because no deviation from this criterion is possible. 
- 
Text in Section 10.1.2.4.2 (Phase 3 part) was added: “and anti-EGFR mAb therapy for ≥ 4 months)” to 
align with the Study Plan (Section 4.1.1). 
- 
Text was added in Section 10.1.2.4.2.1 under the subheading Subgroup analyses: response to previous 
treatment with anti-EGFR (CR/PR, SD), last previous regimen (anti-EGFR, no anti-EGFR), skin toxicity 
with previous anti-EGFR (yes, no), skin toxicity with previous anti-EGFR (Grade 1-2, Grade 3-4, no 
toxicity), duration of previous anti-EGFR (< 8, ≥ 8 months), Race (White, American Indian/Alaska native, 
Asian, Black/African American, Native Hawaiian/Other pacific islander)” due to the additional subgroup 
analysis. 
- 
Text regarding statistical analyses were revised in Section 10.1.2.4.2.4 under the subheading (Secondary 
estimands based on ORR and DCR) per FDA feedback.  
- 
Text in Section 17.2 (Concerning the sponsor) regarding supplying the investigator with the Product 
Information and Investigator Brochure was corrected. 
- 
Appendix 9 under the subheading B. Grading of Infusion-Related Reactions, table rows (Allergic reaction, 
Cytokine release syndrome) wording was revised to align with CTCAE version 5. Similar change was 
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Protocol 
No 
Substantial 
amendment 
Final version 
date 
Countries 
concerned 
Nature of key modifications 
made in Appendix 10 (Futuximab/modotuximab Management of Management of Rash, Paronychia, 
Xerosis, and Pruritus) and Appendix 11 (Management of Hypomagnesemia). 
- 
Appendix 10 under the subheading A. Prophylaxis for futuximab/modotuximab-Related Dermatologic 
AEs, the title of the table was revised to “Options for Premedication for Dermatologic AEs”, per FDA 
feedback. 
- 
PK and ADA sample collection at predose was extended from 5-30 min before start of infusion to 5-60 
min before start of infusion 
2.1 
NA 
10 February 
2022 
CHN 
- 
See Appendix 14 
3.0 
2 
26 July 2022 
All 
- 
Typographical errors were corrected globally. 
- 
Revised number of participating centres and countries, and updated study initiation and completion dates. 
- 
“Phase 3 part” was changed to “Randomised part” for clarity throughout the protocol. 
- 
Replaced BICR with Investigator assessment; BICR will be performed only if needed, retrospectively, and 
will not be provided to investigators for decisions regarding patient treatment. 
- 
Revised text regarding management of skin toxicity globally per FDA feedback. 
- 
Molecular weight of futuximab and modotuximab was corrected in Section 2.2. 
- 
Addition in Section 2.3.2 of the description and results of study WJOG8916G. 
- 
Correction of DC definition in Table (3.4) 1 and Table (3.4) 2, and in Sections 10.1.2.4.1 and 10.1.2.4.2: 
suppression of “24 weeks” for SD since it corresponds to a different endpoint (clinical benefit) not 
evaluated in this study.    
- 
Changed naming of “Inclusion” period to “Screening” period to align with study plan Figure (4.1.1) 2 
Figure (4.1.1) 3 and added wording regarding televisits in Section 4.1.1. Added QoL to C2D1 in 
Figure (4.1.1) 3 to align with the investigation schedule. 
- 
Changed ‘futuximab/modotuximab’ to study treatments in footnote #7 in Table (4.1.2) 1 and throughout 
the protocol where applicable for clarity. 
- 
Footnote #9 in Table (4.1.2) 1 and Footnote #12 in Table (4.1.2) 2 was revised to align with criterion 
#32a. 
- 
Footnote #13 in Table (4.1.2) 1 was revised to align with modifications in Section 9.1.1.3. 
- 
Footnote #13 in Table (4.1.2) 2 was revised to align with modifications in Section 9.6. 
- 
Footnote #17 in Table (4.1.2) 2 was revised to align with modifications in Section 9.1.1.3. 
- 
Text in Section 4.1.3.2 was revised to better specify DLT period. 
- 
Figure (4.1.3.4) 1 was revised to specify ‘evaluable’ for 6, 12, and 25 participants. 
- 
Section 4.1.4, criterion #6a and corresponding text regarding previous treatment with anti-EGFR mAb 
therapy was revised to for ≥16 weeks. 
- 
Criterion #5a was revised to remove “based on clinical evaluation” for clarity. 
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Protocol 
No 
Substantial 
amendment 
Final version 
date 
Countries 
concerned 
Nature of key modifications 
- 
Criterion #32b was revised to add “per the investigator’s discretion” for consistency. 
- 
Text was revised in Section 6.1 regarding COVID-19, as with the advanced knowledge on the COVID-19 
infection, the period to re-start study treatment can be reduced, to increase at the same time the chances to 
respond to treatment. 
- 
Text revised regarding size of in-filter in Section 6.1.1.2. 
- 
Text was corrected to remove “at C1D1 only” in Section 6.1.1.6. 
- 
Text in Section 6.1.5 was revised for clarity, following modifications regarding dose delays in Section 8. 
- 
Text in Section 6.3.1.1 was revised to align with wording of criterion# 40a.  
- 
Text in Section 8.2.6 was revised to align with wording of criterion# 32a. 
- 
Text regarding “Any events of COVID-19” was removed in Section 8.7 since there is no longer a reason 
to consider COVID-19 events as ERINs because only serious adverse events should be integrated in the 
PV database. 
- 
Text was revised in Sections 8.11, 8.11.1, and 8.11.2, to provide more information about dose delay and 
specify maximum delay periods to allow initiation of both IMPs at the same time in the next cycle or, 
when that is not possible, to have the next cycle started with only one of the IMPs; and to allow treatment 
re-start with the re-administration of a loading dose of 9 mg/kg after 2 consecutive doses of S95026 have 
been omitted, in order to re-achieve steady state and target saturation after treatment interruption, in line 
with the rationale for the initial loading dose at C1D1. 
- 
Revised text in Section 9.1.1.3 to align with amended main ICF. 
- 
Added timepoint in Section 9.6 and investigation schedule.  
- 
Revised subgroup analyses and exploratory analyses in Section10.1.2.4.2.1. 
- 
Added text regarding the PK and PK/PD analysis in Section 10.3.2. 
- 
Revised text regarding composition of SC members in Section 12.4.1. 
- 
Text regarding ICF availability in electronic format added in Section 13.3. 
- 
Added text regarding confirming the authenticity of the data in the e-CRF in Section 14.1. 
- 
Updated Appendix 5 with current version of the EQ-5D-5L scale. 
- 
Added footnote in Appendix 9 regarding use or H1 antagonists.  
- 
Removed Part A in Appendix 10 due to FDA feedback. 
- 
Revised and added footnotes in Appendix 12. 
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SYNOPSIS 
Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
Title of study: A randomised, open-label, multi-centre, two-arm Phase 3 study comparing 
futuximab/modotuximab in combination with trifluridine/tipiracil to trifluridine/tipiracil single agent with a 
Safety Lead-In part in participants with KRAS/NRAS and BRAF wild type metastatic colorectal cancer 
previously treated with standard treatment and anti-EGFR therapy (COLSTAR) 
Study Brief Title: Phase 3 study of futuximab/modotuximab in combination with trifluridine/tipiracil versus 
trifluridine/tipiracil single agent in participants with previously treated metastatic colorectal cancer. 
Study Public Title: A study of futuximab/modotuximab in combination with trifluridine/tipiracil in participants 
with previously treated colorectal cancer that has spread (metastatic).  
Protocol No.: CL3-95026-001 
Study name: COLSTAR 
International Coordinator and Steering Committee Chairman: Prof. Fortunato Ciardiello 
National coordinators and investigators: listed in a separate document 
Study centre(s): 
Safety Lead-In part 
Total number of centres: approximately 25 centres. 
Total number of countries: approximately 8 countries. 
Randomised part  
Total number of centres: approximately 200 centres. 
Total number of countries: approximately 20 countries. 
Study period: 
­ Study duration for the participant: approximately 6.5 months of treatment 
+ follow-up period for survival. 
­ Study initiation date (planned date of first visit first participant (FVFP)):  
 Safety Lead-In part: Q2 2022. 
 Randomised part: Q3 2023. 
­ Study completion date (planned date of last visit last participant (LVLP)): 
Approximately Q4 2026. 
Study development phase: 
Phase 3 with Safety Lead-In part  
Objectives / Endpoints:  
Safety Lead-In part 
Primary 
­ To assess safety and tolerability of futuximab/modotuximab in combination with trifluridine/tipiracil 
according to National Cancer Institute Comment Terminology Criteria for Adverse Events (NCI-CTCAE) 
v5.0. 
Secondary 
­ To assess anti-tumour activity of futuximab/modotuximab in combination with trifluridine/tipiracil per 
investigator assessment using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 in terms of: 
 Objective Response Rate (ORR). 
 Best Overall Response (BOR). 
 Disease Control Rate (DCR). 
 Progression Free Survival (PFS). 
­ To assess anti-tumour activity of futuximab/modotuximab in combination with trifluridine/tipiracil in terms 
of: 
 Overall Survival (OS). 
­ To characterise the pharmacokinetic (PK) profile of futuximab/modotuximab, trifluridine and tipiracil in the 
combination of futuximab/modotuximab with trifluridine/tipiracil. 
­ To evaluate the immunogenicity of futuximab/modotuximab (i.e. occurrence of anti-drug antibody [ADA]). 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
Exploratory 
­ To explore biomarkers as potential predictors of response and to track the emergence of resistance. 
Randomised part 
Primary 
­ To compare OS of futuximab/modotuximab in combination with trifluridine/tipiracil vs trifluridine/tipiracil 
monotherapy in participants with tumours that are KRAS/NRAS and BRAF wild-type (WT) (Double 
negative [DN]). 
Key Secondary 
­ To compare OS of futuximab/modotuximab in combination with trifluridine/tipiracil vs trifluridine/tipiracil 
monotherapy in participants with tumours that are KRAS/NRAS, BRAF WT and EGFR-extracellular domain 
WT (Triple negative [TN]). 
Secondary 
­ To compare anti-tumour activity of futuximab/modotuximab in combination with trifluridine/tipiracil vs 
trifluridine/tipiracil monotherapy per investigator’s assessment using RECIST v1.1 in terms of:  
 PFS. 
 ORR. 
 DCR. 
 Duration of response (DoR). 
 Time to Response (TTR). 
­ To assess anti-tumour activity of futuximab/modotuximab in combination with trifluridine/tipiracil vs 
trifluridine/tipiracil monotherapy in terms of:  
 Time to Next Treatment (TTNT). 
 Time to Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (TtPS2). 
­ To further evaluate and to compare the safety profile of futuximab/modotuximab in combination with 
trifluridine/tipiracil vs trifluridine/tipiracil monotherapy. 
­ To compare Quality of life (QoL) of futuximab/modotuximab in combination with trifluridine/tipiracil vs 
trifluridine/tipiracil monotherapy Appendix 5 and Appendix 6. 
­ To characterise the pharmacokinetic (PK) profile of futuximab/modotuximab, trifluridine and tipiracil in the 
combination futuximab/modotuximab with trifluridine/tipiracil. 
­ To further evaluate the immunogenicity of futuximab/modotuximab (i.e. occurrence of ADAs). 
Exploratory  
­ To explore the PK/pharmacodynamic (PD) relationship for safety and/or efficacy of the combination 
futuximab/modotuximab with trifluridine/tipiracil. 
­ To explore biomarkers as potential predictors of response and to track the emergence of resistance. 
Methodology:  
This is a Phase 3 study, with a Safety Lead-In part. 
The Safety Lead-In is an international, open-label, single-arm, non-randomised part, with the aim to evaluate the 
safety and tolerability of futuximab/modotuximab in combination with trifluridine/tipiracil in participants 
previously treated by chemotherapy (including oxaliplatin, irinotecan and 5-fluorouracil, anti-VEGF agents) and 
by anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy for ≥ 16 weeks, 
KRAS/NRAS and BRAF WT metastatic colorectal cancer (mCRC). 
The Randomised part is an international, open-label, randomised, multi-centre, parallel-group, 2-arm part. The 
participants previously treated by chemotherapy (including oxaliplatin, irinotecan and 5-fluorouracil, anti-VEGF 
agents) and with anti-EGFR mAb therapy for ≥ 16 weeks with KRAS/NRAS and BRAF WT mCRC will be 
randomised in a 1:1 ratio, to either futuximab/modotuximab in combination with trifluridine/tipiracil (Arm A) 
or trifluridine/tipiracil (Arm B).  
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
The participants will be stratified according to: 
­ Performance Status (PS) (0 vs 1). 
­ Extracellular domain EGFR mutations (ECD) (presence vs absence). 
­ Previous regimens of treatment (2 vs ≥ 3). 
Number of included participants: 
Planned: Approximately 25 participants with a minimum of 3 Japanese participants in Safety Lead-In part and 
approximately 500 participants in Randomised part. 
Number of primary events: For Randomised part 383 OS events. 
Diagnosis and main criteria for inclusion (Section 5) 
Screening criteria 
Demographic characteristics 
 Male or female participant aged ≥ 18 years old. 
Medical and therapeutic criteria 
 Participants must have histologically or cytologically confirmed adenocarcinoma of mCRC (all other 
histological types are excluded), not amenable to surgical intervention due to either medical 
contraindications or non-resectability of the tumour. 
 Based on circulating tumour DNA (ctDNA) screening blood test analysis participants should be: 
­ Without RAS (KRAS and NRAS) mutations in any of the following codons: 
 
 
 
 
 
 
­ Without BRAF 
. 
 Participants must have measurable or non-measurable lesion according to RECIST v1.1. 
 Participants must have received at least 2 prior regimens of standard chemotherapy for mCRC and had 
demonstrated progressive disease or intolerance to their last regimen. The following characteristics 
apply: 
­ Prior standard chemotherapy must not have included trifluridine/tipiracil but must have included all 
of the following agents approved and available in each country: 
 Fluoropyrimidines, irinotecan and oxaliplatin. 
 At least one anti-vascular endothelial growth factor (VEGF) pathway inhibitor (bevacizumab 
and/or aflibercept and/or ramucirumab and/or regorafenib). 
 At least one anti-EGFR mAb (cetuximab or panitumumab). 
 Patients with known MSI-H/dMMR tumours are eligible if they have received previous treatment 
with immune checkpoint inhibitors according to approved indication. 
­ Participants must have progressed during or within 6 months of the last administration of last 
standard chemotherapy regimen. Participants who have withdrawn from standard treatment due to 
unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the 
same agent prior to progression of disease will be eligible to enter the study. 
­ Participants who received adjuvant/neoadjuvant chemotherapy and had recurrence during or within 
6 months of completion of the adjuvant/neoadjuvant chemotherapy are permitted to count the 
adjuvant/neoadjuvant therapy as one regimen of chemotherapy. 
 Participants should have received previous treatment with commercially available anti-EGFR mAbs for 
≥ 16 weeks.  
 Ability to swallow oral medication. 
 Estimated life expectancy ≥ 12 weeks. This criterion should be rechecked at inclusion visit (Safety 
Lead-in part) or randomisation visit. 
 ECOG performance status 0 or 1 (or equivalent Karnofsky PS of 70% to 100%). This criterion should 
be rechecked at inclusion visit (Safety Lead-in part) or randomisation visit (Appendix 2). 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
Informed consent 
 Written informed consent obtained prior any study-specific procedure as described in Section 13.3. 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
Non-screening criteria 
General criteria 
 Pregnancy, possibility of becoming pregnant during the study and breast-feeding woman. 
 Unlikely to cooperate in the study. 
 Participation in another interventional study at the same time or within 4 weeks prior to the inclusion 
visit (Safety Lead-in part) or randomisation visit. Participation in study follow-up part without IMP 
administration non-interventional registry or epidemiological study is allowed. 
 Patients currently receiving or having received anticancer therapies within 4 weeks prior to the 
inclusion visit (Safety Lead-in part) or randomisation visit. 
 Participant already enrolled in the study (informed consent form [ICF] signed). 
Inclusion criteria  
Medical and therapeutic criteria 
 Adequate haematological function based on the last assessment performed within 7 days prior to the 
inclusion visit (Safety Lead-in part) or randomisation visit, defined as: 
­ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
­ Haemoglobin ≥ 90 g/L. In case of blood transfusion, the haemoglobin assessment must be performed 
2 weeks or more after the transfusion. 
­ Platelet count ≥ 100 x 109/L. 
­ Adequate coagulation function for all participants. For participants receiving anti-coagulant therapy 
(except platelet anti-aggregates) the adequate therapeutic levels of international normalized ratio 
(INR) should be confirmed. 
 Adequate renal function based on the last assessment performed within 7 days prior to the inclusion 
visit (Safety Lead-in part) or randomisation visit defined as: 
­ Creatinine clearance ≥ 30 mL/min assessed using the Cockcroft & Gault formula (Appendix 3). 
 Adequate hepatic function based on the last assessment performed within 7 days prior to the inclusion 
visit (Safety Lead-in part) or randomisation visit, defined as: 
­ Total serum bilirubin < 1.5 x upper limit of normal (ULN) (unless Gilbert disease confirmed). 
­ Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) ≤ 2.5 x ULN 
(if liver function abnormalities are due to underlying liver metastasis, AST [SGOT] and ALT [SGPT] 
≤ 5 x ULN). 
 Serum potassium, serum phosphates, serum magnesium within normal limits with or without 
supplementation based on the last assessment performed within 7 days prior to the inclusion visit 
(Safety Lead-in part) or randomisation visit. 
 Women of childbearing potential (WOCBP) must use a highly effective method of birth control 
(Section 5.5) during study treatment beginning within 2 weeks prior to the inclusion visit (Safety Lead-
in part) or randomisation visit and continuing at least 6 months after the last IMP administration. In 
case of oral contraception, women should have been stable on the same contraceptive drug (i.e. same 
active principle) for at least 3 months prior to the inclusion visit (Safety Lead-in part) or randomisation 
visit. 
 Male participants with WOCBP partners must use a condom during the study and until at least 6 months 
after the last IMP administration. In addition, highly effective contraception should be considered for 
their female partners. Contraceptive measures do not apply if the participant is sterile, vasectomised or 
sexually abstinent. Sperm donation will not be allowed during the study and for 6 months after the last 
IMP administration. 
Exclusion criteria 
Medical and therapeutic criteria 
 Major surgery within 4 weeks prior to the inclusion visit (Safety Lead-in part) or randomisation visit or 
participants who have not recovered from side effects of the surgery. 
 Participants with any other serious/active/uncontrolled infection, any infection requiring parenteral 
antibiotics, or unexplained fever > 38ºC within 2 weeks prior to the inclusion visit (Safety Lead-in part) 
or randomisation visit. 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
 Known clinically significant cardiovascular disease or condition, including: 
­ Any uncontrolled arrhythmia (per the investigator’s discretion). 
­ Severe conduction disturbance (e.g. 3rd degree heart block) (per the investigator’s discretion). 
­ Uncontrolled hypertension (per the investigator’s discretion). 
­ Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) 
Functional Classification (Appendix 4). 
­ History of acute coronary syndromes (including myocardial infarction and unstable angina), 
coronary angioplasty, stenting or bypass grafting within 6 months prior to inclusion (Safety Lead-in 
part) or randomisation. 
­ QTc interval > 480 ms 
 Participants with a significant gastrointestinal abnormality, including: 
­ Diarrhoea of Grade > 1 at the time of inclusion. 
­ Requirement for IV alimentation. 
­ In the investigator’s opinion, that might significantly interfere with proper absorption of the study 
treatments. 
 Participants with skin rash of Grade > 1 from prior anti-EGFR at the time of inclusion (Safety Lead-in 
part) or randomisation, or any other skin toxicity precluding participation in the study according to 
investigator’s discretion. 
 Other malignancies including those which were radically treated and for which the remission period at 
the time of screening is less than five years. Exemptions for this minimally required duration of 
remission period may be applied for carcinoma in situ of the cervix, basal cell skin cancer and 
carcinoma in situ of gastric and oesophageal cancer that are deemed to be cured by adequate treatment. 
 Treatment with systemic immunosuppressive therapy within 4 weeks prior to inclusion (Safety Lead-
in part) or randomisation (except steroids given in prophylactic setting or at a chronic low dose [≤ 20 
mg/day prednisone equivalent]). 
 Prior radiotherapy if completed less than 4 weeks before the inclusion visit (Safety Lead-in part) or 
randomisation visit, except if provided as a short course for symptoms palliation only. Tumour lesions 
if previously irradiated cannot be chosen as target lesions for response evaluation. 
Test drug: 
IMPs: 
Safety Lead-In part: futuximab/modotuximab + trifluridine/tipiracil 
Randomised part: futuximab/modotuximab (Arm A) + trifluridine/tipiracil vs trifluridine/tipiracil (Arm B) 
Futuximab/modotuximab  
Premedication:  
­ Premedication for Infusion-Related Reactions (IRR): There is an inherent risk for IRRs with the 
administration of mAbs, therefore premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of futuximab/modotuximab. All participants will be premedicated with standard therapies that include 
a glucocorticoid and an H1 antagonist. Where indicated, consideration may be given to include an H2 
antagonist and/or acetaminophen (Section 6.1.2.1). 
­ Premedication for skin toxicity: Management of skin toxicity will be done throughout the study according to 
the investigator’s discretion. Para-aminobenzoic acid (PABA)-free sun protection factor (SPF) ≥ 15 
ultraviolet (UV) A and UVB sunscreen protection is recommended to be applied to exposed skin areas before 
going outdoors. (Section 6.1.2.2). 
 
­ Premedication for other toxicities: In the event of other futuximab/modotuximab associated AEs, participants 
may be pre-medicated with standard therapies at the investigator’s discretion, to reduce the potential for such 
reactions in the future. The sponsor may implement additional mandatory premedication for all participants 
treated in this study if a pattern emerges of other mild-to-moderate futuximab/modotuximab -related AEs 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
(e.g., mucositis, diarrhoea) that are amenable to prophylaxis with standard agents (Section 6.1.2.3). Such 
action will occur following discussions between the investigator(s) and the sponsor. 
Administration schedule: futuximab/modotuximab will be administered at a dose 9 mg/kg on Cycle 1 Day 1 
(C1D1) (loading dose) and then at a 6 mg/kg weekly (± 2 days) beginning on C1D8 (maintenance doses) for all 
subsequent administrations, by IV infusion, after trifluridine/tipiracil intake. 
Infusion duration: The first infusion on C1D1 (9 mg/kg in 500 mL) is to be administered over 1 hour. The 
maximum rate of infusion of 500 mL/hour should not be exceeded throughout the administration. Subsequent 
infusions (6 mg/kg in 250 mL) may be delivered over 30 minutes, maintaining the maximum infusion rate of 
500 mL/hour. 
Observation requirements: 
The participants will be observed for a minimum of 2 hours following completion of the first administration of 
futuximab/modotuximab on C1D1 and a minimum of 1 hour following completion of subsequent infusions of 
futuximab/modotuximab (C1D8, onward). Participants could be hospitalized for 24 hours after the 
administration of futuximab/modotuximab per the investigator’s discretion and/or local practice per country, to 
enable a close in-patient safety monitoring. 
At the end of each infusion, the IV line must remain in place for at least 1 hour to allow administration of IV 
drugs, if necessary. 
Futuximab/modotuximab infusions will take place under the close supervision of physician or other study 
personnel experienced in administration of IV agents and in an environment where full resuscitation facilities 
are immediately available. 
Trifluridine/tipiracil 
Premedication: Anti-emetic therapy is recommended to prevent nausea and vomiting (Section 6.1.4). 
Administration schedule: Trifluridine/tipiracil will be administered, before futuximab/modotuximab 
administration, at a dose 35 mg/m²/dose, orally twice a day (BID), within 1 hour after completion of morning 
and evening meals (or in accordance with the local SmPC [Summary of Product Characteristics] of 
trifluridine/tipiracil), 5 days on/2 days off, over 14 days (2 weeks), followed by a 14-day (2 weeks) rest. 
This treatment cycle will be repeated every 28-days (4 weeks). 
Comparator (Only for Randomised part): 
The comparator agent (control) is trifluridine/tipiracil. 
Trifluridine/tipiracil will be administered at a dose 35 mg/m²/dose, orally BID, within 1 hour after completion 
of morning and evening meals (or in accordance with the local SmPC of trifluridine/tipiracil), 5 days on/2 days 
off, over 14 days (2 weeks), followed by a 14-day (2 weeks) rest.  
This treatment cycle will be repeated every 28-days (4 weeks). 
Duration of treatment: 
Active treatment period: 
Participants will be treated until they meet a discontinuation criterion (Section 5.8.1). Administration will be at 
the same dose level (unless dose reduction is necessary) and infusion duration established for the participant 
during Cycle 1, and on the same weekly schedule provided retreatment criteria are met.  
Follow-up period:  
After the withdrawal visit, all treated participants will be followed every 8 weeks (±10 calendar days): 
­ For tumour assessment (unless patient had discontinued study treatments for radiologic disease progression 
or withdrawal of consent) until radiologic progression regardless of initiation of a new anticancer therapy 
­ For survival status until death or until end of the study is reached (whichever occur first) 
If a participant is still receiving IMPs at the end of the study, please see Section 6.5 for procedures to be followed. 
Criteria for evaluation: 
Efficacy measurements: 
Tumour assessments will be performed as per RECIST version 1.1 (Eisenhauer, 2009) at baseline and then every 
8 weeks (± 7 calendar days) from C1D1 until radiologic progression, death or end of study, whichever occurs 
first. 
Safety measurements: 
AEs will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 5.0. AEs will be reported up to 30 calendar days after the last IMPs intake and the serious AEs 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
related to the research product will be reported without any time delay. Information of any change or addition 
of a new concomitant treatment at each visit must be obtained. 
Safety assessments will include: 
­ Concomitant medication/procedure surveys. 
­ ECOG PS assessment. 
­ Vital sign assessment (including temperature, pulse, respiratory rate, and blood pressure). 
­ Physical examination (with weight, body surface area [BSA] calculation, and dermatologic examination). 
­ Dermatologic examination (additional for futuximab/modotuximab participants in Safety Lead-In part and 
ARM A in Randomised part). 
­ Haematology panel. 
­ Biochemistry panel. 
­ Serum 
magnesium 
(Mg), 
total 
calcium 
(Ca), 
potassium 
(K) 
monitoring 
(additional 
for 
futuximab/modotuximab participants in Safety Lead-In part and ARM A in Randomised part). 
­ Coagulation panel. 
­ Urinalysis. 
­ Pregnancy testing (if applicable). 
­ Electrocardiogram (ECG), 12-lead. 
 
For each participant, DLT assessment will be performed during Safety Lead in part. Assessments include all 
toxicities observed during the initial 28-day treatment period (Cycle 1). A DLT is defined as: 
­ A clinically significant AE graded according to the NCI-CTCAE version 5.0, observed during the initial 28-
day treatment period following the first IMP administration. 
­ Assessed as unrelated to underlying disease, disease progression, intercurrent illness, or concomitant 
medications. 
­ At least possibly related to the IMPs (futuximab/modotuximab or trifluridine/tipiracil or both) by the 
investigator and meeting any of the following criteria: 
 Anaemia ≥ Grade 3. 
 Febrile neutropenia. 
 Uncomplicated Grade 4 neutropenia that lasts ≥ 1 week. 
 Uncomplicated Grade 4 thrombocytopenia (less than 25,000 per mm3) that lasts ≥ 1 week or any Grade 
≥ 3 thrombocytopenia with bleeding episodes or thrombocytopenia requiring platelet transfusion. 
 Grade 3 diarrhoea for >2 days despite adequate treatment or with fever and/or dehydration. 
 Any Grade 3 skin toxicity lasting for more than 2 weeks, or Grade 4 skin toxicity regardless of the 
duration1. 
 Grade ≥ 3 infusion-related reaction. 
 AST or ALT ≥ 3 x ULN along with a total bilirubin > 2.0 x ULN and confirmed Hy’s law cases according 
to FDA guidance. 
 Grade ≥ 3 isolated AST or ALT. 
 Any laboratory value Grade ≥ 3 with a duration ≥ 3 days, considered unrelated to underlying disease, 
disease progression, intercurrent illness or concomitant medications/therapies. 
 Any other Grade 3 or Grade 4 non-haematologic AE (except for Grade 3 nausea and/or vomiting 
controlled by anti-emetic therapy that last less than 72 h, or Grade 3 diarrhoea responsive to anti-diarrheal 
medication). 
1acne, cellulitis, dermatitis acneiform, dry skin, erysipelas, erythema, folliculitis, hypertrichosis, paronychia, pruritus, rash, rash 
maculopapular, rash vesicular, skin exfoliation, skin hyperpigmentation and xerosis 
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Name of the sponsor: 
I.R.I.S. 
Name of Finished Product: 
Futuximab/modotuximab (also known as S95026 or Sym004) 
Name of Active Ingredient: 
futuximab and modotuximab 
Pharmacokinetic measurements: 
­ Individual PK parameters such as area under the plasma concentration-time curve (AUC) or maximum 
plasma concentration (Cmax) will be derived using a population PK modelling approach, which is described 
in a separate data analysis plan (DAP). 
­ Exploratory assessment of the relationship between individual PK parameters and PD endpoints for efficacy 
or safety may be performed; a separate DAP will be written. 
Other measurements 
Genomic Analysis 
Genomic analysis for defining patient eligibility and stratification will be based on assessment of ctDNA in 
plasma with an oncogene panel. The genomic analysis includes a series of genes frequently mutated in cancer, 
but will be focused on the following genes: 
­ BRAF 
 
 
­ KRAS / NRAS 
 
 
­ EGFR-ECD 
 
Futuximab/modotuximab Immunogenicity 
ADA in serum will be measured 
Quality of life assessments (QoL) 
QoL assessments will be performed at baseline, after the end of cycle 1 (C2D1), then from cycle 3 (C3D1) every 
2 cycles during the treatment period, at the withdrawal visit, and every 8 weeks (2 months) during the follow-up 
period until death or until end of the study is reached (whichever occur first), using EORTC QLQ-C30 and EQ-
5D-5L questionnaires Appendix 5 and Appendix 6. 
Data Monitoring Committee:   
Safety data collected during the Safety Lead-In part will be reviewed by a Data Monitoring Committee (DMC) 
to assess whether 1) the drug combination is tolerable, 2) if the maximum tolerated dose (MTD) has been 
exceeded, and 3) if the randomised portion of the study may proceed. 
During the Safety Lead-In part, the DMC will initially assess tolerability after 6 evaluable participants, then after 
12 evaluable participants treated and finally when all 25 participants will have been treated. 
During the Randomised part the DMC will meet approximately every 4 months in the first year and 
approximately twice a year thereafter and at the planned interim analysis as well. For more details see 
Section 4.1.3.4. 
The composition and role of the DMC will be described in a charter finalised before the trial is initiated. 
Specific COVID-19 situation 
In case of highly suspected COVID-19 infection (based on typical symptoms or typical chest CT scan images) 
or confirmed COVID-19 infection (based on positive COVID-19 biological testing), the study treatment(s) 
should be immediately interrupted. The study treatment(s) could be restarted if participant is asymptomatic and 
a period of at least 7 days after the diagnosis has been respected, and with a negative test (if the testing is required 
by the institutional site). 
Vaccination against COVID-19 is highly encouraged for all patients, preferably before study inclusion or 
whenever possible for patients included in the study. In this case, it is recommended to avoid vaccination 
48 hours before or after futuximab/modotuximab administration if possible, for all cycles. 
 
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Contractual signatories 
I, the undersigned, have read the foregoing protocol and the “Participant information and consent form” 
document attached to the protocol and agree to conduct the study in compliance with such documents, Good 
Clinical Practice and the applicable regulatory requirements. 
 
INVESTIGATOR: 
 
NAME

CENTER NUMBER

DATE

SIGNATURE

 
 
HEAD OF GLOBAL DEVELOPMENT GI INDICATIONS 
 
NAME
 
DATE
SIGNATURE
 
Digitally signed by 
 
 
Date: 2022.07.26 18:23:45 
+02'00'
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Other signatories 
BIOSTATISTICS HEAD ONCOLOGY OR DESIGNEE: 
NAME
DATE

SIGNATURE

 

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Table of contents 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 30 
2. BACKGROUND INFORMATION ................................................................................. 30 
2.1. Metastatic Colorectal Cancer .......................................................................................... 30 
2.2. Futuximab/modotuximab ................................................................................................ 31 
2.2.1. Non-clinical development ............................................................................................ 31 
2.2.2. Clinical development .................................................................................................... 33 
2.2.3. Clinical pharmacokinetic properties ............................................................................. 35 
2.2.4. Rationale for selected dose ........................................................................................... 35 
2.3. Trifluridine/tipiracil in third-line mCRC ........................................................................ 36 
2.3.1. Trifluridine/tipiracil as single-agent in third treatment of mCRC ................................ 36 
2.3.2. Trifluridine/tipiracil in combination with anti-EGFR mAbs for the treatment of 
mCRC ........................................................................................................................... 36 
2.4. Rationale for the Study ................................................................................................... 37 
2.5. Design of the trial ........................................................................................................... 37 
2.6. Expected overlapping toxicities ...................................................................................... 38 
2.7. Clinical pharmacokinetic properties and selected dose rationale ................................... 38 
2.8. Known Risks of the Therapeutic Regimen ..................................................................... 39 
3. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 39 
3.1. Primary objective ............................................................................................................ 39 
3.2. Secondary objectives ...................................................................................................... 39 
3.3. Exploratory objectives .................................................................................................... 39 
3.4. Endpoints ........................................................................................................................ 39 
4. STUDY DESIGN ............................................................................................................... 42 
4.1. Investigational Plan ......................................................................................................... 42 
4.1.1. Study plan ..................................................................................................................... 42 
4.1.2. Investigation schedule .................................................................................................. 47 
4.1.3. Safety Lead-In Part ....................................................................................................... 56 
4.1.3.1. 
Dose administration schedule .................................................................................. 56 
4.1.3.2. 
DLT definition ......................................................................................................... 56 
4.1.3.3. 
DLT management .................................................................................................... 57 
4.1.3.4. 
Safety Lead-In and Tolerability Evaluation Procedure ........................................... 58 
4.1.3.5. 
Communication plan between the sponsor and centres ........................................... 60 
4.1.4. Randomised Part ........................................................................................................... 60 
4.2. Measures to minimise bias .............................................................................................. 60 
4.3. Study products and blinding systems.............................................................................. 60 
4.3.1. Products administered .................................................................................................. 61 
4.3.2. IMPs management ........................................................................................................ 62 
4.3.2.1. 
Futuximab/modotuximab ......................................................................................... 63 
4.3.2.2. 
Trifluridine/tipiracil ................................................................................................. 63 
4.3.3. Management of blinding systems ................................................................................. 63 
4.4. Discontinuation of the study or temporary halt .............................................................. 64 
4.4.1. Premature discontinuation of the study or temporary halt ........................................... 64 
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4.4.2. Premature discontinuation of the study in an investigator site (early site closure) ...... 64 
4.4.3. Discontinuation of the study in the event of objective reached .................................... 64 
4.5. Source data ...................................................................................................................... 65 
5. SCREENING AND WITHDRAWAL OF PARTICIPANTS ........................................ 65 
5.1. Screening criteria ............................................................................................................ 65 
5.1.1. Demographic characteristics ........................................................................................ 65 
5.1.2. Medical and therapeutic criteria ................................................................................... 65 
5.1.3. Informed consent .......................................................................................................... 66 
5.2. Non-screening criteria ..................................................................................................... 66 
5.2.1. General criteria ............................................................................................................. 66 
5.3. Inclusion criteria ............................................................................................................. 67 
5.3.1. Medical and therapeutic criteria ................................................................................... 67 
5.4. Exclusion criteria ............................................................................................................ 67 
5.4.1. Medical and therapeutic criteria ................................................................................... 67 
5.5. Definition of women of childbearing potential and contraception methods .................. 69 
5.6. Retest management during screening period .................................................................. 70 
5.7. Additional information recorded at the screening/inclusion visit ................................... 70 
5.8. Participant withdrawal .................................................................................................... 70 
5.8.1. Withdrawal criteria ....................................................................................................... 70 
5.8.2. Procedure ...................................................................................................................... 70 
5.8.3. Lost to follow-up .......................................................................................................... 71 
6. TREATMENT OF PARTICIPANTS .............................................................................. 72 
6.1. IMPs and NIMPs administered ....................................................................................... 72 
6.1.1. Administration of futuximab/modotuximab ................................................................. 72 
6.1.1.1. 
Dose ......................................................................................................................... 72 
6.1.1.2. 
Route of Administration .......................................................................................... 72 
6.1.1.3. 
Schedule ................................................................................................................... 73 
6.1.1.4. 
Diluent and Delivery ................................................................................................ 73 
6.1.1.5. 
Volume of Infusion .................................................................................................. 73 
6.1.1.6. 
Duration of Infusion ................................................................................................ 73 
6.1.1.7. 
Observation requirements ........................................................................................ 73 
6.1.2. Premedication before futuximab/modotuximab administration ................................... 74 
6.1.2.1. 
Premedication for Infusion-Related Reactions ........................................................ 74 
6.1.2.1.1. Infusion-Related Reactions ................................................................................... 74 
6.1.2.1.2. Premedication for IRRs (Beginning with the First Dose) ..................................... 74 
6.1.2.1.3. Premedication for IRRs (following an IRR) ......................................................... 75 
6.1.2.2. 
Premedication for skin toxicity ................................................................................ 75 
6.1.2.3. 
Premedication for other futuximab/modotuximab-related toxicities ....................... 75 
6.1.3. Administration of trifluridine/tipiracil .......................................................................... 75 
6.1.3.1. 
Dose/Route .............................................................................................................. 75 
6.1.3.2. 
Schedule ................................................................................................................... 76 
6.1.4. Premedication for trifluridine/tipiracil ......................................................................... 77 
6.1.5. Retreatment criteria ...................................................................................................... 77 
6.2. IMP and NIMPs dispensing ............................................................................................ 78 
6.3. Previous and concomitant treatments ............................................................................. 78 
6.3.1. Prohibited treatments .................................................................................................... 79 
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6.3.1.1. 
Before the study ....................................................................................................... 79 
6.3.1.2. 
During the study treatment period ........................................................................... 79 
6.3.2. Authorised treatments ................................................................................................... 79 
6.4. IMP compliance .............................................................................................................. 80 
6.5. Discontinuation of the IMP............................................................................................. 80 
7. ASSESSMENT OF EFFICACY ...................................................................................... 81 
7.1. Efficacy measurements ................................................................................................... 81 
7.2. Methods and measurement times .................................................................................... 81 
7.2.1. Measurement times ....................................................................................................... 81 
7.2.2. Method of imaging ....................................................................................................... 81 
7.2.3. Tumour definitions ....................................................................................................... 82 
7.2.3.1. 
Measurable lesions ................................................................................................... 82 
7.2.3.2. 
Non-measurable lesions ........................................................................................... 82 
7.2.3.3. 
Special considerations regarding lesion measurability ............................................ 82 
7.2.4. Documentation of “target” and “non-target” lesions .................................................... 83 
7.2.4.1. 
Target lesions ........................................................................................................... 83 
7.2.4.2. 
Non-target lesions .................................................................................................... 84 
7.2.4.3. 
Response criteria ...................................................................................................... 84 
7.2.4.4. 
Target and Non-target Response Assessments ........................................................ 84 
7.2.4.5. 
New lesions .............................................................................................................. 85 
7.2.4.6. 
Overall Response Assessment ................................................................................. 86 
7.2.5. Best Overall Response Assessment .............................................................................. 86 
8. ASSESSMENT OF SAFETY ........................................................................................... 86 
8.1. Specification of safety parameters .................................................................................. 86 
8.2. Methods and measurement times .................................................................................... 87 
8.2.1. Vital signs ..................................................................................................................... 87 
8.2.2. ECOG Performance Status ........................................................................................... 88 
8.2.3. Physical Examination ................................................................................................... 88 
8.2.4. Height and weight......................................................................................................... 88 
8.2.5. Dermatologic examination (Only for futuximab/modotuximab-treated 
participants (Safety Lead-In part and Arm A of Randomised part) ............................. 89 
8.2.6. Electrocardiogram (ECG) ............................................................................................. 89 
8.2.7. Laboratory Assessments ............................................................................................... 89 
8.2.7.1. 
Haematology ............................................................................................................ 90 
8.2.7.2. 
Biochemistry ............................................................................................................ 90 
8.2.7.3. 
Serum Magnesium, Calcium, and Potassium (Only for 
futuximab/modotuximab-treated participants (Safety Lead-In part and Arm A 
of Randomised part) ................................................................................................ 91 
8.2.7.4. 
Coagulation .............................................................................................................. 91 
8.2.7.5. 
Urinalysis ................................................................................................................. 92 
8.2.7.6. 
Pregnancy Testing ................................................................................................... 92 
8.3. Definition of Adverse events .......................................................................................... 93 
8.4. Definition of Serious adverse events .............................................................................. 94 
8.5. Definition of Overdose ................................................................................................... 94 
8.6. Definition of Adverse event of special interest .............................................................. 94 
8.7. Definition of Events requiring an immediate notification (ERIN) ................................. 95 
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8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) ....... 95 
8.9. Reporting procedures ...................................................................................................... 96 
8.9.1. Time frame for AE reporting ........................................................................................ 96 
8.9.2. Responsibilities of the investigator .............................................................................. 97 
8.9.2.1. 
Documentation of the event ..................................................................................... 97 
8.9.2.2. 
Follow-up of adverse events .................................................................................... 98 
8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP/NIMP by a person 
around the participant) ............................................................................................. 98 
8.9.2.4. 
Recording Methods in the e-CRF ............................................................................ 99 
8.9.2.5. 
Procedure for an event requiring an immediate notification ................................... 99 
8.9.3. Responsibilities of the sponsor ..................................................................................... 99 
8.10. Responsibilities of Data Monitoring Committee .......................................................... 100 
8.11. Management of treatment dose adaptations due to toxicities ....................................... 100 
8.11.1. Management of treatment dose adaptations due to trifluridine/tipiracil toxicities ..... 101 
8.11.2. Management of treatment dose adaptations due to futuximab/modotuximab 
toxicities ..................................................................................................................... 103 
8.11.2.1. Decrease of infusion rate ....................................................................................... 103 
8.11.2.2. Dose Delay ............................................................................................................. 103 
8.11.2.3. Dose Reduction ...................................................................................................... 104 
8.12. Recommendations regarding treatment of toxicities .................................................... 104 
8.12.1. Management of nausea and vomiting ......................................................................... 104 
8.12.2. Management of diarrhoea ........................................................................................... 104 
8.12.3. Management of febrile neutropenia and anaemia ...................................................... 105 
8.12.4. Management of Infusion related reactions ................................................................. 106 
8.12.4.1. Decrease of infusion rate ....................................................................................... 106 
8.12.5. Management of dermatologic toxicity........................................................................ 107 
8.12.6. Management of hypomagnesemia, hypocalcemia, and hypokalemia ........................ 107 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY 
OR SAFETY .................................................................................................................... 107 
9.1. Assessments related to screening/inclusion criteria ...................................................... 107 
9.1.1. Assessments related to inclusion criteria .................................................................... 107 
9.1.1.1. 
Informed consent ................................................................................................... 107 
9.1.1.2. 
Histological/Cytological Confirmation ................................................................. 107 
9.1.1.3. 
KRAS/NRAS/BRAF status ................................................................................... 107 
9.1.2. Assessments not related to inclusion criteria.............................................................. 108 
9.1.2.1. 
Patient Numbering (Only for Randomised part) ................................................... 108 
9.1.2.2. 
ECOG performance status ..................................................................................... 108 
9.1.2.3. 
Medical history ...................................................................................................... 108 
9.1.2.4. 
Previous surgery, radiotherapy and treatments related to the colorectal cancer .... 108 
9.1.2.5. 
Baseline Signs and Symptoms ............................................................................... 108 
9.1.2.6. 
MMR/MSI status ................................................................................................... 108 
9.1.2.7. 
Demography .......................................................................................................... 108 
9.2. Measurement of drug concentration ............................................................................. 108 
9.2.1. Sample Collection Timepoints ................................................................................... 108 
9.2.2. Sampling Methods ...................................................................................................... 109 
9.3. Pharmacodynamic measurements ................................................................................. 110 
9.4. Assessment of biomarkers ............................................................................................ 110 
9.4.1. Mandatory assessment ................................................................................................ 110 
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9.4.1.1. 
Sampling, processing and storage .......................................................................... 110 
9.4.1.2. 
Labelling and transfer to analytical centre ............................................................. 111 
9.4.1.3. 
Transfer of analytical results.................................................................................. 111 
9.4.2. Retrospective analysis ................................................................................................ 111 
9.4.3. Transfer of pharmacogenomics results ....................................................................... 111 
9.4.4. Interpretation .............................................................................................................. 112 
9.5. Immunogenicity ............................................................................................................ 112 
9.6. Quality of Life Assessments (Only for Randomised part) ........................................... 112 
10. 
STATISTICS ............................................................................................................... 113 
10.1. Statistical analysis ......................................................................................................... 113 
10.1.1. Analysis sets / Treatment groups ................................................................................ 113 
10.1.1.1. Analysis sets .......................................................................................................... 113 
10.1.1.2. Treatment groups ................................................................................................... 114 
10.1.2. Statistical methods ...................................................................................................... 114 
10.1.2.1. General considerations ........................................................................................... 114 
10.1.2.2. Disposition and baseline characteristics ................................................................ 114 
10.1.2.3. Treatments of participants ..................................................................................... 114 
10.1.2.4. Efficacy analysis .................................................................................................... 115 
10.1.2.4.1. Safety Lead-In part .............................................................................................. 115 
10.1.2.4.2. Randomised Part .................................................................................................. 115 
10.1.2.4.2.1. Primary estimand based on the OS ................................................................... 118 
10.1.2.4.2.2. Key secondary estimand based on the OS ........................................................ 119 
10.1.2.4.2.3. Supplementary estimand based on OS .............................................................. 120 
10.1.2.4.2.4. Secondary estimands based on PFS, OR, DC, DoR, TTNT, TTR and 
TtPS2 ................................................................................................................. 121 
10.1.2.5. Quality of Life analysis ......................................................................................... 122 
10.1.2.5.1. Analysis ............................................................................................................... 122 
10.1.2.5.1.1. EORTC QLQ-C30 ............................................................................................ 122 
10.1.2.5.1.2. EORTC EQ-5D-5L ........................................................................................... 123 
10.1.2.6. Safety analysis ....................................................................................................... 124 
10.1.2.6.1. Adverse events .................................................................................................... 124 
10.1.2.6.2. Clinical laboratory evaluation ............................................................................. 124 
10.1.2.6.3. Vital signs, clinical examination and other observations related to safety ......... 124 
10.1.2.6.3.1. Vital signs and clinical examination ................................................................. 124 
10.1.2.6.3.2. Electrocardiogram ............................................................................................. 124 
10.1.2.7. Biomarkers analysis ............................................................................................... 125 
10.1.2.8. Interim analysis ...................................................................................................... 125 
10.2. Determination of sample size ....................................................................................... 125 
10.3. Pharmacokinetic analyses and PK/PD analysis ............................................................ 126 
10.3.1. Safety Lead-In part ..................................................................................................... 126 
10.3.2. Randomised Part ......................................................................................................... 126 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................................... 127 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 127 
12.1. Study monitoring .......................................................................................................... 127 
12.1.1. Before the study .......................................................................................................... 127 
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12.1.2. During the study ......................................................................................................... 127 
12.2. Computerised medical file ............................................................................................ 128 
12.3. Audit - Inspection ......................................................................................................... 129 
12.4. Supervisory committees ................................................................................................ 129 
12.4.1. Steering Committee .................................................................................................... 129 
12.4.2. Data Monitoring Committee....................................................................................... 130 
12.4.3. Blinded Independent Central Review (only for Randomised part) ............................ 130 
13. 
ETHICS ....................................................................................................................... 130 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) ................................ 130 
13.2. Study conduct ............................................................................................................... 131 
13.3. Participant information and informed consent .............................................................. 131 
13.4. Modification of the information and consent form ....................................................... 131 
14. 
DATA HANDLING AND RECORD KEEPING ..................................................... 132 
14.1. Study data ..................................................................................................................... 132 
14.2. Data management ......................................................................................................... 133 
14.3. Archiving ...................................................................................................................... 134 
15. 
INSURANCE ............................................................................................................... 134 
16. 
OWNERSHIP OF THE RESULTS - DATA SHARING POLICY AND 
PUBLICATION POLICY .............................................................................................. 134 
17. 
ADMINISTRATIVE CLAUSES ............................................................................... 135 
17.1. Concerning the sponsor and the investigator ................................................................ 135 
17.1.1. Persons to inform ........................................................................................................ 135 
17.1.2. Substantial protocol amendment and amended protocol ............................................ 136 
17.1.3. Final study report ........................................................................................................ 136 
17.2. Concerning the sponsor ................................................................................................ 137 
17.3. Concerning the investigator .......................................................................................... 137 
17.3.1. Confidentiality - Use of information .......................................................................... 137 
17.3.2. Organisation of the centre .......................................................................................... 138 
17.3.3. Documentation supplied to the sponsor ..................................................................... 138 
18. 
REFERENCES ............................................................................................................ 139 
19. 
APPENDICES ............................................................................................................. 142 
 
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List of tables 
Table (3.4) 1 - Endpoints for the Safety Lead-In Part .............................................................. 40 
Table (3.4) 2 - Endpoints for the Randomised part .................................................................. 41 
Table (4.1.2) 1 - CL3-95026-001 Investigation schedule for the Safety Lead-In part ............ 48 
Table (4.1.2) 2 - CL3-95026-001 Investigation schedule for the Randomised part ................ 51 
Table (4.1.3.2) 1 - Dose-limiting toxicity criteria .................................................................... 57 
Table (4.3.1) 1 - Description of the investigational medicinal products .................................. 61 
Table (4.3.1) 2 - Investigational medicinal product packaging ................................................ 61 
Table (6.1.3.2) 1 - Number of tablets of trifluridine/tipiracil per dose (standard dose) 
according to body surface area ................................................................................................. 76 
Table (6.1.3.2) 2 - Number of tablets of trifluridine/tipiracil per dose (reduced dose) 
according to body surface area ................................................................................................. 76 
Table (7.2.4.4) 1 - Target lesions response definitions ............................................................ 84 
Table (7.2.4.4) 2 - Non-target lesions response definitions ..................................................... 85 
Table (7.2.4.6) 1 - Time point response for participants with target, or/and non-target 
disease ...................................................................................................................................... 86 
Table (8.2.7.2) 1 - Correspondence between urea and BUN values ........................................ 91 
Table (8.2.7.5) 1 - Correspondence between qualitative and quantitative proteinuria 
values ........................................................................................................................................ 92 
Table (8.11.1) 1 - Dose interruption and resumption criteria for haematological 
toxicities related to myelosuppression ................................................................................... 102 
Table (8.11.1) 2 - Recommended dose modifications in case of haematological adverse 
event related to myelosuppression ......................................................................................... 102 
Table (8.11.1) 3 - Recommended dose modifications in case of non-haematological 
adverse event related to trifluridine/tipiracil .......................................................................... 102 
Table (8.11.2.3) 1 - Dose reduction of futuximab/modotuximab .......................................... 104 
Table (9.2.1) 1 - Sample collection timepoints for futuximab/modotuximab and 
trifluridine/tipiracil (Pharmacokinetics during the Safety Lead-In and Arm A of 
Randomised part) ................................................................................................................... 109 
Table (9.2.1) 2 - Sample collection timepoints for trifluridine/tipiracil 
(Pharmacokinetics in Arm B of Randomised part) ................................................................ 109 
Table (9.4.1.1) 1 - Biomarker(s) experimental conditions ..................................................... 111 
Table (9.5) 1 - Sample Collection Timepoints for futuximab/modotuximab (during the 
Safety Lead-In and Arm A of Randomised part) ................................................................... 112 
Table (10.1.2.4.2) 1 - Studied estimands ................................................................................ 116 
Table (10.2) 1 - Interim analysis specifications ..................................................................... 126 
 
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List of figures 
Figure (2.2.2) 1 - Kaplan-Meier curve of OS for the futuximab/modotuximab Sym004-
05 patients with DN disease ..................................................................................................... 34 
Figure (4.1.1) 1 - CL3-95026-001 Study Design ..................................................................... 43 
Figure (4.1.1) 2 - Study plan for the Safety Lead-In Part ........................................................ 44 
Figure (4.1.1) 3 - Study plan for the Randomised part ............................................................ 45 
Figure (4.1.3.4) 1 - Safety and tolerability evaluation procedure for dose evaluation in 
the Safety Lead-In part ............................................................................................................. 59 
Figure (8.9.1) 1 - Rules for Adverse Event reporting .............................................................. 97 
 
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List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki ........................................ 143 
Appendix 2: Patient performance status ................................................................................. 149 
Appendix 3: Cockroft formula ............................................................................................... 150 
Appendix 4: New York Heart Association (NYHA) classification ....................................... 151 
Appendix 5: EQ-5D-5L .......................................................................................................... 152 
Appendix 6: EORCT QLQ-C30 ............................................................................................. 153 
Appendix 7: New Response Evaluation Criteria in Solid Tumours: Revised RECIST 
guideline (version 1.1), Eisenhauer, 2009 .............................................................................. 155 
Appendix 8: DATA PROTECTION / GDPR (General Data Protection Regulation of 27 
April 2016 n°2016/679) - ....................................................................................................... 164 
Appendix 9: Management of Infusion-related Reactions ...................................................... 165 
Appendix 10: Management of Dermatologic Adverse Events ............................................... 168 
Appendix 11: Management of Hypomagnesemia .................................................................. 174 
Appendix 12: Maximum Total Blood Collection Volumes ................................................... 175 
Appendix 13: Local modification of the clinical study protocol requested by Danish 
Ethic Committee ..................................................................................................................... 176 
Appendix 14: Local modification of the clinical study protocol requested by China 
Center for Drug Evaluation .................................................................................................... 179 
 
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List of abbreviations 
ABPM 
: Ambulatory Blood Pressure Monitoring 
ADA 
: Anti-Drug Antibody 
ADL 
: Activities of Daily Living 
ADME 
: Absorption Distribution Metabolism Excretion 
AE 
: Adverse Event 
ALT 
: Alanine Aminotransferase 
ANC 
: Absolute Neutrophil Count 
AST 
: Aspartate Aminotransferase 
AUC 
: Area Under the Plasma Concentration-Time Curve 
BICR 
: Blinded Independent Central Review 
BID 
: Twice Daily 
BOR 
: Best Overall Response 
BSA 
: Body Surface Area 
BSC 
 
Best Supportive Care 
BPM 
: beats per minute 
BUN 
: Blood Urea Nitrogen 
CFR 
: Code of Federal Regulations 
CISO 
: Chief Information Security Officer 
Cmax 
: Maximum Plasma Concentration 
CMH 
: Cochran-Mantel-Haenszel 
CMP 
: Clinical Monitoring Plan 
CNS 
: Central Nervous System 
CR 
: Complete Response 
CRC 
: Colorectal Cancer 
ctDNA 
: Circulating tumour DNA 
CT 
: Computerized Tomography 
CV 
: Curriculum Vitae 
DAP 
: Data Analysis Plan 
DCR 
: Disease Control Rate 
DDI 
: Drug-Drug Interaction 
DLT 
: Dose-Limiting Toxicity 
DMC 
: Data Monitoring Committee 
DN 
: Double-Negative 
DoR 
: Duration Of Response 
DPO 
: Data Protection Officer 
ECD 
: Extracellular Domain 
ECG 
: Electrocardiogram 
e-COA 
: Electronic Clinical Outcome Assessment 
ECOG 
: Eastern Cooperative Oncology Group 
e-CRF 
: Electronic Case Report Form 
EEA 
: European Economic Area 
EGFR 
: Epidermal Growth Factor Receptor 
EMA 
: European Medicines Agency 
EoI 
: End of Infusion 
EORTC 
: European Organization For Research And Treatment Of Cancer 
e-PRO 
: Electronic Participant-Reported Outcomes 
ERIN 
: Event Requiring Immediate Notification 
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ESMO 
: European Society for Medical Oncology 
FAS 
: Full Analysis Set 
FDA 
: Food and Drug Administration 
FDG 
: Fluorodeoxyglucose 
GCP 
: Good Clinical Practice 
GDPR 
: General Data Protection Regulation 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
GHS 
: Global Health Status 
HER 
: Human Epidermal Growth Factor Receptor 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HIV 
: Human Immunodeficiency Virus 
HR 
: Hazard Ratio 
HRT 
: Hormone Replacement Therapy 
I.R.I.S. 
: Institut De Recherches Internationales Servier 
IB 
: Investigator’s Brochure 
IC 
: Investigator’s Choice 
ICF 
: Informed Consent Form 
ICH 
: International Council For Harmonisation Of Technical Requirements For 
Pharmaceuticals For Human Use 
IE 
: Intercurrent Event 
IEC 
: Independent Ethics Committee 
IMP 
: Investigational Medicinal Product  
INR 
: International Normalized Ratio 
IRB 
: Institutional Review Board 
IRR 
: Infusion-Related Reaction 
ITT 
: Intention-To-Treat 
IV 
: Intravenous (Route) 
IWRS 
: Interactive Web Response System 
JSCCR 
: Japanese Society for Cancer of The Colon And Rectum 
LDH 
: Lactate Dehydrogenase 
LLN 
: Lower Limit of Normal 
MA 
: Marketing Authorisation 
LVEF 
: Left Ventricular Ejection Fraction 
MAF 
: Mutant Allele Frequency 
MASCC 
: Multinational Association of Supportive Care In Cancer 
MedDRA 
: Medical Dictionary f or Regulatory Activities 
MMR 
: Mismatch Repair 
MoA 
: Mechanism of Action 
MRI 
: Magnetic Resonance Imaging 
MSI 
: Microsatellite Instability 
MTD 
: Maximum Tolerated Dose 
NCI-CTCAE 
: National Cancer Institute - Common Terminology Criteria For Adverse 
Events 
NE 
: Not Evaluable 
NIMP 
: Non-Investigational Medicinal Product  
NYHA 
: New York Heart Association 
OR 
: Objective Response 
ORR 
: Objective Response Rate 
OS 
: Overall Survival 
PABA 
: Para-Aminobenzoic Acid 
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PD 
: Progressive Disease 
PFS 
: Progression Free Survival 
PK 
: Pharmacokinetics 
PMDA 
: Pharmaceuticals and Medical Devices Agency 
PO 
: Orally 
PPS 
: Per Protocol Set 
PR 
: Partial Response 
PRO 
: Participant-Reported Outcome 
PS 
: Performance Status 
PTT 
: Partial Thromboplastin Time 
QoL 
: Quality of Life 
QTc 
: Corrected QT Interval 
RBC 
: Red Blood Cells 
RECIST 
: Response Evaluation Criteria In Solid Tumours 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SARS 
: Severe Acute Respiratory Syndrome 
SC 
: Steering Committee 
SD 
: Stable Disease 
SOC 
: System Organ Class 
SmPC 
: Summary of Product Characteristics 
SPF 
: Sun Protection Factor 
STEAEs 
 
Serious Treatment Emergent Adverse Events 
TdP 
: Torsade De Pointes 
TEAE 
: Treatment Emergent Adverse Event 
TK 
: Thymidine Kinase 
TMDD 
: Target-Mediated Drug Disposition 
TtPS2 
: Time to ECOG Performance Status ≥ 2 
TTNT 
: Time To Next Treatment 
TTR 
: Time To Response 
ULN 
: Upper Limit of Normal 
US 
: United States 
VEGF 
: Vascular Endothelial Growth Factor 
WBC 
: White Blood Cells 
WHO 
: World Health Organization 
WHO-Drug 
: World Health Organization, Drug Dictionary 
WMA 
: World Medical Association 
WNL 
: Within Normal Limits 
WOCBP 
: Woman Of Child Bearing Potential 
WT 
: Wild Type 
WV 
: Withdrawal Visit 
 
 
 
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1.
ADMINISTRATIVE STRUCTURE OF THE STUDY
Non-sponsor parties, sponsor parties and contract research organizations responsible for local 
management of the study are described in a separate document entitled: “Administrative part 
of clinical study protocol.”  
The list of investigators is given in a separate document attached to the protocol and entitled 
“Investigators list.” 
The composition and role of the supervisory committees are described in Sections 8.10 and 
12.4. 
2.
BACKGROUND INFORMATION
2.1. Metastatic Colorectal Cancer
Colorectal cancer (CRC) is the third most common cancer type in the world in terms of 
incidence and the second one in terms of mortality, with an estimated 1,800,000 new cases and 
881,000 deaths in 2018.1  
Approximately 25% of patients present with metastases at initial diagnosis and approximately 
50% of patients with early-stage disease will develop metastases, which contribute to the high 
mortality rates reported for CRC.2  
Therapy for patients with metastatic CRC (mCRC) has mostly palliative intention, except for 
patients with limited metastatic disease in the liver for whom a surgical approach with curative 
intent may be used. Systemic therapy for mCRC typically pairs a chemotherapy backbone 
regimen with a biologic agent. Oxaliplatin, irinotecan and 5-fluorouracil commonly form the 
chemotherapy backbone in various regimens of two-drug or three-drug regimens. A biologic 
agent such as anti-vascular endothelial cell growth factor (VEGF) or anti-epidermal growth 
factor receptor (EGFR) antibody is added to the chemotherapy regimen depending on tumour-
specific and patient-specific factors. Molecular testing of the tumour is required before 
considering treatment with anti-EGFR antibodies such as cetuximab and panitumumab. 
Mutations in hot spot regions of 
 of KRAS or of NRAS genes (occurring in 
approximately 55% of mCRC patients) and the BRAF-
 (occurring in 
approximately 5-15% of mCRC patients) have been associated with lack of benefit from anti-
EGFR treatment.3-5 Additionally, “sidedness” of the tumour has a key role in the metastatic 
setting and is increasingly recognised as a predictive marker of response to anti-EGFR drugs, 
with left sided tumours demonstrating better outcome.2 
Participants with mCRC typically receive several lines of therapy. In clinical practice, of all 
mCRC patients receiving first-line chemotherapy, approximately 50% go on to receive second 
line chemotherapy, and of these patients, approximately 25% go on to receive third-line 
chemotherapy.6 This “continuum of treatment” with several subsequent lines of therapy has led 
to an improvement of the clinical outcome for patients with mCRC, in the last decade. Today, 
the median overall survival (OS) for patients with mCRC is approximately 30 months; more 
than double that of 20 years ago.7 
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Most patients with mCRC will eventually become insensitive or unresponsive to first- and 
second-line chemotherapy (chemo-refractory) or will not tolerate multiple cycles of 
chemotherapy (chemo-intolerant). The treatment options available in chemo-refractory mCRC 
in the third-line setting are limited. Regorafenib (STIVARGA®) received United States (US) 
Food and Drug Administration (FDA) approval in 2012, and European Medicines Agency 
(EMA) approval in 2013; trifluridine/tipiracil (TAS-102, LONSURF®)8 received 
Pharmaceuticals and Medical Devices Agency (PMDA) approval in 2014, FDA approval in 
2015 and EMA approval in 2016. Both treatments are approved in Europe for patients with 
mCRC “who have been previously treated with, or are not considered candidates for, available 
therapies” including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-
VEGF agents and, anti-EGFR agents. Regorafenib and trifluridine/tipiracil represent the 
standard of care options for patients with mCRC in the third-line setting,7,9 producing an 
expected median OS of 6.4 months and 7.1 for regorafenib10 and trifluridine/tipiracil,11 
respectively. For patients with wild-type (WT) RAS not previously treated with anti-EGFR 
antibodies in the third-line/salvage therapy setting, cetuximab in combination with irinotecan 
or panitumumab monotherapy can also be considered.12 
2.2.  Futuximab/modotuximab 
Futuximab/modotuximab (also known as S95026 or Sym004) is a biological compound 
composed of a 1:1 mixture (by concentration) of two monoclonal antibodies, futuximab and 
modotuximab, both of which bind to non-overlapping epitopes on the extracellular domain 
(ECD) of the EGFR. The two drug substances (futuximab and modotuximab) have the same 
formulation and protein concentration in futuximab/modotuximab and the drug product is 
released as a mixture of the antibodies. 
Futuximab is a chimeric IgG1 mAb that contains two light chains of 214 amino acid residues 
each and two heavy chains of 452 amino acid residues each, and a theoretical molecular weight 
of 149180 Da. Modotuximab is a chimeric IgG1 mAb that contains two light chains of 
219 amino acid residues each and two heavy chains of 448 amino acid residues each, and a 
theoretical molecular weight of 149325 Da. 
The dosage form of futuximab/modotuximab is a sterile, liquid product, it is further diluted at 
the participant level into a specific total volume using 0.9% sodium chloride for injection. 
The route of administration is an intravenous infusion (IV) with a maximum infusion rate of 
500 mL/hour. This maximum infusion rate should not be exceeded throughout the 
administration. Futuximab/modotuximab is administered on a weekly basis at a recommended 
dose of 9 mg/kg on Cycle 1 Day 1 (C1D1) (loading dose) and then at a 6 mg/kg weekly 
beginning on C1D8 (maintenance doses). 
2.2.1. 
Non-clinical development 
Futuximab/modotuximab was identified through a phenotypic screen of hundreds of anti-EGFR 
antibody mixtures searching for a synergistic mixture with superior growth inhibitory activity 
compared to individual monoclonal antibodies.13 The mixture of modotuximab and futuximab 
was discovered to be the most synergistic antibody mixture tested. The two antibodies had little 
inhibitory activity on their own and thus are highly synergistic when combined.14 
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Mechanistic studies of futuximab/modotuximab demonstrated that the superior activity of 
futuximab/modotuximab was achieved by induction of effective internalisation and subsequent 
degradation of EGFR as shown in a range of cancer cell lines of different tissue origin.14,15 The 
effective internalisation and degradation were only obtained when both full-length antibodies 
were present and the superior activity of futuximab/modotuximab was lost when either of the 
two antibodies were replaced with a Fab fragment.14 Efficient removal of the receptor from the 
cancer cell has the advantage of eliminating all interactions of EGFR with other proteins such 
as EGFR ligands, other members of the human epidermal growth factor receptor (HER) family 
(HER2 and HER3) and other cell surface receptors. This mechanism of action (MoA) is critical 
to the therapeutic potential of futuximab/modotuximab as compensatory upregulation of EGFR 
ligands and cross-talk with HER2 and HER3 are common mechanisms of primary and acquired 
resistance to anti-EGFR antibodies in clinical use.16 In line with this, futuximab/modotuximab, 
but not the individual mAbs futuximab or modotuximab, has the ability to inhibit cancer cells 
in settings of cetuximab/panitumumab resistance where clinically, other anti-EGFR antibodies 
have failed.16-18 
The efficient removal of EGFR from cancer cells in vitro translated into a superior 
futuximab/modotuximab anti-tumour response in vivo in preclinical models, compared to 
individual antibodies and reference antibodies13,14. The efficacy of futuximab/modotuximab 
was tested in several xenograft models and found to be superior in many of these models as 
compared to approved monoclonal antibody therapies, such as cetuximab and panitumumab. 
Futuximab/modotuximab was clearly superior to both futuximab and modotuximab 
monotherapy in vivo, indicating that the futuximab/modotuximab synergy observed in vitro 
also translated to in vivo studies.14  
The nonclinical safety profile of futuximab/modotuximab was extensively characterised in 
cynomolgus monkeys and included a side-by-side comparison with cetuximab in dose-range 
finding studies and a side-by-side comparison with futuximab and modotuximab in the Good 
Laboratory Practice 8-week toxicology study. Futuximab and modotuximab, bind to EGFR 
from human and cynomolgus monkeys with similar affinity. Futuximab/modotuximab is 
cleared faster than the individual antibodies in the monkeys, reflecting a more efficient target-
mediated drug disposition in the presence of both antibodies, which again reflects the 
synergestic MoA described in vitro and in vivo. 
The general higher incidence and severity of skin and gastrointestinal toxicity in the toxicology 
studies suggest that futuximab/modotuximab exerts a greater pharmacological effect than the 
individual antibodies, futuximab and modotuximab, at the same dose level. As compared to 
cetuximab, futuximab/modotuximab induced a more rapid onset of expected anti-EGFR-
mediated pharmacological effects (toxicity). Importantly, futuximab/modotuximab did not 
demonstrate any novel safety findings not previously observed with cetuximab in cynomolgus 
monkeys. 
In conclusion, non-clinical studies support extensive EGFR down-modulation as a novel MoA 
for futuximab/modotuximab that is different from that of approved anti-EGFR monoclonal 
antibodies. The EGFR down-regulation by futuximab/modotuximab is only achieved when 
both antibodies (futuximab and modotuximab) are present as shown both in vitro and in vivo 
and these consistent findings provide a clear rationale for evaluating futuximab/modotuximab 
as a fixed mixture in clinical trials with human EGFR-positive cancers. 
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2.2.2. 
Clinical development 
Phase 1 study  
The futuximab/modotuximab Sym004-01 was a Phase 1 dose escalation study that included a 
total of 111 patients (20 patients with refractory or recurrent advanced solid tumours in the 
Phase 1a dose escalation part and 91 patients with heavily pre-treated mCRC and acquired 
resistance to previous anti-EGFR therapy into five Phase 2 dose expansion cohorts). The 
recommended Phase 2 dose (R2PD) levels of two regimens of futuximab/modotuximab were 
defined based on safety and tolerability and were identified as 12 mg/kg when administered 
weekly and 18 mg/kg when administered on a every two weeks schedule. The adverse effect 
profile was similar to that observed with previously studied anti-EGFR mAbs with no novel 
safety findings identified, although cutaneous toxicity and hypomagnesemia were observed 
more frequently and were more severe in patients treated with futuximab/modotuximab at the 
R2PD on each of these schedules. This apparent difference in the AE profile may be due to 
differences in the doses or schedule of futuximab/modotuximab utilised, differences due to its 
unique MoA, or to the potential enrichment for patients likely to manifest these specific AEs. 
As it has been documented in other studies, cutaneous AEs and hypomagnesemia have been 
shown to be associated with responsiveness to anti-EGFR therapies,19,20 and the patients studied 
in cohorts B-F were selected based on documented development of refractoriness following 
prior response to or prolonged disease stabilisation (> 16 weeks) while receiving one or more 
of the available anti-EGFR mAbs (cetuximab, panitumumab) approved for the treatment of 
mCRC. 
Two dosage regimens cohorts (Parts B: 12 mg/kg weekly and F: 9 mg/kg loading dose followed 
by 6 mg/kg weekly) were chosen for further evaluation in subsequent trials. Confirmed 
objective response rate was 6.9% (2/29 patients) and 0% (0/20 patients) with 12 mg/kg and 
9/6 mg/kg dose regimens, respectively. 
Phase 2 study 
The futuximab/modotuximab Sym004-05 is an open-label, randomised, controlled, multicentre, 
Phase 2 trial that enrolled 254 patients with mCRC cancer refractory or intolerant to 
chemotherapy (5-FU, irinotecan and oxaliplatin), who had responded to and progressed on prior 
anti-EGFR mAb therapy (i.e. acquired resistance to anti-EGFR mAbs).  
Patients were randomly assigned in a 1:1:1 ratio to either of two dose regimens of 
futuximab/modotuximab, 12 mg/kg weekly (Arm A; 83 patients, 83 treated), loading dose of 
9 mg/kg on Day 1 followed by maintenance dose of 6 mg/kg weekly beginning on Day 8 
(Arm B; 86 patients, 84 treated), or to a control group treated with the investigator`s choice (IC) 
therapy of capecitabine (61 patients), 5-FU (13 patients), or Best Supportive Care (BSC) (4 
patients) (Arm C; 85 patients, 78 treated). The primary endpoint of the study was OS.  
The primary endpoint was not met. Median OS in the intention-to-treat (ITT) population was 
7.9 months (95% CI, 6.5-9.9), 10.3 months (95% CI, 9.0-12.9), and 9.6 months (95% CI, 
8.3-12.2) for arms A, B and C, respectively (HR, 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 
0.97; 95% CI, 0.68-1.4 for B vs C). Median PFS in the ITT population was 2.8 months (95% 
CI, 1.8-3.2), 2.7 months (95% CI, 2.6-3.3), and 2.6 months (95% CI, 1.4-3.1) for arms A, B, 
and C, respectively. 
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Response rates for evaluable patients in the ITT population were 11 PRs (14.1%), 8 PRs (9.6%), 
and 1 complete response (CR) and 1 PR (2.9%) in arms A, B and C, respectively. A per protocol 
analysis excluded patients from Russia as these patients were less refractory to standard 
EGFR mAb and considered more sensitive to therapy. For these reasons, this population was 
excluded from further analysis. 
Baseline ctDNA mutation profiles of 70 genes (Guardant Health360 V2.9) were obtained from 
blood samples collected from 193 patients in the trial. An exploratory analysis of efficacy was 
carried out in a genomically defined subpopulation, which excluded patients with clonal RAS 
(KRAS/NRAS) and BRAF 
 (named double-negative [DN] mCRC; n = 170). 
This exploratory biomarker defined analysis showed an increase in median OS of 3.5 months 
in the DN mCRC population of patients treated with futuximab/modotuximab 9/6 (arm B; 
11.9 months) compared with patients randomised to IC (Arm C; 8.4 months) (Figure (2.2.2) 1). 
Figure (2.2.2) 1 - Kaplan-Meier curve of OS for the futuximab/modotuximab Sym004-05 patients 
with DN disease 
 
The futuximab/modotuximab AE profile was consistent with other anti-EGFR mAbs, although 
the frequency and severity of both dermatologic AEs (94.0% and 92.9% for arms A and B, 
respectively, compared with 10.3% in the IC arm) and hypomagnesemia (68.7% and 56.0%f or 
arms A and B, respectively, compared with 7.7% in the IC arm) were higher than those found 
with other approved anti-EGFR mAb therapies. In contrast, the frequency of gastrointestinal 
AEs appeared to be lower than has been reported for other anti-EGFR mAbs (51.8% and 48.8% 
for arms A and B, respectively, compared with 47.4% in IC arm). Treatment with both regimens 
of futuximab/modotuximab was less well tolerated than the heterogeneous standard treatments 
administered to patients on the IC arm. Treatment Emerging AEs (TEAEs), related TEAEs, 
serious TEAEs, > Grade 3 related TEAEs, and treatment-related Serious AEs (SAEs) were 
more frequent in patients receiving either dose of futuximab/modotuximab compared to patients 
in the IC treatment group. The futuximab/modotuximab regimen of 12 mg/kg (12) weekly was 
less well tolerated than the 9 mg/kg loading dose followed by a 6 mg kg (9/6) weekly dosing 
schedule. 
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Compared to patients on the 9/6 arm (Arm B), patients receiving 12 mg/kg of 
futuximab/modotuximab had more serious TEAEs (32.5% vs 27.4%), TEAEs leading to dose 
reduction (34.9% vs 20.2%), TEAEs leading to treatment discontinuation (14.5% vs 6%), and 
> Grade 3 related TEAEs (69.9% vs 48.8%). 
2.2.3. 
Clinical pharmacokinetic properties 
The noncompartmental analysis and the population PK model found that the PK of 
futuximab/modotuximab was non-linear which is typical for mAb where target-mediated drug 
disposition (TMDD) impacts the elimination. Indeed, the observed half-life increased with the 
dose which was less than 2 days for dose levels of 3 mg/kg and below, whereas for dose levels 
of 6 mg/kg and above the half-life was 3-6 days. At dose levels of 6 mg/kg and above, the dose-
normalised AUCtau was constant, suggesting that the TMDD was close to saturation. For weekly 
dosing of 6 mg/kg and higher, futuximab/modotuximab accumulated approximately 2-fold 
from the first to the 3rd/4th dose. But, a lower accumulation (<= 1.3-fold) for the 9/6 mg/kg 
regimen was observed, indicating that steady state was reached after the first doses, which is 
expected with a loading dose followed by a maintenance dose. 
Drug-drug interaction 
As 
PK-related 
drug-drug 
interaction 
(DDI) 
between 
trifluridine/tipiracil 
and 
futuximab/modotuximab are unlikely to occur, no dose adjustment is required when co-
administered. 
Trifluridine is metabolized by Thymidine Phosphorylase (TPase) and transported by the 
nucleoside transporters CNT1, ENT1 and ENT2; while Tipiracil is not metabolized (neither in 
human liver S9 nor cryopreserved hepatocytes) and is a substrate for OCT2 and MATE1 
transporters. As a mixture of the two monoclonal antibodies futuximab and modotuximab, 
futuximab/modotuximab is not expected to interact with TPase, OCT2, MATE1 or nucleoside 
transporters. Therefore, futuximab/modotuximab is unlikely to have a significant effect on 
Trifluridine and Tipiracil metabolic clearance or transport. 
The clearance of the monoclonal antibodies futuximab and modotuximab is mainly driven by 
TMDD as a consequence of their binding to the target EGFR and subsequent internalisation 
and degradation into small peptides and amino acids. Therefore, trifluridine/tipiracil is unlikely 
to have a significant impact on futuximab/modotuximab PK. 
2.2.4. 
Rationale for selected dose 
From the Phase 2b Sym004-05 study, the futuximab/modotuximab regimen of 12 mg/kg (12) 
weekly was less well tolerated than the 9/6 mg/kg regimen. Compared to patients on the 
9/6 arm, patients receiving 12 mg/kg of futuximab/modotuximab had more serious Treatment 
Emerging AEs (TEAEs) (32.5% vs 27.4%), TEAEs leading to dose reduction (34.9% vs 
20.2%), TEAEs leading to treatment discontinuation (14.5% vs 6.0%), and > Grade 3 related 
TEAEs (69.9% vs 48.8%). Efficacy results from Sym004-05 were consistent with results of the 
study Sym004-01 for these 2 dose regimens (12 mg/kg and 9/6 mg/kg). The proportion of 
patients achieving objective responses (OR) on the 12 mg/kg weekly regimen in both the 
Sym004-01 expansion part (29 patients, 6.9% ORR) and in Sym004-05 (83 patients, 14.1% 
ORR) was higher than in patients treated on the 9/6 regimen (20 patients, 0% ORR in 
Sym004-01 and 86 patients, 9.6% ORR in Sym004-05). In contrast OS was longer for the 9/6 
mg/kg regimen than the 12 mg/kg regimen in primary analysis sets in both studies (9.6 vs 
6.9 months in Sym004-01 and 10.3 vs 7.9 months in Sym004-05). 
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The results of both trials document that the 9/6 regimen was better tolerated and resulted in 
more robust evidence of anti-tumour efficacy than observed in patients treated with the higher 
weekly doses of 12 mg/kg. 
The proposed futuximab/modotuximab dose regimen for the study CL3-95026-001 (9 mg/kg 
followed by 6 mg/kg weekly dosing) was selected as the optimal dose regimen based on a 
benefit-risk assessment of available clinical data. In addition, the PK evaluation indicates that 
the target is saturated within the one-week dosing interval with this dose regimen. 
2.3. Trifluridine/tipiracil in third-line mCRC 
2.3.1. 
Trifluridine/tipiracil as single-agent in third treatment of mCRC 
Trifluridine/tipiracil is approved by EMA, FDA and the Pharmaceuticals and Medical Devices 
Agency for the treatment of adult patients with mCRC who have been previously treated with, 
or are not considered candidates for, available therapies including fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and, anti-EGFR 
agents.7,9,21 
The approved indication in European Union was supported by the results of the global Phase 3 
study (RECOURSE). TPU-TAS-102-301 (RECOURSE) study was a multinational, double-
blind, two-arm, parallel-group, randomised, Phase 3 study evaluating the efficacy and safety of 
trifluridine/tipiracil plus BSC vs placebo plus BSC in Western (EU, USA and Australia) and 
Japanese patients with refractory mCRC who had failed previous treatment with standard 
chemotherapies.11 The study randomly assigned 800 patients, in a 2:1 ratio, to receive 
trifluridine/tipiracil or placebo with OS as primary endpoint. The median OS improved from 
5.3 months with placebo to 7.1 months with trifluridine/tipiracil, and the HR for death in the 
trifluridine/tipiracil group versus the placebo group was 0.68 (95% confidence interval [CI], 
0.58 to 0.81; P < 0.001). 
2.3.2. 
Trifluridine/tipiracil in combination with anti-EGFR mAbs for the treatment of 
mCRC 
APOLLON was an investigator-sponsored, open-label, single-arm Phase 1/2 study that 
evaluated the efficacy and safety of panitumumab in combination with trifluridine/tipiracil in 
patients with KRAS/NRAS WT mCRC, EGFR-naïve and refractory to standard therapy 
(fluoropyrimidines, irinotecan, oxaliplatin or anti-angiogenesis therapy).22 Fifty-six patients 
were treated with panitumumab 6 mg/kg on Days 1 and 15, every 4 weeks (Q4W) and 
trifluridine/tipiracil at 35 mg/m² twice daily (BID) on Days 1–5 and 8–12, Q4W. No dose-
limiting toxicities (DLT) occurred in Phase 1 and the recommended dose was determined to be 
6 mg/kg for panitumumab and 35 mg/m2 for trifluridine/tipiracil. In Phase 2 part, the PFS rate 
at 6 months (n = 54) was 33.3% (90% CI: 22.8–45.3; p = 0.24), and median PFS and OS were 
5.8 months (95% CI: 4.5–6.5) and 14.1 months (95% CI: 12.2–19.3), respectively. The response 
rate and disease control rate were 37.0% and 81.4%, respectively. The most common Grade 3 
or higher AEs (n = 55) were neutropenia (10.9%), febrile neutropenia (9.1%), stomatitis (9.1%), 
and dermatitis acneiform (9.1%). There were no treatment-related deaths or unexpected safety 
signals. 
The WJOG8916G trial evaluated the efficacy and safety of concomitant administration of 
cetuximab (anti-EGFR antibody) and trifluridine/tipiracil in patients with mCRC who had been 
previously treated with irinotecan, oxaliplatin, fluoropyrimidine, and anti-angiogenic therapy 
and were refractory to anti-EGFR antibody (re-challenge strategy).23 The study did not 
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demonstrate any new safety signal with the combination and AEs observed were the AEs of 
each single agent. The study had only one dose level tested (full dose of trifluridine/tipiracil 
and full dose of cetuximab, as per the EMA summary of product characteristics8,24,25) in the 
safety cohort of 6 patients and according to the protocol no observation period was imposed 
between enrolment of each patient. According to the protocol in the safety part of the initial 6 
patients, if a DLT was observed in > 3/6 patients, the initial doses would be reconsidered. Out 
of 6 patients, only 1 DLT was observed, so the trial continued as planned. Overall, 56 patients 
were included and treated at the planned dose. The most frequently reported AEs were anaemia, 
dermatitis acneiform, hypomagnesemia, neutropenia, dry skin, platelet count decreased, 
fatigue, and decreased appetite. The most frequent Grade 3 or higher AEs were neutropenia 
(55%), anaemia (30%) and hypomagnesemia (16%). No new safety signals were observed with 
the combination treatment, and the observed AEs were similar to those observed with each 
single agent.  
2.4. Rationale for the Study 
Acquired resistance to anti-EGFR antibodies in mCRC is caused by both genomic and non-
genomic mechanisms. Emergence of clones with mutations in KRAS, NRAS or BRAF are 
common and confer resistance to anti-EGFR therapies as in the primary resistance setting.26 
However, a significant portion of patient tumours will remain dependent on the EGFR pathway 
and second-generation EGFR targeting agents such as futuximab/modotuximab has been 
designed to address these resistance mechanisms. The Sym004-05 study has evaluated the 
potential of futuximab/modotuximab to overcome acquired resistance to approved anti-EGFR 
mAbs in mCRC and has demonstrated encouraging results in a subgroup of molecularly 
selected patients with KRAS/NRAS and BRAF WT mCRC. To further improve the anti-tumour 
activity in this patient population the strategy is to combine futuximab/modotuximab with 
trifluridine/tipiracil. The combination of anti-EGFR antibodies and trifluridine/tipiracil has 
been explored in several pre-clinical CRC models and demonstrated synergistic or additive 
activity.27,28 Moreover, trifluridine/tipiracil can be safely combined with anti-EGFR therapies 
with encouraging efficacy, as demonstrated by the APOLLON and the WJOG8916G studies. 
22,23 
Servier plans to develop futuximab/modotuximab (investigational medicinal product [IMP]) in 
combination with trifluridine/tipiracil to provide a new third-line or later treatment option for 
patients with KRAS/NRAS and BRAF WT mCRC previously treated with chemotherapy 
(including oxaliplatin, irinotecan and 5-fluorouracil, anti-VEGF agents) and with anti-EGFR 
mAb therapy for ≥ 16 weeks, or not considered candidates for available therapies including 
fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies and anti-VEGF agents. 
Trifluridine/tipiracil is a standard of care option in that setting and is an approved agent in the 
EU, US, and Japan.7,9,21 
2.5. Design of the trial 
CL3-95026-001 is an international, randomised, open label, multi-centre, two-arm Phase 3 
study to evaluate futuximab/modotuximab in combination with trifluridine/tipiracil versus 
trifluridine/tipiracil monotherapy in participants ≥ 18 years of age with KRAS/NRAS and 
BRAF WT mCRC who were previously treated with chemotherapy (including oxaliplatin, 
irinotecan and 5-fluorouracil, anti-VEGF agents) and with anti-EGFR mAb therapy for 
≥ 16 weeks. The study will comprise two parts- a Safety Lead-In part with approximately 
25 participants and a Randomised part with approximately 500 participants.  
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The safety of trifluridine/tipiracil in combination with anti-EGFR antibody (panitumumab and 
cetuximab) was judged as acceptable in previous trials22,23; however, the safety of the 
combination of trifluridine/tipiracil and futuximab/modotuximab has not been evaluated. Study 
CL3-95026-001 will therefore begin with a safety and tolerability assessment prior to dosing in 
the Randomised part of the study. A similar approach with a Safety Lead-In part for safety 
evaluation was incorporated into the design of other Phase 3 studies recently in patients with 
mCRC.29 
CL3-95026-001 is an open label study. Given the immediately identifiable differences in the 
toxicity profiles of trifluridine-tipiracil and futuximab/modotuximab, it is not possible to 
conduct a blinded study. The high incidence of dermatological AEs in the 
futuximab/modotuximab plus trifluridine-tipiracil arm compared with the lack of 
dermatological events in the trifluridine-tipiracil single-agent arm, will allow the differentiation 
of the two treatment arms even in the case a blinded design is used.  
Another important issue is related to the differences in the route of administration in both study 
arms. The experimental arm includes an oral drug and an IV administered drug, while the 
control arm includes only an oral drug. Given the type of population included, i.e., patients with 
metastatic colorectal cancer, we consider unethical to subject patients to additional risk of harm 
or even to uncomfortable conditions such as administration of a dummy IV drug, at this stage 
of life. 
2.6. Expected overlapping toxicities  
Considering the safety profile of futuximab/modotuximab (skin toxicities, hypomagnesemia, 
infusion-related reactions and gastro-intestinal disorders) and the one of trifluridine/tipiracil 
(bone marrow suppression especially neutropenia, gastro-intestinal disorders such as diarrhoea, 
nausea and vomiting), the potential risks of the combination could be an increased risk of skin 
infections and of gastro-intestinal disorders. 
2.7. Clinical pharmacokinetic properties and selected dose rationale 
Trifluridine is metabolized by Thymidine Phosphorylase (TPase) and transported by the 
nucleoside transporters CNT1, ENT1 and ENT2 while tipiracil is not metabolized (neither in 
human liver S9 nor in cryopreserved hepatocytes) and is a substrate for OCT2 and MATE1 
transporters.8 As described for other monoclonal antibodies, the clearance of futuximab and 
modotuximab is expected to be mainly driven by TMDD as a consequence of their binding to 
the target EGFR and subsequent internalisation and degradation into small peptides and amino 
acids  
Based on their non-overlapping PK properties, PK-related DDI between trifluridine/tipiracil 
and futuximab/modotuximab (futuximab and modotuximab) are unlikely to occur. Therefore, 
no dose adjustment is required when co-administered. 
Overall, the proposed futuximab/modotuximab dose regimen for the study CL3-95026-001 
(9 mg/kg followed by 6 mg/kg weekly dosing) was selected as the optimal dose regimen based 
on a benefit-risk assessment of available clinical data. In addition, the PK evaluation indicates 
that the target is saturated within the one-week dosing interval with this dose regimen. 
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2.8. Known Risks of the Therapeutic Regimen 
In the dose-expansion part of the Phase 1 Sym004-01 study, 20 patients with heavily pre-treated 
mCRC were treated with the 9/6 regimen of futuximab/modotuximab. All 20 patients 
experienced an AE of “skin and subcutaneous disorders” (58 AEs in 20 patients, 100.0%). The 
most frequently experienced AEs in this system organ class (SOC) were rash (18 patients, 
90.0%) and skin fissures (10 patients, 50.0%). Additionally, 18 events of hypomagnesemia 
(11 patients, 55.0%), were reported. 
In the randomised Phase 2 Sym004-05 study, a total of 84 pre-treated mCRC patients were 
included in the 9/6 arm. A total of 78 patients (93%) experienced an AE of “dermatological 
toxicity”, while 47 patients (56%) were reported with any Grade of hypomagnesemia AE. 
Additional details are provided in the futuximab/modotuximab Investigator’s Brochure. 
Neither dermatological toxicity, nor hypomagnesemia are reported as common toxicities of 
single-agent trifluridine/tipiracil; the most frequently observed adverse drug reactions (≥ 30%) 
in patients receiving trifluridine/tipiracil are neutropenia (53% [34% ≥ Grade 3]), nausea (34% 
[1% ≥ Grade 3]), fatigue (32% [4% ≥ Grade 3]) and anaemia (32% [12% ≥ Grade 3]).8  
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
the ethical principles that have their origin in the Declaration of Helsinki Appendix 1 and the 
applicable regulatory requirements. 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. Primary objective 
Please refer to Table (3.4) 1 and Table (3.4) 2. 
3.2. Secondary objectives 
Please refer to Table (3.4) 1 and Table (3.4) 2. 
3.3. Exploratory objectives 
Please refer to Table (3.4) 1 and Table (3.4) 2. 
3.4. Endpoints 
The study endpoints for the Safety Lead-In and Randomised parts are listed in Table (3.4) 1 
and Table (3.4) 2 respectively.  
 
 
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Table (3.4) 1 - Endpoints for the Safety Lead-In Part 
 
Objectives 
Endpoints  
Primary 
To 
assess 
safety 
and 
tolerability 
of 
futuximab/modotuximab in combination with 
trifluridine/tipiracil according to National Cancer 
Institute Comment Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0  
­ Incidence of dose-limiting toxicities (DLTs) 
­ Incidence, 
severity 
and 
relationship 
of 
Treatment Emergent Adverse Events (TEAEs) 
and Serious Treatment Emergent Adverse 
Events (STEAEs) 
­ AEs leading to dose interruption, modification, 
delays and permanent treatment stop 
­ Changes from baseline in key laboratory safety 
assessments, and vital signs 
Secondary 
To 
assess 
anti-tumour 
activity 
of 
futuximab/modotuximab in combination with 
trifluridine/tipiracil per investigator assessment 
using Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.1 in terms of: 
­ Objective Response Rate (ORR)  
 
 
­ Best Overall Response (BOR)  
 
 
­ Disease Control Rate (DCR) 
 
 
 
 
 
 
­ Progression Free Survival (PFS)  
 
 
 
To 
assess 
anti-tumour 
activity 
of 
futuximab/modotuximab in combination with 
trifluridine/tipiracil in terms of: 
­ Overall Survival (OS)  
 
To characterise the pharmacokinetic (PK) profile 
of 
futuximab/modotuximab, 
trifluridine 
and 
tipiracil 
in 
the 
combination 
of 
futuximab/modotuximab with trifluridine/tipiracil  
 
To 
evaluate 
the 
immunogenicity 
of 
futuximab/modotuximab (i.e. occurrence of anti-
drug antibody [ADA]) 
 
 
 
 
 
­ Objective Response (OR): achievement of 
complete response (CR) or partial response (PR)  
­ BOR: the best response recorded from screening 
through disease progression/recurrence  
­ Disease Control (DC): achievement of best 
response: 
 CR: disappearance of all target lesions 
 PR: ≥ 30% decrease in the sum of the longest 
diameter of target lesions, or 
 Stable Disease (SD)  
­ PFS: the time from the first administration of 
first IMP date until the date of the investigator-
assessed radiological disease progression or 
death, whichever occurs first 
 
 
­ OS: the time from the first administration of first 
IMP date to death from any cause 
 
 
­ Derived PK parameters (e.g. Cmax, AUC) for 
futuximab/modotuximab, 
trifluridine 
and 
tipiracil 
 
­ ADA development for futuximab/modotuximab 
Exploratory 
To explore biomarkers as potential predictors of 
response and to track the emergence of resistance  ­ Circulating tumour DNA (ctDNA) monitoring 
 
 
 
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Table (3.4) 2 - Endpoints for the Randomised part 
 
Objectives 
Endpoints  
Primary 
To compare OS of futuximab/modotuximab in 
combination 
with 
trifluridine/tipiracil 
vs 
trifluridine/tipiracil monotherapy in participants 
with tumours that are KRAS/NRAS and BRAF 
WT (Double negative [DN]) 
­ OS (in DN) is defined as the time from date of 
randomisation into the study to death from any 
cause 
Key 
secondary  
To compare OS of futuximab/modotuximab in 
combination 
with 
trifluridine/tipiracil 
vs 
trifluridine/tipiracil monotherapy in participants 
with tumours that are KRAS/NRAS, BRAF WT 
and EGFR-extracellular domain WT (Triple 
negative [TN])  
­ OS (in TN) is defined as the time from date of 
randomisation into the study to death from any 
cause 
Secondary 
To 
compare 
anti-tumour 
activity 
of 
futuximab/modotuximab in combination with 
trifluridine/tipiracil 
vs 
trifluridine/tipiracil 
monotherapy per investigator’s assessment using 
RECIST v1.1 in terms of:  
­ Progression Free Survival (PFS)  
 
 
 
­ Objective Response Rate (ORR)  
 
­ Disease Control Rate (DCR) 
 
 
 
 
 
­ Duration of response (DoR) 
 
 
 
­ Time to Response (TTR)  
 
 
To 
assess 
anti-tumour 
activity 
of 
futuximab/modotuximab in combination with 
trifluridine/tipiracil 
vs 
trifluridine/tipiracil 
monotherapy in terms of:  
­ Time to Next Treatment (TTNT) 
 
 
­ Time to ECOG Performance Status ≥ 2 
(TtPS2) 
 
  
 
 
 
 
 
 
­ PFS: the time from date of randomisation until 
the date of the investigator-assessed radiological 
disease progression or death, whichever occurs 
first 
­ OR: achievement of confirmed, complete 
response (CR) or partial response (PR)  
­ DC: achievement of best response: 
 CR: disappearance of all target lesions 
 PR: ≥ 30% decrease in the sum of the longest 
diameter of target lesions, or 
 Stable Disease (SD)  
­ DoR: the time from the first documentation of 
confirmed tumour response (CR or PR) to the 
first 
documentation 
of 
objective 
tumour 
progression or to death due to any cause 
­ TTR: the time from randomisation until first 
radiologically confirmed tumour response (CR 
or PR)  
 
 
 
 
­ TTNT: the time from the randomisation to 
initiation of the next systemic anti-cancer 
therapy 
­ TtPS2: the time from the date of randomisation 
to the date when ECOG PS score of ≥ 2 is 
observed for the first time 
  
 
 
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Table (3.4) 2 (Cont’d) - Endpoints for the Randomised part 
 
Objectives 
Endpoints  
 
To further evaluate and to compare the safety 
profile of futuximab/modotuximab in combination 
with trifluridine/tipiracil vs trifluridine/tipiracil 
monotherapy 
 
 
 
 
To 
compare 
Quality 
of 
life 
(QoL) 
of 
futuximab/modotuximab in combination with 
trifluridine/tipiracil 
vs 
trifluridine/tipiracil 
monotherapy 
 
To characterise the pharmacokinetic (PK) profile 
of 
futuximab/modotuximab, 
trifluridine 
and 
tipiracil 
in 
the 
combination 
futuximab/modotuximab with trifluridine/tipiracil 
 
To further evaluate the immunogenicity of 
futuximab/modotuximab 
(i.e. 
occurrence 
of 
antidrug antibody [ADA]) 
­ Incidence, severity and relationship of TEAEs 
and STEAEs collected from administration of 
the first dose of IMPs 
­ AEs leading to dose interruption, dose delays 
and permanent treatment stop 
­ Changes from baseline in key laboratory safety 
assessments, and vital signs 
­ QoL is assessed by 2 questionnaires European 
Organization for Research and Treatment of 
Cancer (EORTC) QLQ-C30 and EQ-5D-5L  
 
­ Derived PK parameters (e.g. Cmax, AUC) for 
futuximab/modotuximab, 
trifluridine 
and 
tipiracil 
 
 
ADA development for futuximab/modotuximab 
Exploratory 
To explore the PK/pharmacodynamic (PD) 
relationship for safety and/or efficacy of the 
combination 
futuximab/modotuximab 
with 
trifluridine/tipiracil  
To explore biomarkers as potential predictors of 
response and to track the emergence of resistance 
­ Relationship between exposure and PD (as 
safety and efficacy) 
 
­ Circulating tumour DNA (CtDNA) monitoring 
4. STUDY DESIGN 
4.1. Investigational Plan 
4.1.1. 
Study plan 
This is a randomised, open label, multi-centre, two-arm Phase 3 study to evaluate 
futuximab/modotuximab in combination with trifluridine/tipiracil versus trifluridine/tipiracil 
monotherapy in participants ≥ 18 years of age with KRAS/NRAS and BRAF WT mCRC who 
were previously treated with chemotherapy (including oxaliplatin, irinotecan and 5-
fluorouracil, anti-VEGF agents) and with anti-EGFR mAb therapy for ≥ 16 weeks. 
The study will comprise two parts a Safety Lead-In part in approximately 25 participants and a 
Randomised part in approximately 500 participants.  
The study design is depicted in Figure (4.1.1) 1. 
 
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Figure (4.1.1) 1 - CL3-95026-001 Study Design 
  
 
 
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Figure (4.1.1) 2 - Study plan for the Safety Lead-In Part 
 
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Figure (4.1.1) 3 - Study plan for the Randomised part 
 
 
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The study start is defined as the date of the first visit of the first participant. 
The study will be divided into the following periods for each participant: 
­ Screening visit/Screening period (maximum 28 days):  
 Screening visit: after signature of the Informed Consent Form(s) (ICF) to check screening 
criteria and decide if participant can be screened for the study. 
 Screening period: if the participant is screened in the study, check the inclusion and 
exclusion criteria and decide if participant can be included in the study. 
 Randomisation: included participants will be randomly assigned to one of the two 
treatment groups: 
 Arm A: trifluridine/tipiracil + futuximab/modotuximab. 
 Arm B: trifluridine/tipiracil. 
­ Treatment period: participants will be treated until they meet a discontinuation criterion as 
described in Section 5.8.1. The participants should receive the first dose of first IMP (Day 1 
of Cycle 1) within 3 days after inclusion (in the Safety Lead-in part) or after randomisation. 
­ Withdrawal visit (WV): should be conducted within approximately 4 weeks following the 
date of study treatment withdrawal and before the start of a new anticancer therapy. 
­ Follow-up period: after the WV the participant will be followed every 8 weeks (± 10 calendar 
days): 
 For survival status until the end of the study. This follow-up can be done remotely by 
using various telecommunication technologies including but not limited to phone, 
internet, and shared electronic medical records. 
 For tumour assessment (if the patient was withdrawn from the study for another reason 
than radiologic disease progression) (compared to the last assessment) until radiologic 
progression regardless of initiation of new anticancer therapy. 
This study will deploy Televisits as part of the study schedule in the randomised part only. This 
means that some study visits could be conducted using a telehealth video remote visit platform. 
The system used is HIPAA, 21 CFR part 11 and GDPR compliant, and provides easy to use, 
on-demand Televisits to provide a remote environment for the investigator and his/her site team 
and study participants to remain closely connected throughout the life of the study. These visits 
can be utilised to address changes in patient activities, healthcare or health status in order to 
make timely decisions around ongoing clinical care and adverse event management. Options to 
convert non-critical study visits to a televisit will also help ease the study burden for participants 
and hence minimise drop-out. Televisits will be available to the participants and site on an ad-
hoc basis in addition to the regular schedule should the need arise. 
End of Trial is defined as the date of the last follow-up of the last participant (including a contact 
phone), or the date of last contact attempt if the last participant is declared lost to follow-up, or 
when the target number of OS events is reached, whichever occurs first. 
Any participants still receiving IMPs at the end of the study will be allowed to continue at the 
discretion of the investigator and as long as none of the treatment discontinuation criteria are 
met. 
If some participants are still receiving study treatments when the end of study is met, please see 
Section 6.5 for procedures to be followed. 
Due to the exceptional circumstances in relation to the coronavirus disease pandemic, the 
sponsor, in accordance with competent regulatory authority’s guidelines, could decide to 
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implement precautionary measures during the study to ensure participants safety, while 
maintaining compliance with GCP and study data integrity. These precautionary measures will 
remain in effect only for the duration of national public health emergency. 
4.1.2. 
Investigation schedule 
Table (4.1.2) 1 and Table (4.1.2) 2 describe the efficacy, safety and other assessments 
performed during the Safety Lead-In and Randomised parts of the study, respectively. 
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Table (4.1.2) 1 - CL3-95026-001 Investigation schedule for the Safety Lead-In part 
 
SCR INCL 
Cycle 1 
Cycle 2 
Cycles 3 and after 
WV 
within 4 weeks 
after treatment 
withdrawal and 
before new 
anticancer 
treatment 
Follow-up 
period 
Every 8 weeks, 
until death or end 
of study 
Protocol 
section 
D1 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.3 
Screening criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2.7 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Current medical condition 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1 
Medical/surgical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 / 8 / 6.3 
Previous treatments 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Concomitant treatments 
 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
STUDY TREATMENT 
Futuximab/modotuximab2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
6.1.1 
Trifluridine/tipiracil3 
 
 
D1-5 
D8-12 
 
 
D1-5 
D8-12 
 
 
D1-5 
D8-12 
 
 
 
 
6.1.3 
EFFICACY 
Radiological and clinical 
tumour measurement4 
 
X4a 
 
 
 
 
 
 
 
 
X4b 
 
 
 
X4c 
X4d 
7.2 
SAFETY 
Vital signs5 
 
X 
X pre-dose6; 
EoI (± 5 min) 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
X 
 
8.2.1 
ECOG 
 
X 
X pre-dose6 
 
 
 
X pre-
dose7 
 
 
 
X pre-
dose7 
 
 
 
X 
 
8.2.2 
Physical examination 
 
X 
X pre-dose6 
 
 
 
X pre-
dose7 
 
 
 
X pre-
dose7 
 
 
 
X 
 
8.2.3 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4 
Body weight  
 
X 
X pre-dose6 
 
 
 
X pre-
dose7 
 
 
 
X pre-
dose7 
 
 
 
X 
 
Pregnancy testing8 
 
X8a 
X8b 
 
 
 
X8b 
 
 
 
X8b 
  
 
 
X8b 
X8b 
8.2.7.6 
ECG9 
 
X 
X pre-dose6 
 
 
 
X pre-
dose7 
 
 
 
 
 
 
 
 
 
8.2.6 
Adverse events 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
8.3 
Dermatologic examination  
 
X 
 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
 
X pre-
dose7 
X pre-
dose7 
X pre-
dose7 
 
 
8.2.5 
LABORATORY EXAMINATIONS 
Blood hematology10 
 
X 
X pre-dose6 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X 
 
8.2.7.1 
Blood biochemistry 
 
X 
X pre-dose6 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X 
 
8.2.7.2 
Serum Mg, Ca, K 
 
 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
X pre-
dose7 
 
 
8.2.7.3 
Blood coagulation 
 
X 
X pre-dose6 
 
 
 
X pre-
dose7 
 
 
 
X pre-
dose7 
 
 
 
X 
 
8.2.7.4 
Urinary biochemistry11 
 
X 
X pre-dose6 
 
 
 
X pre-
dose7 
 
 
 
X pre-
dose7 
 
 
 
X 
 
8.2.7.5 
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Table (4.1.2) 1 (Cont’d) - CL3-95026-001 Investigation schedule for the Safety Lead-In part 
 
SCR INCL 
Cycle 1 
Cycle 2 
Cycles 3 and after 
WV 
within 4 weeks 
after treatment 
withdrawal and 
before new 
anticancer 
treatment 
Follow-up 
period 
Every 8 weeks, 
until death or end 
of study 
Protocol 
section 
D1 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
PHARMACOKINETICS 
Blood sample for 
futuximab/modotuximab12 
 
 
X pre-dose*; 
EoI**; 1-2h 
after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose* 
 
 
 
X 
 
9.2 
Blood sample for 
trifluridine/tipiracil12 
 
 
X pre-dose*; 
EoI**; 1-2h 
after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
 
 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
 
 
 
 
 
 
X 
 
Anti-futuximab/ 
modotuximab antibodies12 
 
 
X pre-dose* 
 
X pre-
dose* 
 
X pre-
dose* 
 
X pre-
dose* 
 
X pre-
dose* *** 
 
 
 
X 
 
9.5 
GENOMIC ANALYSIS 
Blood sample for ctDNA13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.1.3 
BIOMARKERS 
Blood exploratory 
biomarkers14 
 
 
X pre-dose 
 
 
 
X pre-dose 
 
 
 
X pre-dose 
 
 
 
X 
 
9.4 
 
 
________________________________________________________
__________________________________________________________________
_________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________
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1. Sign Informed Consent Form (ICF): written informed consent must be obtained during the screening visit, prior to the performance of any study procedure 
2. Futuximab/modotuximab administration: futuximab/modotuximab will be administered at a dose 9 mg/kg on Cycle 1 Day 1 (C1D1) (loading dose) and then at a 6 mg/kg weekly (± 2 days) beginning on C1D8 
(maintenance doses), by IV infusion  
3. Trifluridine/tipiracil administration: Trifluridine/tipiracil will be administered at a dose 35 mg/m²/dose, orally twice a day, within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 
2 weeks, followed by a 14-day rest (or in accordance with the local SmPC (Summary of Product Characteristics) of trifluridine/tipiracil) 
4. Tumour measurements: tumour assessments should be performed according to RECIST version 1.1. The same method of assessment and the same technique must be used for all evaluations. To include diagnostic 
imaging by CT or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis, and other sites as indicated based on tumour location and clinical judgment in order to assess the status of the underlying 
malignancy. Use of contrast is preferred but is at the discretion of the investigator, as medically indicated. At each time point, obtain imaging-based evaluation of the chest, abdomen, and pelvis at a minimum (other 
localisations if clinically indicated). 
a. 
Baseline: tumour assessment will be done within 28 days prior to the first administration of first IMP. Images obtained prior to participant signed informed consent form (ICF) may be used if the date of the 
images is within 28 days of randomisation (first administration of first IMP for Safety Lead-In part) and if in line with methods and techniques that will be used during study 
b. Treatment period: tumour assessments will be done every 8 weeks from C1D1 (± 7 calendar days) until radiologic progression is documented 
c. 
Withdrawal visit: tumour assessments will be performed only if not performed within previous 8 weeks. Every effort should be made to perform the WV tumour assessments prior to the start of new anti-cancer 
therapy 
d. Follow-up period: unless patient had discontinued study treatments for radiologic disease progression or withdrawal of consent, obtain tumour assessments within 8 weeks after the last previous tumour assessment 
and then every 8 weeks (± 10 calendar days) until documentation of radiologic disease progression, regardless of initiation of a new anticancer therapy 
5. Vital signs: Vital signs including body temperature, pulse rate, respiratory rate, blood pressure, oxygen saturation by pulse oximetry 
6. Study procedures prior to the first IMP administration: to be done at C1D1 prior to the first IMP administration only if baseline procedures have been done more than 7 days prior to C1D1 
7. Study procedures obtained within 48 hours prior to study treatments administration  
8. Pregnancy testing 
a. 
Pregnancy testing at screening period: with serum βHCG test only (Within 7 days prior to first administration of first IMP) 
b. Pregnancy tests should be performed at the beginning of each cycle during the treatment period, upon treatment discontinuation, at the first follow-up visit, and additionally if clinically indicated, for all relevant 
patients. More frequent pregnancy tests should be performed if required by local law or as clinically indicated. 
9. ECG assessment: To include standard 12-lead ECG with measurement of PR interval, QRS duration, time from the beginning of the QRS complex, representing ventricular depolarization, to the end of the T wave, 
resulting from ventricular repolarization (QT) interval, and QTc interval [ms], as well as heart rate [beats per minute (BPM)]). 
To be evaluated locally; ECGs should be performed using the calibrated instrument at each study centre and should be conducted after the participant has been supine (or semirecumbent) for > 10 minutes. 
Participants with a QTc interval >480 ms at baseline are excluded. Participants with a QTc interval > 480 ms during the treatment period should not be treated; dosing to be delayed. 
In the event of significant electrolyte abnormalities, the evaluation frequency should be increased to include additional evaluations between the scheduled assessments, as clinically indicated.  
An ECG should be performed in the event of ≥ Grade 3 hypomagnesemia 
10. Blood haematology: In the event of haematologic toxicity, the evaluation frequency should be increased to include additional evaluations between the scheduled assessments, as clinically indicated 
11. Urinary biochemistry: Collect urine samples  
12. PK/ADA assessment 
*i.e. 5-60 minutes before infusion of futuximab/modotuximab 
**i.e. within 10 minutes before to the end of infusion of futuximab/modotuximab 
***The frequency of futuximab/modotuximab immunogenicity assessments will be reduced to every 2 months after the first 6 months in the first year and every 4 months after the first year.  
13. Genomic analysis from peripheral whole blood sample for defining patient eligibility and stratification will be based on assessment of ctDNA in plasma with an oncogene panel. After isolation of the plasma, the 
sample will be submitted for mutation analysis prior to first administration of first IMP. The genomic analysis includes a series of genes frequently mutated in cancer, but will be focused on the following genes: 
- 
BRAF 
 
- 
KRAS & NRAS 
 
 
- 
EGFR-ECD 
 
 
14. Exploratory biomarkers from peripheral whole blood sample collected pre-dose at C1D1, C2D1, C3D1, then every 2 cycles along with tumour assessment and at withdrawal, for ctDNA monitoring 
 
ctDNA = circulating tumour DNA; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; INCL = inclusion; EoI = end of infusion; IV = intravenous; SCR = screening.  
________________________________________________________
__________________________________________________________________
_________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________
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Table (4.1.2) 2 - CL3-95026-001 Investigation schedule for the Randomised part 
 
SCR 
INCL 
Cycle 1 
Cycle 2 
Cycles 3 and after 
WV 
within 4 weeks 
after treatment 
withdrawal and 
before new 
anticancer 
treatment 
Follow-up 
period 
Every 8 
weeks, until 
death or end of 
study 
Protocol 
section 
D1 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.3 
Screening criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2.7 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Current medical 
condition 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1 
Medical/surgical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 / 8 / 6.3 
Previous treatments 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Concomitant treatments 
 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Randomisation2 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 
IWRS3 
 
X 
X 
X10 
X 
X10 
X 
X10 
X 
X10 
X 
X10 
X 
X10 
X 
 
 
STUDY TREATMENT 
Futuximab/ 
modotuximab4, 10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
6.1.1 
Trifluridine/tipiracil5 
 
 
D1-5 
D8-12 
 
 
D1-5 
D8-12 
 
 
D1-5 
D8-12 
 
 
 
 
6.1.3 
EFFICACY 
Radiological and 
clinical tumour 
measurement6 
 
X6a 
 
 
 
 
 
 
 
 
X6b 
 
 
 
X6c 
X6d 
7.2 
SAFETY 
Vital signs7 
 
X 
X pre-dose; 
EoI (± 5 min)8 
X pre-
dose9, 10 
X pre-
dose9 
X pre-
dose9, 10 
X pre-
dose9 
X pre-
dose9,10 
X pre-
dose9 
X pre-
dose9,10 
X pre-
dose9 
X pre-
dose9,10 
X pre-
dose9 
X pre-
dose9, 10 
X 
 
8.2.1 
ECOG 
 
X 
X pre-dose8 
 
 
 
X pre-
dose9 
 
 
 
X pre-
dose9 
 
 
 
X 
 
8.2.2 
Physical examination 
 
X 
X pre-dose8 
 
 
 
X pre-
dose9 
 
 
 
X pre-
dose9 
 
 
 
X 
 
8.2.3 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4 
Body weight  
 
X 
X pre-dose8 
 
 
 
X pre-
dose9 
 
 
 
X pre-
dose9 
 
 
 
X 
 
Pregnancy testing11 
 
X11a 
X11b 
 
 
 
X11b 
 
 
 
X11b 
 
 
 
X11b 
X11b 
8.2.7.6 
ECG12 
 
X 
X pre-dose8 
 
 
 
X pre-
dose9 
 
 
 
 
 
 
 
 
 
8.2.6 
Adverse events 
 
X 
→ 
→10 
→ 
→10 
→ 
→10 
→ 
→10 
→ 
→10 
→ 
→10 
→ 
→ 
8.3 
Dermatologic 
examination10  
 
X 
 
X pre-
dose9 
X pre-
dose9 
X pre-
dose9 
 
X pre-
dose9 
X pre-
dose9 
X pre-
dose9 
 
X pre-
dose9 
X pre-
dose9 
X pre-
dose9 
 
 
8.2.5 
________________________________________________________
__________________________________________________________________
_________________________________________________________
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SCR 
INCL 
Cycle 1 
Cycle 2 
Cycles 3 and after 
WV 
within 4 weeks 
after treatment 
withdrawal and 
before new 
anticancer 
treatment 
Follow-up 
period 
Every 8 
weeks, until 
death or end of 
study 
Protocol 
section 
D1 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
QUALITY OF LIFE ASSESSMENT 
Quality of life 
assessment13 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
9.6 
Table (4.1.2) 2 (Cont’d) - CL3-95026-001 Investigation schedule for the Randomised part 
 
SCR 
INCL 
Cycle 1 
Cycle 2 
Cycles 3 and after 
WV 
within 4 weeks 
after treatment 
withdrawal and 
before new 
anticancer 
treatment 
Follow-up 
period 
Every 8 
weeks, until 
death or end of 
study 
Protocol 
section 
D1 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
LABORATORY EXAMINATIONS 
Blood hematology14 
 
X 
X pre-dose8 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X 
 
8.2.7.1 
Blood biochemistry 
 
X 
X pre-dose8 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X 
 
8.2.7.2 
Serum Mg, Ca, K10 
 
 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
X pre-
dose9 
 
 
8.2.7.3 
Blood coagulation 
 
X 
X pre-dose8 
 
 
 
X pre-
dose9 
 
 
 
X pre-
dose9 
 
 
 
X 
 
8.2.7.4 
Urinary biochemistry15 
 
X 
X pre-dose8 
 
 
 
X pre-
dose9 
 
 
 
X pre-
dose9 
 
 
 
X 
 
8.2.7.5 
PHARMACOKINETICS 
Blood sample for 
futuximab/ 
modotuximab 
(Arm A)16 
 
 
X pre-dose*; 
EoI**; 1-2h 
after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose* 
 
 
 
X 
 
9.2 
Blood sample for 
trifluridine/tipiracil 
(Arm A)16 
 
 
X pre-dose*; 
EoI**; 1-2h 
after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
 
 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
X pre-
dose*; 
EoI**; 0.5-
1h after EoI 
 
 
 
 
 
 
X 
 
Blood sample for 
trifluridine and tipiracil 
(Arm B) 16 
 
 
X 
beginning, end 
of visit 
 
X 
during visit 
 
X 
during visit 
 
X 
during visit 
 
 
 
 
 
X 
 
Anti-futuximab/ 
modotuximab 
antibodies10; 16 
 
 
X pre-dose* 
 
X pre-
dose* 
 
X pre-
dose* 
 
X pre-
dose* 
 
X pre-
dose* *** 
 
 
 
X 
 
9.5 
GENOMIC ANALYSIS 
Blood sample for 
ctDNA17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.1.3 
________________________________________________________
__________________________________________________________________
_________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________
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SCR 
INCL 
Cycle 1 
Cycle 2 
Cycles 3 and after 
WV 
within 4 weeks 
after treatment 
withdrawal and 
before new 
anticancer 
treatment 
Follow-up 
period 
Every 8 
weeks, until 
death or end of 
study 
Protocol 
section 
D1 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
D1 
± 2 days 
D8 
± 2 days 
D15 
± 2 days 
D22 
± 2 days 
BIOMARKERS 
Blood exploratory 
biomarkers18 
 
 
X pre-dose 
 
 
 
X pre-dose 
 
 
 
X pre-dose 
 
 
 
X 
 
9.4 
 
 
 
________________________________________________________
__________________________________________________________________
_________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________
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1. Sign Informed Consent Form (ICF): written informed consent must be obtained during the screening visit, prior to the performance of any study procedure 
2. Randomisation must be done ≤ 3 days prior C1D1 
3. IWRS: to obtain participant's number at screening, randomisation of participant, allocation and re-allocation of therapeutic units (other visits) and to register the end of treatment for a participant at withdrawal visit  
4. Futuximab/modotuximab administration: futuximab/modotuximab will be administered at a dose 9 mg/kg on Cycle 1 Day 1 (C1D1) (loading dose) and then at a 6 mg/kg weekly (± 2 days) beginning on C1D8 
(maintenance doses), by IV infusion  
5. Trifluridine/tipiracil administration: Trifluridine/tipiracil will be administered at a dose 35 mg/m²/dose, orally twice a day, within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 
2 weeks, followed by a 14-day rest (or in accordance with the local SmPC of trifluridine/tipiracil) 
6. Tumour measurements: tumour assessments should be performed according to RECIST version 1.1. The same method of assessment and the same technique must be used for all evaluations. To include diagnostic 
imaging by CT or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis, and other sites as indicated based on tumour location and clinical judgment in order to assess the status of the underlying 
malignancy. Use of contrast is preferred but is at the discretion of the investigator, as medically indicated. At each time point, obtain imaging-based evaluation of the chest, abdomen, and pelvis at a minimum (other 
localisations if clinically indicated). 
a. 
Baseline: tumour assessment will be done within 28 days prior to the first administration of first IMP. Images obtained prior to participant signed informed consent form (ICF) may be used if the date of the 
images is within 28 days of randomisation (first administration of first IMP for Safety Lead-In part) and if in line with methods and techniques that will be used during study 
b. Treatment period: tumour assessments will be done every 8 weeks from C1D1 (± 7 calendar days) until radiologic progression is documented 
c. 
Withdrawal visit: tumour assessments will be performed only if not performed within previous 8 weeks. Every effort should be made to perform the WV tumour assessments prior to the start of new anti-cancer 
therapy. 
d. Follow-up period: unless patient had discontinued study treatments for radiologic disease progression or withdrawal of consent, obtain tumour assessments within 8 weeks after the last previous tumour assessment 
and then every 8 weeks (± 10 calendar days) until documentation of radiologic disease progression, regardless of initiation of a new anticancer therapy 
7. Vital signs, including body temperature, pulse rate, respiratory rate, blood pressure, oxygen saturation by pulse oximetry 
8. Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study treatments administration only if baseline procedures have been done more than 7 days prior to C1D1 
9. Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil intake in Arm B of Randomised part on CXD1) 
10. To be performed only for futuximab/modotuximab participants (Arm A) 
11. Pregnancy testing 
a. 
Pregnancy testing at screening period: with serum βHCG test only (Within 7 days prior to first administration of first IMP) 
b. Pregnancy tests should be performed at the beginning of each cycle during the treatment period, upon treatment discontinuation, at the first follow-up visit, and additionally if clinically indicated, for all relevant 
patients. More frequent pregnancy tests should be performed if required by local law or as clinically indicated. 
12.  ECG assessment: To include standard 12-lead ECG with measurement of PR interval, QRS duration, time from the beginning of the QRS complex, representing ventricular depolarization, to the end of the T wave, 
resulting from ventricular repolarization (QT) interval, and QTc interval [ms], as well as heart rate [beats per minute (BPM)]) 
To be evaluated locally; ECGs should be performed using the calibrated instrument at each study centre and should be conducted after the participant has been supine (or semi recumbent) for > 10 minutes. 
Participants with a QTc interval >480 ms at baseline are excluded. Participants with a QTc interval > 480 ms during the treatment period should not be treated; dosing to be delayed. 
In the event of significant electrolyte abnormalities, the evaluation frequency should be increased to include additional evaluations between the scheduled assessments, as clinically indicated. For 
futuximab/modotuximab participant, an ECG should be performed in the event of ≥ Grade 3 hypomagnesemia 
13. QoL Assessment: QoL Assessment will be done at baseline, after the end of cycle 1 (C2D1), then from cycle 3 (C3D1) every 2 cycles during the treatment period, at the withdrawal visit and every 8 weeks (2 months) 
during the follow-up period, until death or until end of the study is reached (whichever occur first). Evaluation by participant reporting questionnaires including: EORTC QLQ-C30 (v3) and EQ-5D-5L 
14. Blood haematology: In the event of haematologic toxicity, the evaluation frequency should be increased to include additional evaluations between the scheduled assessments, as clinically indicated 
15. Urinary biochemistry: Collect urine samples  
16. PK/ADA assessment 
*i.e. 5-60 minutes before infusion of futuximab/modotuximab 
**i.e. within 10 minutes before to the end of infusion of futuximab/modotuximab 
***The frequency of futuximab/modotuximab immunogenicity assessments will be reduced to every 2 months after the first 6 months in the first year and every 4 months after the first year.  
17. Genomic analysis from peripheral whole blood sample for defining patient eligibility and stratification will be based on assessment of ctDNA in plasma with an oncogene panel. After isolation of the plasma, the 
samples will be submitted for mutation analysis prior to randomisation. The genomic analysis includes a series of genes frequently mutated in cancer, but will be focused on the following genes: 
- 
BRAF 
 
- 
KRAS & NRAS (
 
 
- 
EGFR-ECD 
:
 
18. Exploratory biomarkers from peripheral whole blood sample collected pre-dose at C1D1, C2D1, C3D1, then every 2 cycles along with tumour assessment and at withdrawal, for ctDNA monitoring 
 
________________________________________________________
__________________________________________________________________
_________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________
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CL3-95026-001
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ctDNA = circulating tumour DNA; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; INCL = inclusion; EoI = end of infusion; IV = intravenous; SCR = screening.  
________________________________________________________
__________________________________________________________________
_________________________________________________________
________________________________________________________________________________________________________________________________________________________________________________
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For further practical details, methods of measurement are provided in Sections 7 and 8. 
The approximate total volume of blood collected per participant will be 45 mL for the screening 
period, < 130 mL per cycle for the Cycle 1 and Cycle 2, < 80 mL per cycle for the further 
cycles and <55 mL for WV (Appendix 12). For men and post-menopausal women, the total 
volume of blood collected will be slightly lower (since pregnancy tests do not apply).  
4.1.3. 
Safety Lead-In Part 
The Safety Lead-In part is an open-label, single-arm and non-randomised study phase in 
approximately 25 participants. A minimum of 3 Japanese participants will be enrolled. During 
this part, the safety and tolerability of futuximab/modotuximab in combination with 
trifluridine/tipiracil will be evaluated prior to the start of the Randomised part. Efficacy 
parameters, futuximab/modotuximab and trifluridine/tipiracil PK and futuximab/modotuximab 
immunogenicity will also be evaluated as secondary endpoints.  
The Study plan of Safety Lead-In part is depicted in Figure (4.1.1) 2. The schedule of study 
assessments is provided in Table (4.1.2) 1. 
4.1.3.1. 
Dose administration schedule 
The therapeutic regimen for the Safety Lead-In part Figure (4.1.1) 2 is as follows: 
­ Trifluridine/tipiracil (35 mg/m2 BID) 5 days on/2 days off over 2 weeks followed by 14 days 
off, before futuximab/modotuximab administration. 
­ Futuximab/modotuximab (9 mg/kg) loading dose on C1D1 followed by (6 mg/kg) weekly 
maintenance doses. 
4.1.3.2. 
DLT definition 
For each participant, DLT assessment will be performed during Safety Lead in part. 
Assessments include all toxicities observed during the initial 28-day treatment period (Cycle 
1).A DLT is defined as: 
­ A clinically significant adverse event (AE) graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 observed 
during the initial 28-day treatment period following the first IMP administration. 
­ Assessed as unrelated to underlying disease, disease progression, intercurrent illness, or 
concomitant medications. 
­ At least possibly related to the IMPs (Futuximab/modotuximab or Trifluridine/tipiracil or 
both) by the investigator and meeting any of the criteria included in Table (4.1.3.2) 1. 
________________________________________________________
__________________________________________________________________
_________________________________________________________
__________________________________________________________
_____________________________________________________________
_________________________________________________________
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Table (4.1.3.2) 1 - Dose-limiting toxicity criteria 
Toxicity Class 
Dose-limiting Toxicity Criteria 
Haematological abnormalities 
Anaemia ≥ Grade 3  
Febrile neutropenia 
Uncomplicated Grade 4 neutropenia that lasts ≥ 1 week 
Uncomplicated Grade 4 thrombocytopenia (less than 25 109/L) that lasts 
≥ 1 week or any Grade ≥ 3 thrombocytopenia (between 25 and 50 109/L) 
with bleeding episodes or thrombocytopenia requiring platelet transfusion 
Gastrointestinal disorders 
Grade 3 diarrhoea for > 2 days despite adequate treatment or with fever 
and/or dehydration 
Skin disorders  
Any Grade 3 skin toxicity lasting for more than 2 weeks, or Grade 4 skin 
toxicity regardless of duration1 
Infusion-related reactions 
Grade ≥ 3 infusion related reaction 
Hepatic abnormalities 
AST or ALT ≥ 3 x ULN along with a total bilirubin > 2.0 x ULN and 
confirmed Hy’s law cases according to FDA guidance 
Isolated AST or ALT ≥ CTCAE Grade 3 
Other adverse events 
Any laboratory value Grade ≥ 3 with a duration ≥ 3 days, considered 
unrelated to underlying disease, disease progression, intercurrent illness or 
concomitant medications/therapies 
Any Grade 3 or Grade 4 non-haematologic adverse event (except for 
Grade 3 nausea and/or vomiting controlled by anti-emetic therapy that last 
less than 72h, or Grade 3 diarrhoea responsive to anti-diarrheal medication) 
1 acne, cellulitis, dermatitis acneiform, dry skin, erysipelas, erythema, folliculitis, hypertrichosis, paronychia, pruritus, rash, rash 
maculopapular, rash vesicular, skin exfoliation, skin hyperpigmentation and xerosis 
Participants who meet any following criteria will not be evaluable for DLT and therefore will 
be replaced during the Safety Lead-In part of the study. 
­ Permanently discontinued treatment during DLTs assessment period for reasons other than 
DLT. 
­ Did not undergo a DLT assessment at the end of Cycle 1. 
­ Participants must complete at least the first cycle of treatment with a dose intensity 
[(administered dose in mg/planned dose in mg) x 100] higher than 75% with a minimum 
follow-up duration of 28 days. The dose intensity for single-agent trifluridine/tipiracil in 
Phase 3 studies is approximately 89%; therefore, for the combination a value of 75% is 
considered appropriate. Participants who require a dose interruption or reduction during the 
initial 28-day treatment period (Cycle 1) will remain evaluable for tolerability decisions if 
the reason for the reduction and/or interruption is a DLT. Participants will be replaced if they 
have 
received 
fewer 
than 
75% 
dose 
intensity 
of 
trifluridine/tipiracil 
or 
futuximab/modotuximab for any reason other than an AE or abnormal laboratory value that 
is not related to their disease, disease progression, intercurrent illness or concomitant 
medications/therapies. 
4.1.3.3. 
DLT management 
Study treatments must be delayed for any participant who experienced a DLT. Conditions to 
resume treatment are described in Section 8.11.  
All DLT will be reported to I.R.I.S. within 24 hours via DLT form in the e-CRF. After having 
filled in the DLT form, fill in the “Adverse Event” page of the e-CRF, without waiting for the 
results of the clinical outcome or of additional investigations. When data of the DLT form are 
submitted, an e-mail will be immediately and automatically sent to the sponsor. 
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If the e-CRF is unavailable when the investigator is informed of the DLT, he/she should:  
­ Report the DLT on a paper “DLT form”. 
­ Send 
the 
form 
immediately 
to 
I.R.I.S. 
at 
the 
following 
e-mail 
address 
CL3-95026-001@servier.com, with local project manager and monitor in copy  
As soon as the e-CRF becomes available, the investigator must enter the data in the e-CRF. 
4.1.3.4. 
Safety Lead-In and Tolerability Evaluation Procedure 
The safety and tolerability data obtained from the safety lead-in period will be reviewed by a 
data monitoring committee (DMC) to assess whether: 
­ The drug regimen is tolerable. 
­ The maximum tolerated dose (MTD) has been exceeded. 
­ The Randomised part of the study may proceed. 
The safety evaluation will be conducted as follows: 
­ After the 6th patient has signed the ICF and eligibility for inclusion has been confirmed, 
recruitment will be halted. After the 6th patient has been treated and followed for at least 
one 28-day cycle of treatment, a DMC meeting will be organized to assess safety and 
tolerability. If the 6th patient is not evaluable (see Section 4.1.3.2) then recruitment will re-
start to allow enrolment of a new patient to ensure that a cohort of 6 evaluable patients will 
be available for the DMC first evaluation meeting. Available data beyond the first cycle 
collected from the first 5 participants will also be reviewed and used for decisions regarding 
tolerability of the regimen. If ≤ 2 participants out of the first 6 evaluable participants 
experience a DLT, and the DMC assesses the doses as tolerable based on the totality of safety 
data, the Safety Lead-In will be expanded by an additional cohort of 6 participants. If ≥ 3 of 
the 6 experience a DLT, or the DMC considers the doses to be non-tolerable based on the 
totality of safety data, enrolment will remain halted pending DMC recommendation on study 
continuation, modification or discontinuation. 
­ The DMC will again review all available data when a total of 12 evaluable participants have 
been treated and followed for at least one 28-day cycle of treatment. The DMC will again 
evaluate the totality of safety data and will provide a recommendation regarding tolerability 
of the doses. The enrolment will continue unless ≥ 4 participants experience a DLT. If DMC 
considers the doses to be intolerable, then enrolment will be halted, until DMC 
recommendation on study continuation, modification or discontinuation. 
­ The DMC will meet again at the completion of Safety Lead-In when approximately 
25 participants will have been treated and followed for at least one 28-day cycle of treatment. 
When the 25th patient is enrolled in the study and completes the first 28-day cycle of 
treatment, patients previously enrolled in the study will have received more treatment cycles. 
Safety data from all treatment cycles will be collected for these patients. The overall safety 
profile of the evaluable participants, including data from all cycles of treatment beyond the 
first cycle of treatment, will be used for the safety evaluation. The DMC will review all 
accumulated safety data from all treatment cycles to judge whether the doses are acceptable 
for use in the randomised part of the study. 
The Randomised part will start if < 8/25 evaluable participants experienced DLTs, the DMC 
recommends starting Phase 3 without any modification and no identification of any other new 
important safety risk during Safety Lead-In part. In addition, serum/plasma concentrations from 
the participants included in the Safety Lead-In part will be assessed and compared to the 
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expected PK profiles using the available population PK models for futuximab/modotuximab 
and trifluridine/tipiracil (Visual Predictive Check). 
Throughout the Safety Lead-In part, DLT occurrence will be followed on a continuous basis 
and if the number of participants who experienced at least one DLT in each cohort exceeds the 
maximum number of DLTs that is considered safe (≥ 3/6 evaluable participants, ≥ 4/12 
evaluable participants, ≥ 6/18 evaluable participants and ≥ 8/25 evaluable participants), at any 
time during the Safety Lead-In part the enrolment will be halted, an urgent DMC meeting will 
be organized and DMC will provide recommendations on study continuation, modification or 
discontinuation (Figure (4.13.4) 1).  
DMC can decide at any moment of the study to discontinue the enrolment of new participants. 
At that time participants already treated in the study may continue the treatment if they have 
not experienced any clinically significant toxicity and are benefiting from the treatment 
according to the investigator’s discretion.  
Figure (4.1.3.4) 1 - Safety and tolerability evaluation procedure for dose evaluation 
in the Safety Lead-In part 
 
 
 
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4.1.3.5. 
Communication plan between the sponsor and centres 
The following communication plan between the sponsor and centres is in place in order to 
manage recruitment from multiple centres. A registration form will be completed by the 
investigator for each new patient included in the Safety Lead-In part. The sponsor will 
immediately (within 24/48 hours on working days) send back to the investigator the form 
completed. More details will be provided in the Registration and Prescription guide. The 
sponsor will also ensure a continuous communication with the centres related to the study 
progress, including the enrolment status, and safety observations 
4.1.4. 
Randomised Part 
The Randomised part has an open-label, multi-centre, parallel-group, 2-arm, randomised 
design. Approximately 500 participants previously treated with chemotherapy (including 
oxaliplatin, irinotecan and 5-fluorouracil, anti-VEGF agents) and who have received previous 
treatment with anti-EGFR mAb therapy for ≥ 16 weeks, KRAS/NRAS and BRAF WT mCRC 
will be randomised in a 1:1 ratio to either futuximab/modotuximab in combination with 
trifluridine/tipiracil (Arm A) or trifluridine/tipiracil (Arm B), and stratified according to 
performance status (PS) (0 versus 1), previous regimens of treatment (2 versus ≥ 3) and by the 
presence or absence of EGFR ECD mutations. The Study plan of Randomised part is depicted 
in Figure (4.1.1) 3. The schedule of study assessments is provided in Table (4.1.2) 2. 
4.2. Measures to minimise bias 
The following measures will be taken in order to minimise bias: 
­ Stratification by PS (0 versus 1), previous regimens of treatment (2 versus ≥ 3) and by the 
presence or absence of EGFR ECD mutations. 
­ Analysis of samples for PK and ADAs will be performed in a specific central laboratory to 
minimise the variability of measurements. 
­ Randomisation, allocation, reallocation and dose adjustments will be centralised by 
Interactive Web Response System (IWRS) in the Randomised part. 
­ Screening for participants with mCRC with KRAS/NRAS and BRAF WT will be performed 
based on a central evaluation by using a ctDNA-based analytically and clinically validated 
diagnostic test. 
­ Treatment arms blinding process set-up for OS and PFS related data to preserve the trial 
from dissemination of aggregated efficacy results in order to minimise the potential 
operational bias. 
­ QoL questionnaires (EORTC QLQ-C30 and EQ-5D-5L) will be completed by the patient 
(only for the Randomised part), independently of the study personnel, at the beginning of 
visit and prior to any study procedure. These questionnaires will be completed in the local 
language using an electronic device (electronic participant-reported outcome [e-PRO]). In 
case the patient is not able to use the e-PRO, a caregiver (not a medical/investigator staff) 
will be allowed to read the questions to the patient and to collect the answer without any 
interpretation of the questions and the answers. The objective is to enhance the validity of 
QoL data by reducing missing data and improving the completion rate. Completion of paper 
versions of the QoL questionnaires is not allowed by the protocol. 
4.3. Study products and blinding systems 
This is an open-label study. No blinding to study medication is required. 
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4.3.1. 
Products administered 
Futuximab/modotuximab and trifluridine/tipiracil are the IMPs. Both will be manufactured by 
Les LABORATOIRES Servier Industrie (Gidy France). Futuximab/modotuximab is not 
licenced in any country. Trifluridine/tipiracil is licenced for use in the EU, USA, and Japan. 
The labelling of packages complies with the regulatory requirements of each country involved 
in the study. 
Table (4.3.1) 1 provides a description of the IMPs. Additional details on the characteristics of 
futuximab/modotuximab are provided in the futuximab/modotuximab Investigator Brochure. 
Additional details on the characteristics of trifluridine/tipiracil are provided in the SmPC.8 
Table (4.3.1) 1 - Description of the investigational medicinal products 
Futuximab/ 
modotuximab 
Pharmaceutical form Solution for infusion  
Unit dosage 
20 mL vial  
Appearance, colour 
Clear to opalescent, colourless to slightly yellow solution 
Composition 
25 mg/mL active ingredient formulated with histidine as a buffer 
component, trehalose for tonicity adjustment, polysorbate 20 as 
stabilizer, and Water for Injection as a solvent, contained within a 
20 mL USP Type 1 glass vial with a FluroTec® coated halobutyl/ 
butyl rubber stopper, secured with a cap and flip-off seal. 
Trifluridine/ 
tipiracil 15 mg 
Pharmaceutical form Film-coated tablet 
Unit dosage 
15 mg  
Appearance, colour 
White round tablet printed with “15” on one side and “102” on the 
other side 
Composition 
15 mg trifluridine and 7.065 mg tipiracil hydrochloride, lactose 
monohydrate 
Trifluridine/ 
tipiracil 20 mg 
Pharmaceutical form Film coated table 
Unit dosage 
20 mg 
Appearance colour 
Pale-red round tablet printed with “20” on one side and “102” on the 
other side 
Composition 
20 mg trifluridine and 9.42 mg tipiracil hydrochloride, lactose 
monohydrate 
USP = United States Pharmacopeia 
Table (4.3.1) 2 provides a description of the IMP packaging.  
Table (4.3.1) 2 - Investigational medicinal product packaging 
Futuximab/ 
modotuximab 
Number of units of the pharmaceutical form per primary packaging 
1 vial of 500 mg 
Number of primary packaging per secondary packaging 
1 vial per small box 
Trifluridine/ 
tipiracil 
Number of units of the pharmaceutical form per primary packaging 
10 tablets by blister 
Number of primary packaging per secondary packaging 
2 blisters 
The labelling of packages complies with the regulatory requirements of the country involved in 
the study. 
The 
non-investigational 
medicinal 
products 
(NIMPs) 
are 
the 
drugs 
linked 
to 
futuximab/modotuximab premedication for IRR (glucocorticoid therapy, antihistamine (H1 
antagonist). 
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4.3.2. 
IMPs management 
The IMPs will be sent by Les Laboratoires Servier Industrie (Gidy, France) either directly to 
the study sites or to sub-distribution centres or to local pharmacies depending on the geographic 
areas and the local regulatory requirements.  
The investigator and/or the pharmacist of the study site should only use the IMPs provided for 
the participants involved in the study.  
The investigator and/or pharmacist of the study site is responsible for:  
­ IMPs receipt and storage according to the local procedures and requirements. 
­ IMPs temperature monitoring. 
­ IMPs dispensing according to treatment arm assigned by the IWRS for Randomised part. 
­ Maintaining records of IMPs inventory at study site. 
­ IMPs collection for destruction. 
Storage 
The IMPs should be stored in a secure area with restricted access. For specific storage 
conditions, please refer to the SmPC for trifluridine/tipiracil and to the Pharmacy manual for 
futuximab/modotuximab. 
The investigator and/or pharmacist of the study site will record temperature storage daily, using 
FONT-CIRT-FORM-311 "Therapeutic Unit temperature log sheet - centre" (recording Min-
Max temperature every working day) or an equivalent document.  
In case of temperature deviation, the investigator and/or pharmacist should immediately:  
­ Block the IWRS for the concerned IMPs and place them in quarantine (for Randomised part 
only). 
­ Alert the sponsor monitor and forward all required information. 
­ Put in place an adequate corrective/preventive action after the first temperature deviation 
occurs, in order to avoid recurrence. 
IMPs management will be verified on a regular basis by the study monitor.  
The investigator and/or the pharmacist of the study site and/or a designated person from their 
study team must complete in real time all the documents provided by the sponsor concerning 
IMPs management (therapeutic unit tracking form or an equivalent document…). Therapeutic 
unit tracking form, or an equivalent document, is the source document to fulfil.  
All defects or deterioration of IMPs or of their packaging, including complaints set out by a 
participant (change of taste, appearance…) are to be reported to the sponsor monitor, or to the 
IWRS if applicable.  
Destruction of the IMPs 
Destruction of the IMPs is the responsibility of the sponsor and/or the investigator and/or the 
pharmacist of the study site.  
Remaining 
treatments 
(used 
and 
unused 
IMPs 
except 
for 
used 
vials 
of 
futuximab/modotuximab) will subsequently be collected and stored according to the local 
procedures and requirements, by the person responsible for the IMPs management.  
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A certificated destruction will be performed according to standard modalities for that class of 
product and the attestation must be sent to the sponsor. The practical procedures for destruction 
of unused IMPs will be defined by the sponsor and adapted to the study site. IMPs collection 
and destruction form will be completed before the shipment of IMPs to destruction. Destruction 
of IMPs may be possible (after drug accountability and sponsor authorisation) when the product 
has been used, has expired or after at least the last visit of the last treated participant.  
For futuximab/modotuximab, used vials will be collected and destroyed according to local 
procedure by the study site at the time of preparation/administration along with other wastes. 
Thus, accountability and recovery by monitor are not applicable for used vials of 
futuximab/modotuximab. 
In case of batch recall 
In the event of anticipated return of IMPs to the sponsor (i.e., batch recall), the sponsor will 
prepare a notification letter for the investigator and/or pharmacist of the study site. On letter 
receipt, the investigator and/or the pharmacist will have to identify the participants in possession 
of the IMPs at the moment the incident becomes known, by using, among other tools, the 
therapeutic unit tracking form, or an equivalent document, and will contact them immediately. 
4.3.2.1. 
Futuximab/modotuximab 
Futuximab/modotuximab vials must be stored in a refrigerator at 2-8 °C protected from direct 
sunlight at all times and must not be frozen. For handling conditions and cleaning procedures 
instructions, please refer to the Pharmacy manual. 
4.3.2.2. 
Trifluridine/tipiracil 
Trifluridine/tipiracil tablets should not be sucked, chewed, crushed or kept in mouth. Direct 
contact of the powder from tablets containing trifluridine/tipiracil with the skin or mucous 
membranes should be avoided. If such contact occurs, immediately begin wash with soap and 
running water for minimum 15 minutes.  
The participant must be instructed in the handling of trifluridine/tipiracil as follows:  
­ To store at room temperature. 
­ To keep in a safe place and out of reach of children. 
­ To take within 1 hour after completing a meal (morning and evening meals) with a glass of 
water (or in accordance with the local SmPC of trifluridine/tipiracil). 
­ To make every effort to take doses on schedule. 
­ To remove from the study medication kit, only the number of tablets needed at the time of 
dosing and not to remove doses in advance of the next scheduled dosing. 
­ To wash their hands after handling. 
­ To report any missed doses to the investigator. If doses are missed or held, the participant 
should not make up for missed doses. 
­ If the participant vomits after taking trifluridine/tipiracil, the participant should not take 
another dose. 
­ To bring all used and unused kits to the study site at each CxD1. 
4.3.3. 
Management of blinding systems 
Not applicable. 
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4.4. Discontinuation of the study or temporary halt 
4.4.1. 
Premature discontinuation of the study or temporary halt 
After having informed the coordinator(s), this study may be temporarily halted or prematurely 
discontinued at any time for any sufficient reasonable cause by the sponsor (or by the sponsor 
further to a request from the DMC) or by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) or by the Competent Authorities or if the study meets the criteria for 
futility at the planned interim analyses. 
Two copies of the written confirmation will be dated and signed by the coordinator(s). The 
IRB/IECs and Competent Authorities will be informed according to local regulations. 
If the study is prematurely discontinued, the on-going participants should be seen as soon as 
possible, and the same assessments as described in Section 5.8 should be performed.  
Under some circumstances, the investigator may be informed of additional procedures to be 
followed to ensure that adequate consideration is given to the protection of the participant’s 
interests. 
In case of study temporary halt, the study may resume once concerns about safety, protocol 
compliance and data quality are addressed and satisfy the sponsor and the DMC and following 
approval from the IRB/IEC and/or Competent Authorities, according to local regulations. 
4.4.2. 
Premature discontinuation of the study in an investigator site (early site closure) 
The sponsor reserves the right to close a study site at any time for any sufficient reasonable 
cause at the sole discretion of the sponsor. 
The investigator may also initiate study site closure at any time, provided there is reasonable 
cause(s) and sufficient notice is given in advance of the intended termination. 
Reason for 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 Competent Authorities, the sponsor procedures, or GCP guidelines. 
­ Inadequate recruitment of participants by the investigator. 
­ Discontinuation of further study intervention development. 
The IRB/IEC(s) and competent Authorities will be informed according to local regulations. 
4.4.3. 
Discontinuation of the study in the event of objective reached 
An efficacy interim analysis is planned for the study when approximately 66% of the targeted 
total number of OS events have been reached. In case statistical significance is achieved at this 
planned interim analysis, the study will be stopped early for efficacy. Otherwise, the study will 
proceed to final analysis.  
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After having informed the International Coordinator, the sponsor or the DMC or the 
Institutional Review Board (IRB)/IEC or the Competent Authorities may terminate the study 
before its scheduled term. The IRB/IECs and competent authorities will be informed according 
to local regulations. 
If the study is prematurely discontinued due to objective reached, the ongoing participants 
should be seen as soon as possible, and the assessments described in Section 5.8 should be 
performed. 
Under some circumstances, the investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the 
participant’s interests. 
4.5. Source data 
Source data and source documents of the centre should be clearly identified in a specific, 
detailed and signed document before the beginning of the study 
­ Participant’s medical file (e.g., ECG report, clinical laboratory examinations reports, tumour 
assessment reports, paper diary (Safety lead in part) and e-Diary (Randomised part) and all 
other participant’s examinations results), requisition forms and registration forms, oncogene 
panel report will be considered as source document. 
­ Therapeutic unit tracking form, or an equivalent document. 
­ e-PRO service provider’s database (Randomised part) will be considered as source data. 
5. SCREENING AND WITHDRAWAL OF PARTICIPANTS 
5.1. Screening criteria 
5.1.1. 
Demographic characteristics 
1. Male or female participant ≥ 18 years old. 
5.1.2. 
Medical and therapeutic criteria 
2. Participants must have histologically or cytologically confirmed adenocarcinoma of 
mCRC (all other histological types are excluded), not amenable to surgical intervention 
due to either medical contraindications or non-resectability of the tumour. 
3. Based on ctDNA screening blood test analysis participants should be: 
­ Without RAS (KRAS and NRAS) mutations in any of the following codons: 
 
 
 
 
 
 
­ Without BRAF 
. 
4. Participants must have measurable or non-measurable lesion according to RECIST v1.1. 
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5b. Participants must have received at least 2 prior regimens of standard chemotherapy for 
mCRC and had demonstrated progressive disease or intolerance to their last regimen. 
The following characteristics apply: 
­ Prior standard chemotherapy must not have included trifluridine/tipiracil but must 
have included all of the following agents approved and available in each country: 
 Fluoropyrimidines, irinotecan and oxaliplatin. 
 At least one anti-VEGF pathway inhibitor (bevacizumab and/or aflibercept and/or 
ramucirumab and/or regorafenib). 
 At least one anti-EGFR mAb (cetuximab or panitumumab). 
 Patients with known MSI-H/dMMR tumours are eligible if they have received 
previous treatment with immune checkpoint inhibitors according to approved 
indication. 
­ Participants must have progressed during or within 6 months of the last administration 
of the last standard chemotherapy regimen. Participants who have withdrawn from 
standard treatment due to unacceptable toxicity warranting discontinuation of 
treatment and precluding retreatment with the same agent prior to progression of 
disease will be eligible to enter the study. 
­ Participants who received adjuvant/neoadjuvant chemotherapy and had recurrence 
during or within 6 months of completion of the adjuvant/neoadjuvant chemotherapy 
are permitted to count the adjuvant/neoadjuvant therapy as one regimen of 
chemotherapy. 
6a Participants should have received previous treatment with commercially available 
anti-EGFR mAbs for ≥ 16 weeks. 
7. Ability to swallow oral medication. 
8a. Estimated life expectancy ≥ 12 weeks. This criterion should be rechecked at inclusion 
visit (Safety Lead-in part) or randomisation visit. 
9a. ECOG performance status 0 or 1 (or equivalent Karnofsky PS of 70% to 100%). This 
criterion should be rechecked at inclusion visit (Safety Lead-in part) or randomisation 
visit. (Appendix 2). 
5.1.3. 
Informed consent 
10. Written informed consent obtained prior any study-specific procedure as described in 
Section 13.3. 
5.2. Non-screening criteria 
5.2.1. 
General criteria 
11. Pregnancy, possibility of becoming pregnant during the study and breast-feeding 
women. 
12. Unlikely to cooperate in the study. 
13a. Participation in another interventional study at the same time or within 4 weeks prior 
to the inclusion visit (Safety Lead-in part) or randomisation visit. Participation in study 
follow-up part without IMP administration, non-interventional registry or 
epidemiological study is allowed. 
14a. Patients currently receiving or having received anticancer therapies within 4 weeks 
prior to the inclusion visit (Safety Lead-in part) or randomisation visit. 
15. Participant already enrolled in the study (informed consent signed). 
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5.3. Inclusion criteria 
5.3.1. 
Medical and therapeutic criteria 
16a.  
Adequate haematological function based on the last assessment performed within 
7 days prior to the inclusion visit (Safety Lead-in part) or randomisation visit, defined as: 
­ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
­ Haemoglobin ≥ 90 g/L. In case of blood transfusion, the haemoglobin assessment 
must be performed 2 weeks or more after the transfusion. 
­ Platelet count ≥ 100 x 109/L. 
­ Adequate coagulation function for all participants. For participants receiving anti-
coagulant therapy (except platelet anti-aggregates) the adequate therapeutic levels of 
INR should be confirmed. 
17a. 
Adequate renal function based on the last assessment performed within 7 days 
prior to the inclusion visit (Safety Lead-in part) or randomisation visit defined as: 
­ Creatinine clearance ≥ 30 mL/min assessed using the Cockcroft & Gault formula 
(Appendix 3). 
18a. 
Adequate hepatic function based on the last assessment performed within 7 days 
prior to the inclusion visit (Safety Lead-in part) or randomisation visit, defined as: 
­ Total serum bilirubin < 1.5 x upper limit of normal (ULN) (unless Gilbert disease 
confirmed). 
­ Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; 
SGPT) ≤ 2.5 x ULN (if liver function abnormalities are due to underlying liver 
metastasis, AST [SGOT] and ALT [SGPT] ≤ 5 x ULN). 
19a. 
Serum potassium, serum phosphates, serum magnesium within normal limits 
with or without supplementation based on the last assessment performed within 7 days prior 
to the inclusion visit (Safety Lead-in part) or randomisation visit  
20a. 
Women of childbearing potential (WOCBP) must use a highly effective method 
of birth control (Section 5.5) during study treatment beginning within 2 weeks prior to the 
inclusion visit (Safety Lead-in part) or randomisation visit and continuing at least 6 months 
after the last dose of IMP. In case of oral contraception, women should have been stable on 
the same contraceptive drug (i.e. same active principle) for at least 3 months prior to the 
inclusion visit (Safety Lead-in part) or randomisation visit. 
21a. 
Male participants with WOCBP partners must use a condom during the study 
and until at least 6 months after the last dose of IMP. In addition, highly effective 
contraception should be considered for their female partners. Contraceptive measures do 
not apply if the participant is sterile, vasectomised or sexually abstinent. Sperm donation 
will not be allowed during the study and for 6 months after the last dose of IMP. 
5.4. Exclusion criteria 
5.4.1. 
Medical and therapeutic criteria 
22a. 
WOCBP tested positive in a serum pregnancy test within 7 days prior to the 
inclusion visit (Safety Lead-in part) or randomisation visit (Section 5.5). 
23a. Participants who have not recovered from toxicity of previous anticancer therapy, 
including grade ≥ 2 non-haematologic toxicity, prior to the inclusion visit (Safety Lead-in 
part) or randomisation visit. Certain toxicities will not be considered in this category (e.g. 
Grade 2 alopecia, peripheral neuropathy and/or endocrine end-organ failure being 
adequately managed by hormone replacement therapy). 
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24a. Major surgery within 4 weeks prior to the inclusion visit (Safety Lead-in part) or 
randomisation visit or participants who have not recovered from side effects of the surgery. 
25a. Participants with any other serious/active/uncontrolled infection, any infection 
requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to the 
inclusion visit (Safety Lead-in part) or randomisation visit. 
27. Known Hepatitis B Virus infection determined as HBsAg positive and / or known 
Hepatitis C Virus infection determined as detection of HCV RNA in serum or plasma 
by a sensitive quantitative molecular method. 
28. Known carriers of HIV antibodies. 
29a.Participants with active thrombosis, or a history of deep vein thrombosis or pulmonary 
embolism, within 4 weeks prior to the inclusion visit (Safety Lead-in part) or 
randomisation visit, unless adequately treated and considered by the investigator to be 
stable. 
30. Participants with active uncontrolled bleeding or a known bleeding diathesis. 
31. In the investigator’s opinion, uncontrolled diabetes mellitus even under treatment. 
32b. Known clinically significant cardiovascular disease or condition, including: 
­ Any uncontrolled arrhythmia (per the investigator’s discretion). 
­ Severe conduction disturbance (e.g. 3rd degree heart block) (per the investigator’s 
discretion). 
­ Uncontrolled hypertension (per the investigator’s discretion). 
­ Class III or IV cardiovascular disease according to the New York Heart Association 
(NYHA) Functional Classification (Appendix 4). 
­ History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, stenting or bypass grafting within 6 months prior to 
inclusion (Safety Lead-in part) or randomisation. 
­ QTc interval >480 ms 
33a. Participants with a significant gastrointestinal abnormality, including: 
­ Diarrhoea of Grade > 1 at the time of inclusion (Safety Lead-in part) or 
randomisation. 
­ Requirement for IV alimentation. 
­ In the investigator’s opinion, that might significantly interfere with proper absorption 
of the study treatments. 
34. Participants with non-healing wounds on any part of the body 
35a. Participants with skin rash of Grade > 1 from prior anti-EGFR at the time of inclusion 
(Safety Lead-in part) or randomisation, or any other skin toxicity precluding 
participation in the study according to investigator’s discretion. 
36a. Drainage for ascites, pleural effusion or pericardial fluid within 4 weeks prior to 
inclusion (Safety Lead-in part) or randomisation. 
37. Known, untreated central nervous system (CNS) or leptomeningeal metastases, or 
spinal cord compression; participants with any of these not controlled by prior surgery 
or radiotherapy, or participants with symptoms suggesting CNS involvement for which 
treatment is required. 
38. Other malignancies including those which were radically treated and for which the 
remission period at the time of screening is less than five years. Exemptions for this 
minimally required duration of remission period may be applied for carcinoma in situ 
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of the cervix, basal cell skin cancer and carcinoma in situ of gastric and oesophageal 
cancer that are deemed to be cured by adequate treatment. 
39a. Treatment with systemic immunosuppressive therapy within 4 weeks prior to inclusion 
(Safety Lead-in part) or randomisation (except steroids given in prophylactic setting or at a 
chronic low dose [≤ 20 mg/day prednisone equivalent]). 
40a. Prior radiotherapy if completed less than 4 weeks before the inclusion visit (Safety 
Lead-in part) or randomisation visit, except if provided as a short course for symptoms 
palliation only. Tumour lesions if previously irradiated cannot be chosen as target lesions 
for response evaluation. 
41. Known or suspected hypersensitivity to: 
­ Any 
of 
the 
excipients 
of 
formulated 
futuximab/modotuximab 
and 
trifluridine/tipiracil and of the NIMPs. 
­ Cetuximab or Panitumumab (Grade 3 or 4 hypersensitivity reactions during prior 
therapy with either Cetuximab or Panitumumab). 
42. In the investigator’s opinion, any clinically significant medical condition (e.g. organ 
dysfunction) or laboratory abnormality likely to jeopardise the participant’s safety or to 
interfere with the conduct of the study. 
43. Hereditary problems of galactose intolerance, total lactase deficiency or glucose-
galactose malabsorption. 
44. Active or history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension. 
For concomitant medication, refer to Section 6.3. 
5.5. Definition of women of childbearing potential and contraception methods 
Women of childbearing Potential 
A WOCBP, i.e. fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. 
Contraception methods 
Definition of highly effective contraception methods for the study:  
Highly effective methods of birth control refer to those which result in a low failure rate (i.e. 
less than 1% per year), when used consistently and correctly, such as combined hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), 
progestogen-only hormonal contraception when associated with inhibition of ovulation (oral, 
injectable, implantable), some intra uterine devices, intrauterine hormone-releasing system, true 
sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant), 
bilateral tubal occlusion, male sterilization (vasectomy). 
Women using hormonal contraceptive must also use a barrier method i.e. male or female 
condom, or cap, diaphragm or sponge with spermicide. 
Definition of acceptable contraception methods for the study:  
Acceptable contraception methods for the study are those considered as highly effective 
methods. 
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As it is unknown whether trifluridine/tipiracil may reduce the effectiveness of hormonal 
contraceptives, hormonal contraceptives could be used but must not be relied upon for 
contraceptive efficacy. Women using hormonal contraceptive must also use a barrier method 
i.e. male or female condom, or cap, diaphragm or sponge with spermicide. 
5.6. Retest management during screening period 
A participant who has (a) laboratory result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated providing that the investigator judges it relevant according to the 
participant previous results, or medical history and if s/he considers those laboratory 
abnormalities are likely to be transient. Results of the test(s) repeated should be obtained within 
the allowed screening period. In this case the participant will not be required to sign another 
informed consent, and the original participant ID number assigned by the investigator will be 
used. 
In any case, the last result available for each parameter must be considered for the participant 
inclusion. 
5.7. Additional information recorded at the screening/inclusion visit 
Not applicable. 
5.8. Participant withdrawal 
5.8.1. 
Withdrawal criteria 
A participant may be withdrawn from the study at any time for any reason (e.g. lost to 
follow-up, withdrawal of consent, AE). Premature discontinuation of IMP does not mean that 
the participant prematurely stops the participation in the study. 
Information to be collected during the last visit of these participants is given in Section 5.8.2. 
These follow-up modalities are used to ensure the efficacy and safety evaluation of all 
participants who received IMP. 
The reasons for premature IMP discontinuation are: 
­ Adverse events, incompatible with continuation of the IMP according to the judgment of 
the investigator, including no recovery in safety parameters. 
­ Pregnancy (for reporting, see Section 8.9.2.3).  
­ Major protocol deviation if it interferes with the study evaluations and/or if it jeopardises 
participant’s safety, e.g. any medical event requiring administration of an unauthorised 
concomitant treatment (Section 6.3). 
­ Radiologic progressive disease documented by CT-scan or MRI. 
­ Clinical progressive disease manifested by symptomatic deterioration. 
­ Non-medical reason (e.g. consent withdrawal, participant’s removal). 
­ Other, physician decision (for reasons that cannot be included in any of the criteria listed 
above for example: availability of a better therapeutic alternative for the participant). 
5.8.2. 
Procedure 
Upon discontinuation of study treatment, the investigator must: 
­ Notify the sponsor immediately. 
­ Register the end of treatment for the patient in the IWRS for Randomised part. 
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­ Record this information in the e-CRF, specifying the reason for the study participant’s 
withdrawal. If there are several reasons, the investigator must indicate the main reason. The 
investigator should document the discontinuation in the corresponding medical file. 
A withdrawal visit should always be suggested to the participant and should take place within 
4 weeks after the last IMP administration and prior to the start of a new anticancer therapy. 
In the case of discontinuation due to an AE (event requiring immediate notification [ERIN] or 
not), the investigator must make every effort to collect the information relating to the outcome 
of the event. If necessary, the information will be collected afterwards (Section 8.9.2.1). This 
information is recorded in that part of the e-CRF form which concerns AEs. If the investigator 
cannot collect the information from a visit, he must collect it from the doctor ensuring the 
follow-up of the participant. 
In case of discontinuation due to an ERIN, please refer to Section 8.7. 
Follow-up period: 
After the withdrawal visit, a follow-up will be done every 8 weeks (± 10 calendar days): 
­ For tumour assessment (unless patient had discontinued IMPs for radiologic disease 
progression or withdrawal of consent) until radiologic progression regardless of initiation of 
a new anticancer therapy. 
­ For survival status until death or the end of the study (whichever occur first). This follow-up 
can be done remotely by using various telecommunication technologies including but not 
limited to phone, internet and shared electronic medical records. 
Participants are at any time free to discontinue their participation in the study. If participants 
wish to withdraw their consent to treatment period (i.e. both IMPs and study assessments), they 
will be asked if they are willing to continue with Follow-up period for survival status (which 
can be done by phone). If participants wish to withdraw their consent to further participation in 
the study entirely (treatment period and follow-up period), this should be clearly documented 
in the patient notes and in the clinical study database. During the post-withdrawal follow-up 
period, the patient can participate to another clinical trial. 
A patient is considered discontinued from follow-up period only if one of the following 
occurs: 
­ Participant dies. 
­ At the end of study or if study is terminated by the sponsor or Competent authorities. 
The dispositions to be taken after the IMP discontinuation are described in Section 6.5. 
Subsequent anticancer therapy should be collected in the e-CRF. 
5.8.3. 
Lost to follow-up 
When the investigator has no news of the participant, he/she must make every effort to contact 
him/her or a person around him/her (phone calls, letters including registered ones, etc.), to 
establish the reason for the discontinuation of IMP and to suggest the participant comes to a 
withdrawal visit. If all these attempts to contact the participant fail, the investigator can then 
declare the participant “lost to follow-up”. The investigator should document all these attempts 
in the corresponding medical file. 
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6. TREATMENT OF PARTICIPANTS 
6.1. IMPs and NIMPs administered 
Safety Lead-In part: Futuximab/modotuximab administered in combination with 
trifluridine/tipiracil. 
Randomised part: Arm A futuximab/modotuximab administered in combination with 
trifluridine/tipiracil versus Arm B trifluridine/tipiracil.  
For treatment dose adaptations due to toxicities, please refer to Section 8.11. 
Specific COVID-19 situation: 
In case of highly suspected COVID-19 infection (based on typical symptoms or typical chest 
CT scan images) or confirmed COVID-19 infection (based on positive COVID-19 biological 
testing), the study treatment(s) should be immediately interrupted. 
The study treatment(s) could be restarted if participant is asymptomatic and a period of at least 
7 days after the diagnosis has been respected, and with a negative test (if the testing is required 
by the institutional site). Vaccination against COVID-19 is highly encouraged for all patients, 
preferably before study inclusion or whenever possible for patients included in the study. In 
this case, it is recommended to avoid vaccination 48 hours before or after 
futuximab/modotuximab administration if possible, for all cycles. 
6.1.1. 
Administration of futuximab/modotuximab 
6.1.1.1. 
Dose 
­ Loading dose: 9 mg/kg on C1D1. 
­ Maintenance doses: 6 mg/kg weekly (± 2 days), beginning on C1D8. 
The dose level of futuximab/modotuximab to be administered will be multiplied by the 
participant's weight in kilograms to arrive at the total dose to be delivered. During the 
Randomised part the number of vials needed for each dose will be automatically calculated by 
the IWRS based on weight as measured at the beginning of each cycle. Participants will 
continue to be treated with futuximab/modotuximab at that same assigned dose throughout the 
duration of the treatment period unless dose reduction is required.  
Dose adjustments should be made in the event of noted weight change (± 10%) as measured at 
the beginning of dosing cycle (CxD1). Weight fluctuations due to “third-space”/interstitial fluid 
accumulation (e.g., oedema, ascites, pleural effusion) or medications that result in fluid 
retention (e.g., glucocorticoids) do not require dose adjustment. 
6.1.1.2. 
Route of Administration 
Futuximab/modotuximab will be administered by the IV route, via a venous access catheter. 
The infusion set must contain an in-line filter (0.2-micron pore size). Infusion line should be 
flushed, per standard practice. The catheter may be placed into a peripheral vein (if accessible); 
administration via central venous catheter or port (if in place) is allowed. 
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In those instances when futuximab/modotuximab administration is associated with PK 
sampling, and administration is via peripheral IV catheter, infusions will be delivered into the 
arm contralateral to that from which blood samples for PK analysis are being obtained. 
6.1.1.3. 
Schedule 
­ Once weekly on Day 1, Day 8, Day 15, and Day 22 (± 2 days) of each cycle (4 weeks 
[28 days] equals 1 dosing cycle). 
A weekly dosing schedule is to be maintained, unless delay is required to allow for amelioration 
of toxicities (or in the event of scheduling difficulties associated with extended weekends, 
holidays, etc.). Futuximab/modotuximab should be administered after trifluridine/tipiracil 
intake. 
6.1.1.4. 
Diluent and Delivery 
Commercially available sterile 0.9% Sodium Chloride Injection, USP or local equivalent will 
be utilised as the diluent. 
Once diluted for IV administration, futuximab/modotuximab should be administered within 
8 hours, the infusion must be completed before the 8 hours maximum in-use time. 
6.1.1.5. 
Volume of Infusion 
­ 9 mg/kg dose will be delivered in a total volume of 500 mL. 
­ 6 mg/kg dose (or lower in the event of a dose reduction) will be delivered in a total volume 
of 250 mL. 
6.1.1.6. 
Duration of Infusion 
­ 9 mg/kg to be administered over 1 hour (+ 10 min). The maximum infusion rate of 
500 mL/hour should not be exceeded throughout the administration. 
­ 6 mg/kg to be administered over 30 minutes (+ 10 min), maintaining the maximum infusion 
rate of 500 mL/hour. 
Administration should be at a constant rate using a programmable volumetric infusion pump to 
ensure accuracy of delivery. Start and stop times of each infusion, and any interruptions in 
infusion will be recorded on the participant’s e-CRF. 
Note: In the event of an IRR, instructions for prolongation of the current and subsequent 
infusions are provided (Sections 8.11.2.1 and 8.12.4.1). 
6.1.1.7. 
Observation requirements 
The participants will be observed for a minimum of 2 hours following completion of the first 
administration of futuximab/modotuximab on C1D1 and a minimum of 1 hour following 
completion of subsequent infusions of futuximab/modotuximab (C1D8, onwards). Participants 
could be hospitalized for 24 hours after the administration of futuximab/modotuximab per the 
investigator’s discretion and/or local practice per country, to enable a close in-patient safety 
monitoring. At the end of each infusion, the IV line must remain in place for at least 1 hour to 
allow administration of IV drugs, if necessary. 
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Futuximab/modotuximab infusions will take place under the close supervision of physician or 
other study personnel experienced in administration of IV agents and in an environment where 
full resuscitation facilities are immediately available. 
6.1.2. 
Premedication before futuximab/modotuximab administration 
6.1.2.1. 
Premedication for Infusion-Related Reactions 
6.1.2.1.1. 
Infusion-Related Reactions 
There is an inherent risk for infusion-related reactions (IRRs) with the administration of mAbs. 
An IRR is defined as an AE occurring during the futuximab/modotuximab infusion and up to 
24 hours after the end of infusion (EoI), which is assessed by the investigator to be related to 
the infusion. Signs and symptoms of IRRs may include but are not limited to: 
­ Facial flushing and swelling. 
­ Rash including urticaria. 
­ Headache. 
­ Fever. 
­ Chills, rigors. 
­ Diaphoresis. 
­ Tachycardia. 
­ Hypotension. 
­ Nausea. 
­ Dry mouth. 
­ Chest/back/abdominal pain/discomfort. 
­ Chest and throat tightness. 
­ Shortness of breath. 
­ Cough, wheeze, stridor. 
­ Hypoxia. 
­ Bronchospasm. 
­ Laryngeal edema. 
­ Angioedema. 
­ Shock. 
The risk of an IRR is highest for the first administration of a mAb and diminishes with 
subsequent infusions. If an IRR occurs, it should be classified according to the NCI-CTCAE 
v5.0. 
Guidelines for grading and management of IRRs of all severities are provided (Appendix 9).  
6.1.2.1.2. 
Premedication for IRRs (Beginning with the First Dose) 
Premedication for prophylaxis of IRRs will be mandatory prior to each dose of 
futuximab/modotuximab. The following agents are required; recommended doses are provided: 
­ Glucocorticoid therapy: equivalent to 80 mg-100 mg IV methylprednisolone, approximately 
0.5 to 2 hours prior to the start of futuximab/modotuximab infusion (glucocorticoid 
premedication may be omitted in participants with insulin-dependent diabetes). 
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­ Antihistamine (H1 antagonist): equivalent to 25 mg-50 mg IV diphenhydramine, 
approximately 0.5 hours prior to the start of futuximab/modotuximab infusion (Appendix 9). 
The following agents are optional, and may be added to the premedication regimen at any time 
during the study at the investigator’s discretion; recommended doses are provided: 
­ Antihistamine (H2 antagonist): equivalent to 50 mg IV ranitidine or 20 mg IV famotidine or 
equivalent, approximately 0.5 hours prior to the start of futuximab/modotuximab infusion. 
­ Acetaminophen: 1000 mg IV (where available, or PO), or equivalent, approximately 
0.5 hours prior to the start of futuximab/modotuximab infusion. 
Note: Doses may be adjusted based on institutional practices. Administration of oral 
dexamethasone, 10 mg po, (or equivalent) 12 hours and 6 hours prior to administration of 
futuximab/modotuximab is permissible in participants experiencing IRRs or if an increased 
incidence or severity of IRRs is observed. 
6.1.2.1.3. 
Premedication for IRRs (following an IRR) 
For IRRs while on study, the following premedication instructions are provided: 
­ For Grade 1, Grade 2, or Grade 3 reactions, consider additional premedication or adjustment 
to premedication for subsequent infusions. 
­ For Grade 4 reactions, not applicable as no further treatment with futuximab/modotuximab 
is allowed (Appendix 9). 
6.1.2.2. 
Premedication for skin toxicity 
Management of skin toxicity will be done throughout the study according to the investigator’s 
discretion. PABA free SPF ≥ 15 UVA and UVB sunscreen protection is recommended to be 
applied to exposed skin areas before going outdoors. Guidelines for grading and management 
of dermatologic AEs of all severities are provided (Appendix 10). 
6.1.2.3. 
Premedication for other futuximab/modotuximab-related toxicities 
If following the first dose, a participant experiences symptoms suggestive of other mild-to 
moderate futuximab/modotuximab-related reactions (e.g., diarrhoea,), the participant may be 
premedicated with standard therapies to reduce the potential for such reactions in the future. 
Based on ongoing review of participant safety data, the sponsor (or DMC) may implement 
additional mandatory premedication for all participants treated in this study should a pattern 
emerge of other mild-to-moderate futuximab/modotuximab-related reactions (e.g., IRRs and/or 
any other trends in futuximab/modotuximab-related toxicities) that are amenable to prophylaxis 
with standard agents. Such action will occur following discussions between the investigator(s) 
and the sponsor. 
Any medications administered for either prophylaxis or therapy of signs/symptoms related to 
futuximab/modotuximab will be documented on the appropriate page of the participant’s 
e-CRF. 
6.1.3. 
Administration of trifluridine/tipiracil 
6.1.3.1. 
Dose/Route 
­ 35 mg/m²/dose, orally; maximum of 80 mg per dose based on the trifluridine component. 
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6.1.3.2. 
Schedule 
­ Trifluridine/tipiracil should be administered before futuximab/modotuximab administration. 
­ Trifluridine/tipiracil should only be given on Days 1 through 5 and Days 8 through 12 of 
each cycle. If doses are missed or held on those days, the participant should not make up for 
missed doses. Extension of study treatment into Days 6 to 7 or into the rest period (Days 13 
through 28) is not permitted. 
­ Trifluridine/tipiracil should be taken with a glass of water within 1 hour after completion of 
morning and evening meals (or in accordance with the local SmPC of trifluridine/tipiracil). 
­ Any missed doses reported by the participant should be recorded in the e-CRF. 
­ Trifluridine/tipiracil dosage is calculated according to BSA (Body Surface Area). 
Table (6.1.3.2) 1 shows the number of tablets that are needed per calculated BSA for a dose 
of 35 mg/m². Table (6.1.3.2) 2 shows the number of tablets that are needed per calculated 
BSA for a reduced dose (30 mg/m², 25 mg/m² and 20 mg/m²). 
The BSA will be calculated by the site (in Safety Lead-In part) or IWRS (in Randomised 
part) using the following DuBois formula30 (all BSA calculations are rounded to 2 decimal 
places): BSA (m²) = ([Body Weight (kg)]0.425 x [Height (cm)]0.725) x 0.007184. 
­ If at the beginning of the new treatment cycle, a participant’s body weight decreases by 
≥ 10% from baseline, the site (in Safety Lead-In part) or IWRS (in Randomised part), will 
recalculate the participant’s BSA and adjust trifluridine/tipiracil dosage. 
­ In case of change of dose level in Randomised part, the IWRS will provide the study site 
with the adjusted trifluridine/tipiracil dosage. 
­ No increase in trifluridine/tipiracil dose due to increase in BSA is permitted. 
Table (6.1.3.2) 1 - Number of tablets of trifluridine/tipiracil per dose (standard dose) 
according to body surface area 
Trifluridine/tipiracil 
Dose (2 x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose (2x daily) 
15 mg/6.14 mg 
20 mg/8.19 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥ 2.30 
80 
160 
0 
4 
BSA = body surface area (calculate to 2 decimal places) 
Table (6.1.3.2) 2 - Number of tablets of trifluridine/tipiracil per dose (reduced dose) 
according to body surface area 
Trifluridine/tipiracil
Dose (2 x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose (2x daily) 
15 mg/6.14 mg 
20 mg/8.19 mg 
Level 1 Dose reduction: From 35 mg/m2 to 30 mg/m2 
30 mg/m2 
< 1.09 
30 
60 
2 
0 
1.09 - 1.24 
35 
70 
1 
1 
1.25 - 1.39 
40 
80 
0 
2 
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Trifluridine/tipiracil
Dose (2 x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose (2x daily) 
15 mg/6.14 mg 
20 mg/8.19 mg 
1.40 - 1.54 
45 
90 
3 
0 
1.55 - 1.69 
50 
100 
2 
1 
1.70 - 1.94 
55 
110 
1 
2 
1.95 - 2.09 
60 
120 
0 
3 
2.10 - 2.28 
65 
130 
3 
1 
≥ 2.29 
70 
140 
2 
2 
Level 2 Dose Reduction: From 30 mg/m2 to 25 mg/m2 
25 mg/m2 
< 1.10 
25a 
50a 
2 (PM) a 
1 (AM) a 
1.10 - 1.29 
30 
60 
2 
0 
1.30 - 1.49 
35 
70 
1 
1 
1.50 - 1.69 
40 
80 
0 
2 
1.70 - 1.89 
45 
90 
3 
0 
1.90 - 2.09 
50 
100 
2 
1 
2.10 - 2.29 
55 
110 
1 
2 
≥ 2.30 
60 
120 
0 
3 
Level 3 Dose Reduction: From 25 mg/m2 to 20 mg/m2 
20 mg/m2 
< 1.14 
20 
40 
0 
1 
1.14 - 1.34 
25a 
50a 
2 (PM)a 
1 (AM)a 
1.35 - 1.59 
30 
60 
2 
0 
1.60 - 1.94 
35 
70 
1 
1 
1.95 - 2.09 
40 
80 
0 
2 
2.10 - 2.34 
45 
90 
3 
0 
≥ 2.35 
50 
100 
2 
1 
a At a total daily dose of 50 mg, participants should take 1 x 20 mg/8.19 mg tablet in the morning (AM) and 2 x 15 mg/6.14 mg tablets in the 
evening (PM). BSA = body surface area (calculate to 2 decimal places) 
Note: could be done in accordance with the local SmPC  
6.1.4. 
Premedication for trifluridine/tipiracil 
Trifluridine/tipiracil is associated with a moderate emetic potential; anti-emetic therapy is 
recommended to prevent nausea and vomiting. For more details see Section 8.12.1. 
6.1.5. 
Retreatment criteria  
These criteria are applicable after any dose delay and before the start of each cycle:   
­ ANC ≥ 1.5 x 109/L. 
­ Platelets ≥ 75 x 109/L. 
­ Ongoing AEs (IMP-related) should NOT meet study discontinuation criteria. 
­ Ongoing AEs (IMP-related) should have either ameliorated to ≤ Grade 1 severity, returned 
to baseline status, or resolved, with the exceptions of Grade 2 clinical events that are being 
adequately controlled with best supportive care (e.g. nausea, vomiting, diarrhoea, fatigue, 
rash) and asymptomatic laboratory abnormalities that are considered clinically insignificant 
and uncomplicated or that are resolving spontaneously or with conventional medical 
interventions. 
­ Ongoing AEs which, in the opinion of the investigator, should make it advisable to delay the 
administration of treatments. 
Note: Safety criteria to be met prior to the start of each cycle could be in accordance with 
the local SmPC of trifluridine/tipiracil. 
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6.2. IMP and NIMPs dispensing 
IMPs (futuximab/modotuximab and trifluridine/tipiracil) will be dispensed by the 
pharmacist/responsible of the healthcare establishment upon prescription of the investigator 
only. 
The investigator may only use the IMPs provided for the participants involved in the study and 
treated under his/her responsibility. Further instructions for the preparation and dispensation of 
futuximab/modotuximab are described in the Pharmacy Manual. 
All dosages of IMPs prescribed to the participant and all dose changes during the study must 
be recorded in the e-CRF. The exact dates and times at which futuximab/modotuximab was 
administered by the investigator and trifluridine/tipiracil was taken by the participant must be 
reported in the e-CRF. 
The detachable portion of the label on the IMP box must be stuck by the responsible of the 
healthcare establishment on an IMP label collection form or on the prescription form where the 
IMPs are dispensed by a pharmacist. 
NIMPs will be dispensed in accordance with Section 6.1.2. 
For the Randomised part the treatment arm will be allocated via IWRS using a central 
randomisation (1:1) to trifluridine/tipiracil in combination with futuximab/modotuximab or 
trifluridine/tipiracil monotherapy with stratification by ECOG PS (0 versus 1), ECD EGFR 
mutation (presence versus absence) and previous regimens of treatment (2 versus ≥ 3). A 
connection to the IWRS should be performed at each concerned visit to know the allocated kit 
number(s) to be dispensed to the participant (please see details in IWRS manual). 
6.3. Previous and concomitant treatments 
Collect all the anticancer therapies given for the colorectal cancer since the diagnosis of the 
disease. Collect all other therapies and medications, prescription and over-the-counter, from the 
time of ICF signature through the WV. Use of concomitant treatments should be documented 
in the patient’s source documents. At the Follow-Up Visit(s), collect any new anticancer 
therapy and the dates of treatment.  
In general, the use of any concomitant medication deemed necessary for the care of the 
participant is permitted in this study, except as specifically prohibited. Concomitant 
administration of a drug could result in DDI that could potentially lead to reduced activity or 
enhanced toxicity of the concomitant medication and/or trifluridine/tipiracil and/or 
futuximab/modotuximab.  
Before any intake of a new concomitant treatment from 7 days before the first IMP 
administration, during the study treatment period, and within 7 days following last IMP 
administration, the investigator should assess the potential DDIs with trifluridine/tipiracil and 
futuximab/modotuximab using the summary of product characteristics of the new concomitant 
treatment. The sponsor should be contacted in case of any doubt. If a medication appears on 
both ‘prohibited’ and ‘to be used with caution’ category, the medication is prohibited. 
In all cases, the use of herbal products should be avoided. Comedications could be monitored 
if necessary. 
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6.3.1. 
Prohibited treatments 
6.3.1.1. 
Before the study 
Participants are not permitted to receive: 
­ Previous investigational or anticancer therapy for mCRC within 4 weeks prior to inclusion 
visit (Safety Lead-in part) or randomisation visit. 
­ Prior trifluridine/tipiracil. 
­ Treatment with systemic immunosuppressive therapy within 4 weeks prior to inclusion 
(Safety Lead-in part) or randomisation (except steroids given in prophylactic setting or at a 
chronic low dose [≤ 20 mg/day prednisone equivalent]). 
­ Radiotherapy within 4 weeks prior to inclusion visit (Safety Lead-in part) or randomisation 
visit (except if provided as a short course for symptoms palliation only). 
6.3.1.2. 
During the study treatment period 
Participants are not permitted to receive: 
­ Any other investigational or any other anticancer therapy, including chemotherapy, 
immunotherapy, biological response modifiers, or endocrine therapy. 
­ Treatment with systemic immunosuppressive therapy (except steroids given in prophylactic 
setting or at a chronic low dose [≤ 20 mg/day prednisone equivalent] or short-term 
administration of steroids at daily doses higher than authorised by the protocol in situations 
of acute care management). 
6.3.2. 
Authorised treatments 
­ Prophylaxis 
for 
protocol 
therapy-related 
AEs: 
for 
participants 
receiving 
futuximab/modotuximab, premedication for IRRs are mandatory throughout the study. 
Premedication for other participant-specific futuximab/modotuximab-related AEs may be 
implemented as indicated at the investigator’s discretion. For participants receiving 
trifluridine/tipiracil, antiemetic therapy is recommended to prevent nausea and vomiting. 
­ Treatment 
of 
AEs 
or 
concomitant 
diseases: 
For 
participants 
receiving 
futuximab/modotuximab, instructions for management of hypomagnesemia are provided 
(Appendix 11). Clinical judgment should be used in the treatment of any other treatment-
related AEs or concurrent diseases/conditions that require management during the study and 
follow-up period. 
­ Radiotherapy for pain control against non-target lesions, provided it does not substantially 
influence bone marrow function is allowed. As far as possible, the irradiation of target 
lesions must be avoided. Pre-clinical data showed that trifluridine/tipiracil is a 
radiosensitizer, but no clinical data are available for the concomitant treatment with 
trifluridine/tipiracil and radiotherapy, so caution is required and close monitoring of 
participants is needed.  
­ Surgical procedures: Participants requiring a minor surgical procedure (e.g., port placement, 
stent placement, skin abscess drainage) may continue at the investigator’s discretion 
following discussion with the sponsor. A brief interruption in therapy may be considered. 
Participants requiring a more extensive or major surgical procedure should have protocol 
therapy interrupted but may resume treatment once fully recovered and at a minimum 
2 weeks after the procedure. Protocol retreatment criteria must be met. As far as possible, 
the surgery of target lesions must be avoided. 
­ Warnings related to trifluridine/tipiracil: 
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 Trifluridine and tipiracil are not substrates, inhibitors or inducers of cytochrome P450 
(CYP450) enzymes. Therefore, CYP450-related DDIs with trifluridine/tipiracil are 
unlikely to occur. 
 Trifluridine is activated by Thymidine Kinase (TK), metabolized by Thymidine 
Phosphorylase (TPase) and transported by the nucleoside transporters CNT1, ENT1 and 
ENT2, while Tipiracil is a substrate for OCT2 and MATE1 transporters. Therefore, the 
following drug categories should be used with caution when coadministered with 
trifluridine/tipiracil: 
 CNT1, ENT1 and ENT2 substrates. 
 OCT2 inhibitors. 
 MATE1 inhibitors. 
 TK substrates e.g., zidovudine that may compete with the effector trifluridine. Monitor 
for possible decrease in efficacy and consider switching to alternative antiviral drugs 
that are not TK substrates (e.g., lamivudine, didanosine and abacavir). 
It is unknown whether trifluridine/tipiracil may reduce the effectiveness of hormonal 
contraceptives. Therefore, hormonal contraceptives can be used but must not be relied upon for 
contraceptive efficacy. 
6.4. IMP compliance 
The number of injectable vials (for futuximab/modotuximab) dispensed and the number of 
tablets (for trifluridine/tipiracil) returned by the participant are to be counted by the investigator 
or a designated person from his/her team and recorded in the e-CRF and therapeutic unit 
tracking form, or an equivalent document. 
If the participant did not bring back all blisters of trifluridine/tipiracil dispensed at the previous 
visit, the investigator must estimate the number of IMP units taken by the participant since the 
previous visit, by questioning him/her. Each participant must record the exact time of intake of 
trifluridine/tipiracil in a diary provided by the sponsor. A paper diary will be used for the Safety 
Lead-In part and an electronic device (e-PRO) will be used for the Randomised part. The 
compliance will be assessed from the method described above. 
6.5. Discontinuation of the IMP 
After the discontinuation of the IMPs, participant’s treatment is left to the physician’s 
discretion. Futuximab/modotuximab is not licenced and not available on the market.  
After completion of the study (see Section 4.1.1 for end of study definition), participants 
currently being treated will be offered the option to continue the treatments.  
The sponsor will be responsible for the IMPs dispensing to the participants who are eligible to 
continue the treatments. The IMPs will be not assigned through IWRS, and IMPs will be 
manually assigned to participants by the investigator and/or pharmacist of the study site, based 
on the participant’s BSA/weight at the time of study completion.  
Specific rules may be followed in some countries according to local regulation. 
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7. ASSESSMENT OF EFFICACY 
7.1. Efficacy measurements 
The tumour assessments to be performed during the study are indicated in Table (4.1.2) 1 and 
Table (4.1.2) 2. 
7.2. Methods and measurement times 
7.2.1. 
Measurement times 
Tumour assessments/imaging of the chest, abdomen, and pelvis at a minimum (other 
localisations if clinically indicated) will be obtained at each time point listed below for all 
participants: 
­ Baseline: tumour assessment will be done within 28 days prior to the first administration of 
first IMP. Images obtained prior to participant signed ICF may be used if the date of the 
images is within 28 days of randomisation (first administration of first IMP for Safety 
Lead-In part) and if in line with methods and techniques that will be used during study. 
­ Treatment period: tumour assessments will be done every 8 weeks from C1D1 
(± 7 calendar days) until radiologic progression is documented. 
­ Withdrawal visit: tumour assessments will be done only if not performed within previous 
8 weeks. Every effort should be made to perform the WV tumour assessments prior to the 
start of new anti-cancer therapy. 
­ Follow-up period: tumour assessments will be done for participants who were withdrawn 
for reasons other than radiologic disease progression or consent withdrawal, every 8 weeks 
(± 10 calendar days) during the follow up period until the participant experienced radiologic 
progression, regardless of the initiation of a new anticancer therapy. 
Note: If the investigator determines that a participant develops clinical progression manifested 
by symptomatic deterioration but not supported by radiologic evidence of progression, the 
participant should stop study treatments. Symptoms of clinical progression must be documented 
in the participant’s source documents and in AE form (if judged by the investigator to be more 
severe than expected for the participant’s condition). Tumour assessments will continue every 
8 weeks (± 10 calendar days) until a radiologic progression is documented. 
Note: Evaluation of secondary anti-tumour efficacy endpoints in the Randomised part (PFS, 
OR, DC, DoR, TTR) will be based on the investigator’s assessment. 
All imaging data acquired for efficacy purposes (e.g., CT/magnetic resonance imaging (MRI) 
scans) will be transmitted to an imaging vendor for quality check and storage. Image 
transmission to the imaging vendor should be performed according to the imaging vendor 
manual. Blinded Independent Central Review (BICR) review of stored imaging data will be 
performed only if needed, retrospectively, and will not be provided to investigators for 
decisions regarding patient treatment. Should BICR be needed, the images will be read by 
readers who are blinded to treatment assignment and to other clinical data as specified in the 
BICR charter.  
7.2.2. 
Method of imaging 
­ The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
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­ Images must be acquired of the chest, abdomen and pelvis at a minimum (other localisations 
if clinically indicated) at each time point. 
­ Only CT or MRI must be used for tumour measurement (see specific cases below). 
­ Contrast enhanced CT is the preferred method for tumour assessments. If contrast agent is 
contraindicated in a participant, obtain at least a non-contrast chest CT and MRI of the 
abdomen and pelvis. 
Specific cases: 
­ If new lesions are identified by ultrasound in the course of the study, a confirmation by CT 
or MRI is needed. 
­ Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm 
diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
recommended. When lesions can be evaluated by both clinical examination and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study. 
­ In case of PET CT-scan, the CT portion of the PET–CT can be used for RECIST 
measurements. 
7.2.3. 
Tumour definitions 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
describe in Sections 7.2.3.1, 7.2.3.2, and 7.2.3.3. 
7.2.3.1. 
Measurable lesions 
­ Tumour lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT-scan with a CT-scan slice thickness no greater than 5 mm (when CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness). 
 10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
­ To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm 
in short axis when assessed by CT-scan (CT-scan slice thickness no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
7.2.3.2. 
Non-measurable lesions 
­ All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. 
­ Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
­ All non-measurable lesions can only be selected as non-target lesions. 
7.2.3.3. 
Special considerations regarding lesion measurability 
­ Bone lesions: 
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 Bone scan, PET-scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
­ Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
­ Lesions with prior local treatment: tumour lesions situated in a previously irradiated area, or 
in an area subjected to other loco-regional therapy, are not considered measurable unless 
there has been demonstrated progression in the lesion. 
7.2.4. 
Documentation of “target” and “non-target” lesions 
7.2.4.1. 
Target lesions 
­ When more than one measurable lesion is present at baseline all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
­ Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. 
­ A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then, only the short axis is added into the sum. 
­ The baseline sum diameters will be used as reference to further characterise any objective 
tumour regression in the measurable dimension of the disease. 
Specific situations: 
­ Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
­ While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small (e.g. 
2 mm). However, sometimes lesions or lymph nodes which are recorded as target lesions at 
baseline become so faint on CT-scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being ‘too small to measure’. In this case a value 
must be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
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has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
­ When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane 
between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’. 
­ An option of ‘Not Assessable’ for a lesion will only apply to lesions that that cannot be read 
due to technical reasons, for example: 
 CT artefact. 
 Participant positioning where the lesions are obstructed or cannot be seen. 
 Lesion that may not be seen in their entirety due to CT slice thickness. 
7.2.4.2. 
Non-target lesions 
­ Non-target lesions include all non-measurable lesions and measurable lesions that have not 
been selected as target lesions. 
­ Lymph nodes that have a short axis < 10 mm are considered non-pathological and should 
not be recorded. 
­ All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at Baseline. Measurements are 
not required, but their presence, absence, or unequivocal progression should be followed 
throughout the study. 
For additional guidance refer to RECIST 1.131 and RECIST 1.1: Update and clarification.32 
7.2.4.3. 
Response criteria 
On-site assessments will include the assessment of: 
­ Target and non-target tumour responses. 
­ New lesions if any. 
­ Overall response. 
7.2.4.4. 
Target and Non-target Response Assessments 
Tumour assessments will be performed as per RECIST version 1.131 at baseline and then every 
8 weeks from C1D1 (± 7 calendar days) until radiologic progression, death or end of study, 
whichever occurs first. The definition of responses for Target and Non-target lesions is 
presented in Table (7.2.4.4) 1 and Table (7.2.4.4) 2 respectively. 
Table (7.2.4.4) 1 - Target lesions response definitions 
TARGET LESIONS 
Lesions Response 
Definition 
Complete Response (CR) 
The disappearance of all target lesions. Any pathological lymph nodes must have 
reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of the target lesions, taking as a 
reference the baseline sum diameters. 
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TARGET LESIONS 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of the target lesions, taking as a 
reference the smallest sum on study, including the baseline sum. In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. Definitive new lesion presence also indicates progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as a reference the smallest sum diameter while on study. 
Table (7.2.4.4) 2 - Non-target lesions response definitions 
NON-TARGET LESIONS 
Lesions Response 
Definition 
Complete Response (CR) 
The disappearance of all non-target lesions and normalisation of tumour marker 
level. All lymph nodes must be non-pathological morphologically (i.e., < 10 mm 
in short axis in size). 
Non-CR/Non-PD 
A persistence of ≥ 1 non-target lesion(s) and/or maintenance of tumour marker 
level above the normal limits (not reaching the extent of ‘unequivocal 
progression). 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions (see definition below). 
(Note: the appearance of one or more new lesions is also considered progression). 
When the participant has measurable disease and non-measurable disease, to achieve 
“unequivocal progression” on the basis of the non-target disease, there must be an overall level 
of substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status.  
Tumour markers alone cannot be used to assess objective tumour response. If carcinoembryonic 
antigen level is initially above the upper normal limit, however, it must normalise for a 
participant to be considered in CR. 
For additional guidance refer to RECIST 1.131 and RECIST 1.1: Update and clarification.32 
7.2.4.5. 
New lesions 
­ The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the participant’s baseline lesions show partial or complete 
response. 
­ A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the participant who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The participant’s brain metastases are considered to 
be evidence of PD even if he/she did not have brain imaging at baseline. 
­ If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
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­ For new lesions discovered by fluorodeoxyglucose (FDG)-PET scan please refers to 
RECIST 1.1.31 
7.2.4.6. 
Overall Response Assessment 
Assessments will be based on the definitions provided in Table (7.2.4.6) 1. 
Table (7.2.4.6) 1 - Time point response for participants with target, or/and non-target disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
or 
Not 
all 
evaluated 
No 
PR 
PR 
Non-PD or Not all evaluated 
No 
PR 
SD 
Non-PD or Not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable (NE) 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
7.2.5. 
Best Overall Response Assessment 
The best overall response (BOR) as per RECIST 1.1 is the best response recorded from the start 
of the study treatment until the end of treatment. 
In this study, the minimum time from baseline to assess a response of “stable disease” is 
6 weeks. 
8. ASSESSMENT OF SAFETY 
All AEs and other situations relevant to the safety of the participants must be followed up and 
fully and precisely documented to ensure that the sponsor has the necessary information to 
continuously assess the benefit-risk balance of the clinical trial. 
8.1. Specification of safety parameters 
The safety measurements to be performed during the study are listed in Table (4.1.2) 1 and 
Table (4.1.2) 2. 
The safety assessments will include: 
­ Concomitant medication/procedure surveys. 
­ ECOG PS assessment. 
­ Vital sign assessment. 
­ Physical examination. 
­ Height and weight. 
­ Dermatologic examination (additional for futuximab/modotuximab participants in Safety 
Lead-In part and Arm A in Randomised part). 
­ Haematology panel. 
­ Biochemistry panel. 
­ Serum magnesium (Mg), total calcium (Ca), potassium (K) (additional for 
futuximab/modotuximab participants in Safety Lead-In part and Arm A in Randomised 
part). 
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­ Coagulation panel. 
­ Urinalysis. 
­ Pregnancy testing (if applicable). 
­ Electrocardiogram (ECG) 12-lead. 
8.2. Methods and measurement times 
The following safety measurements will be performed per the schedule outlined in 
Table (4.1.2) 1 and Table (4.1.2) 2. 
8.2.1. 
Vital signs 
Vital signs, including body temperature, pulse rate, respiratory rate, blood pressure and oxygen 
saturation by pulse oximetry to be obtained at the following time points:  
­ Inclusion 
Futuximab/modotuximab participants (Safety Lead-In part and Arm A in Randomised 
part) 
­ Cycle 1: 
 C1D1:  
 Pre-dose*.  
 EoI (± 5 min). 
 C1D8 (Pre-dose**). 
 C1D15 (Pre-dose**). 
 C1D22 (Pre-dose**). 
­ All subsequent cycles: 
 CxD1 (Pre-dose**). 
 CxD8 (Pre-dose**).  
 CxD15 (Pre-dose**). 
 CxD22 (Pre-dose**). 
­ WV. 
­ As clinically indicated. 
Trifluridine/tipiracil participants (Arm B in Randomised part) 
­ Cycle 1: 
 C1D1 (Pre-dose*). 
 C1D15.  
­ All subsequent cycles: 
 CxD1 (Pre-dose**). 
 CxD15. 
­ WV. 
­ As clinically indicated. 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part on CxD1). 
Obtain all the vital signs in a position that is consistent for all time points for each participant. 
Blood pressure should be measured with the participant in supine position.  
When measuring blood pressure, particular care should be taken to: 
­ Take measurements after at least 5 minutes rest. 
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­ Use a cuff appropriate to arm width and place the cuff at heart level. 
8.2.2. 
ECOG Performance Status 
ECOG performance status score (Appendix 2) to be performed at the following time points:  
­ Inclusion.  
­ Cycle 1: 
 C1D1 (Pre-dose*). 
­ All subsequent cycles: 
 CxD1 (Pre-dose**).  
­ Withdrawal visit. 
­ As clinically indicated.  
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part). 
8.2.3. 
Physical Examination 
Complete physical examination, including BSA calculation, and dermatologic examination to 
be performed at the following time point: 
­ Inclusion. 
­ Cycle 1: 
 C1D1 (Pre-dose*). 
­ All subsequent cycles: 
 CxD1 (Pre-dose**). 
­ WV. 
­ As clinically indicated. 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part). 
8.2.4. 
Height and weight 
Participant’s height to be obtained during the screening period. 
Body weight to be collected at the following time point: 
­ Inclusion. 
­ Cycle 1: 
 C1D1 (Pre-dose*). 
­ All subsequent cycles: 
 CxD1 (Pre-dose**).  
­ WV. 
­ As clinically indicated. 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part).  
For weight measurement, only scales with a valid calibration certificate must be used 
throughout the study. 
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8.2.5. 
Dermatologic 
examination 
(Only 
for 
futuximab/modotuximab-treated 
participants (Safety Lead-In part and Arm A of Randomised part) 
Timepoints shown are in addition to dermatologic examination performed as part of scheduled 
physical examinations; intention is to achieve weekly assessment during the treatment period. 
Dermatological examination to be performed at the following time point: 
­ Inclusion. 
­ Cycle 1: 
 C1D8, C1D15, C1D22 (Pre-dose**). 
­ All subsequent cycles: 
 CxD8, CxD15, CxD22 (Pre-dose**). 
­ As clinically indicated. 
**Study procedures obtained within 48 hours prior to study treatments administration  
8.2.6. 
Electrocardiogram (ECG) 
To include standard 12-lead ECG with measurement of PR interval, QRS duration, QT interval, 
RR interval, and QTc interval [ms] (using Fridericia's formula QTcF = QT / ³√RR), as well as 
heart rate [beats per minute (BPM)]). 
To be evaluated locally; ECGs should be performed using the calibrated instrument at each 
study centre and should be conducted after the participant has been supine (or semi-recumbent) 
for > 10 minutes. Participants with a QTc interval >480 ms at baseline are excluded. Participants 
with a QTc interval >480 ms during the treatment period should not be treated; dosing to be 
delayed. 
In the event of significant electrolyte abnormalities, the evaluation frequency should be 
increased to include additional evaluations between the scheduled assessments, as clinically 
indicated. An ECG should be performed in the event of ≥ Grade 3 hypomagnesemia. 
ECG to be performed at following time point: 
­ Inclusion  
­ Cycle 1: 
 C1D1 (Pre-dose*). 
­ Cycle 2: 
 C2D1 (Pre-dose**). 
­ As clinically indicated. 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part). 
8.2.7. 
Laboratory Assessments  
Laboratory tests will be collected and analysed by the study site’s certified laboratory during 
screening period and at C1D1 only if there is more than 7 days since screening assessment. In 
all cases, the full validated set of normal ranges values will be collected, as well as any update 
in these values during the study and must be documented on the corresponding page of the 
e-CRF. 
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It is preferable for all biochemistry blood samplings to be taken in fasting conditions except if 
the participant’s general health status does not permit it. 
Laboratory tests are to be performed as required per protocol. All laboratory values that are out 
of the normal range are to be evaluated for their clinical significance before exposing the 
participant to the next dose of study medication. 
Any laboratory abnormality that has a clinical impact on the participant, e.g., results in delay 
of study medications dosing, study discontinuation, requires treatment due to abnormal values, 
or is considered by the investigator to be medically important, must be reported as an AE, unless 
it is considered a supporting analysis to a clinical diagnosis that is already reported as an AE.  
All laboratory data will be analysed using NCI-CTCAE grade criteria (version 5.0). 
Repeat the evaluation of any clinically significant laboratory test, as clinically indicated, until 
the value returns to the baseline level or clinically stabilises, or until another treatment is given. 
8.2.7.1. 
Haematology 
Sample for haematological assessments to be collected at the following time points: 
­ Inclusion. 
­ Cycle 1: 
 C1D1 (Pre-dose*). 
 C1D15 (Pre-dose**). 
­ All subsequent cycles: 
 CxD1 (Pre-dose**).  
 CxD15 (Pre-dose**).  
­ WV. 
­ As clinically indicated. 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (only for CxD1: 
trifluridine/tipiracil intake in Arm B of Randomised part). 
Measure the following haematology parameters: haemoglobin, red blood cell count, white 
blood cell (WBC) count and differential count (neutrophils, lymphocytes), platelets. 
Note: for neutrophils and lymphocytes, parameters must be available in absolute value (not in 
percentage of WBC). 
8.2.7.2. 
Biochemistry 
Samples for biochemistry assessments to be collected at the following time points: 
­ Inclusion 
­ Cycle 1 
 C1D1 (Pre-dose*) 
 C1D15 (Pre-dose**) 
­ All subsequent cycles 
 CxD1 (Pre-dose**)  
 CxD15 (Pre-dose**)  
­ WV 
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­ As clinically indicated 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (only for CxD1: 
trifluridine/tipiracil intake in Arm B of Randomised part). 
Measure the following serum biochemistry parameters: albumin, ionogram (sodium, potassium, 
chloride, total calcium, magnesium, phosphate), blood urea nitrogen (BUN), serum creatinine, 
glucose, AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, total bilirubin (in case of 
elevation in total bilirubin, fractionation (direct/indirect) should be performed), LDH. 
Note: If BUN is not available, use the following conversion: 
Table (8.2.7.2) 1 - Correspondence between urea and BUN values 
BUN (mmol/L) = UREA (mmol/L) 
BUN (mg/dL) = UREA (mg/dL) x 0.467 
BUN (mg/dL) = UREA (mmol/L) / 0.3571 
8.2.7.3. 
Serum 
Magnesium, 
Calcium, 
and 
Potassium 
(Only 
for 
futuximab/modotuximab-treated participants (Safety Lead-In part and Arm A 
of Randomised part) 
Samples for serum magnesium, total calcium, and potassium assessment to be collected at the 
following time points: 
­ Cycle 1: 
 C1D8 (Pre-dose*). 
 C1D22 (Pre-dose*). 
­ All subsequent cycles: 
 CxD8 (Pre-dose*).  
 CxD22 (Pre-dose*).  
­ As clinically indicated**. 
*Study procedures obtained within 48 hours prior to study treatments administration  
** An ECG should be performed in the event of ≥ Grade 3 hypomagnesemia and if otherwise clinically 
indicated. 
Timepoints shown are in addition to testing performed as part of scheduled biochemistry panels; 
intention is to achieve weekly magnesium, total calcium, and potassium testing during the 
treatment period. 
8.2.7.4. 
Coagulation 
Samples for coagulation assessments to be collected at the following time points: 
­ Inclusion. 
­ Cycle 1: 
 C1D1 (Pre-dose*).  
­ All subsequent cycles: 
 CxD1 (Pre-dose**).  
­ WV. 
­ As clinically indicated. 
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*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part). 
To include the following coagulation parameters: partial thromboplastin time [PTT] and/or 
activated PTT [aPTT], prothrombin time. 
8.2.7.5. 
Urinalysis 
Samples to be collected at the following time points: 
­ Inclusion. 
­ Cycle 1: 
 C1D1 (Pre-dose*).  
­ All subsequent cycles: 
 CxD1 (Pre-dose**).  
­ WV. 
­ As clinically indicated. 
*Study procedures prior to the first study treatments administration: to be done at C1D1 prior to study 
treatments administration only if baseline procedures have been done more than 7 days prior to C1D1. 
**Study procedures obtained within 48 hours prior to study treatments administration (trifluridine/tipiracil 
intake in Arm B of Randomised part). 
Multipanel chemical test strips are acceptable and should include assessment of specific gravity, 
pH, protein, glucose, ketones, leukocytes, nitrite, bilirubin, urobilinogen, and blood. 
Microscopic examination of sediment, if clinically indicated, to include assessment of cells 
[WBC and red blood cells (RBC)] per high power field and casts. 
If dipstick proteinuria ≥ 2+, a 24 hours-collection urine is required, and quantitative assessment 
of proteinuria will be performed. 
Note: If only quantitative proteinuria is done by the study site, the correspondence between 
quantitative and qualitative values must be clearly described. 
If no correspondence is available, please use the one in the table below: 
Table (8.2.7.5) 1 - Correspondence between qualitative and quantitative proteinuria values 
­ Negative < 10 mg/dL 
­ 2+ [100 - 300] mg/dL 
­ Trace [10 - 30] mg/dL 
­ 3+ [300 - 1000] mg/dL 
­ 1+ [30 - 100] mg/dL 
­ 4+ > 1000 mg/dL 
8.2.7.6. 
Pregnancy Testing 
If the participant is female of childbearing potential, perform pregnancy testing with serum 
beta-human chorionic gonadotropin (β-HCG) or highly sensitive urine test (except during 
screening period), and record the date, time, and test results in the participant’s source 
documents: 
Pregnancy tests should be performed at screening period (with serum βHCG test only, within 
7 days prior to first administration of first IMP), at the beginning of each cycle during the 
treatment period, upon treatment discontinuation, at the first follow-up visit, and additionally if 
clinically indicated, for all relevant participants. 
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Note: more frequent pregnancy tests should be performed if required by local law or as 
clinically indicated. 
8.3. Definition of Adverse events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject participating 
in a clinical study, whether or not there is a causal relationship with the IMP and/or 
experimental procedures, occurring or detected from the date the participant signs the 
information and consent form, irrespective of the period of the study (periods without 
administration of the IMP (e.g. run-in period) are also concerned). 
An AE can therefore be: 
­ Any unfavourable and unintended sign (including an abnormal finding from an additional 
examination such as laboratory tests, X-rays, ECG, …) which is deemed clinically relevant 
by the investigator. 
­ Any symptom or disease. 
­ Any worsening during the study of a symptom or a disease already present when the 
participant entered the study (increase in frequency and/or intensity). 
­ Fatal studied disease progression. 
and detected during a study visit or at an additional examination or occurred since the previous 
study visit (including relevant event reported in safety evaluation scale or e-PRO). 
Of note: 
­ Any hospitalisation for administration of anti-tumoural treatment and/or associated 
protocol (during or after the study) or other care measures for cancer (e.g. overnight 
hospital stay to receive a blood or platelets transfusion), for social reasons, educational 
purpose (e.g. learning of diabetes management by the participant) or routine check-up 
should not be considered as an AE event and should not be reported in the e-CRF. 
­ Any clinical finding or clinically significant abnormal laboratory findings or other abnormal 
safety assessments, which are associated with the studied disease should not be considered 
as an AE unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
­ A non-fatal “studied disease progression” itself should not be considered as an AE. 
­ The following procedures, whether planned before the study or not, whether leading to a 
hospitalisation or not, should not be reported in the e-CRF and kept in the source data 
(or participant file):   
 Therapeutic procedures related to a non-aggravated medical history (e.g. cataract 
extraction not due to an aggravation of the cataract during the study, haemodialysis 
sessions related to a renal insufficiency not aggravated during the study). 
 Prophylactic procedures (e.g. sterilisation, wisdom teeth removal). 
 Comfort procedures (e.g. cosmetic surgery). 
 Control procedures of a pre-existing condition without aggravation (e.g. colonoscopy to 
control the remission of colon cancer). 
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8.4. Definition of Serious adverse events 
Any AE that at, any dose: 
­ Results in death. 
­ Is life-threatening(1). 
­ Requires inpatient hospitalization or prolongation of existing hospitalization. 
­ Is medically significant(2). 
­ Results in persistent or significant disability/incapacity(3). 
­ Is a congenital anomaly/birth defect(4). 
(1) Life-threatening in this context 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.  
(2) Any event that might not be immediately life-threatening or result in death or hospitalisation, but might 
jeopardise the participant or might require intervention to prevent one of these outcomes (for example: oedema 
or allergic bronchospasm that required intensive treatment at home, blood dyscrasia, convulsions that do not 
result in hospitalisation, or development of drug dependence or drug abuse). The investigator should exercise 
his/her scientific and medical judgement to decide whether or not such an event requires expedited reporting to 
sponsor. 
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the participant to 
lead a normal life, in other words leads to a persistent or permanent significant change, deterioration, injury or 
perturbation of the participant's body functions or structure, physical activity and/or quality of life. 
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men or women) or 
during pregnancy that resulted in an adverse outcome in the child. 
8.5. Definition of Overdose 
This refers to any intake of a quantity of IMP or a product other than the IMP taken as part of 
the protocol (NIMP) which is above the maximum dose recommended in the study protocol, 
independently of the occurrence of any AE. 
The quantity should be considered per administration or cumulatively regarding the maximum 
dose recommended in the study protocol.  
An overdose with trifluridine/tipiracil is defined as taking a dose beyond the recommended dose 
in one day or beyond the recommended total dose in each cycle (i.e., 35 mg/m²/dose or 
> 160 mg/day for trifluridine/tipiracil). There is no known antidote available in case of 
trifluridine/tipiracil overdose.  
An overdose with futuximab/modotuximab is defined as administration of a dose above the 
recommended dose (above 9 mg/kg as loading dose or above 6 mg/kg for other 
administrations). 
Overdose should be managed aggressively with close monitoring and administration of 
prophylactic and symptomatic therapies to prevent or correct potential side effects. 
For procedures to be followed in case of overdose, please see Sections 8.7 and 8.9.2.3. 
8.6. Definition of Adverse event of special interest 
Not applicable. 
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8.7. Definition of Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. without delay and within 24 hours of awareness 
at the latest) to the sponsor if it is: 
­ A serious adverse event (SAE). 
­ An overdose of the IMP/NIMP even if asymptomatic. 
­ Any intake of IMP/NIMP by a person around the participant. 
­ A pregnancy. 
8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) 
It is important that the investigator gives his/her own opinion regarding the seriousness, the 
intensity of the event as well as the cause-effect relationship between an AE and the research 
(IMP, NIMP or study protocol). This evaluation must be assessed by the investigator and 
reported in the AE form. In addition, the sponsor will be responsible for the evaluation the 
expectedness of the event (Section 8.9.3).  
The Seriousness should be evaluated according to international guidance (see definition 
Section 8.4, in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Topic E2A33 and EU DIRECTIVE 
2001/20/EC of 4 April 2001.34 
The severity of all AEs will be graded according to the NCI-CTCAE on a five-point scale 
(Grade 1 to 5) (version 5.0): 
­ Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
­ Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)1. 
­ Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL2. 
­ Grade 4: Life-threatening consequences; urgent intervention indicated. 
­ Grade 5: Death related to AE. 
The cause-effect relationship  
The investigator must make an assessment in the AE form whether the AE is related or not to 
the research, meaning:  
­ AE related to IMP(s). 
­ AE related to study protocol i.e. related to:  
 A procedure scheduled in the study protocol (i.e. exercise test, MRI, etc.), or  
 A change or withdrawal of previous / concomitant treatment related to the conditions of 
the protocol or 
 A product other than the IMP, taken as part of the protocol (NIMP or other). 
 
1 Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
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Moreover, the investigator has to assess if the AE is related to disease progression. Cases ticked 
“related” by the investigator or judged by the sponsor as having a reasonable suspected causal 
relationship to the IMP (AE linked to the MoA of the IMP…), will be considered as suspected 
Adverse Drug Reaction. In general, if a relationship between AE and IMP is at least reasonably 
possible (i.e. the relationship cannot be ruled out) it is to be considered as “related”. 
If in the investigator’s opinion there is a causal relationship with the NIMP, the AE must be 
considered as related to study protocol. 
8.9. Reporting procedures 
8.9.1. 
Time frame for AE reporting 
Any event meeting the above mentioned definitions (see Sections 8.3 and 8.7) must be reported 
to the sponsor on an adverse event form if it occurred: 
­ Before the first administration of IMP, for fatal events and events related to the research. 
­ At any time after the first administration of IMP up to the participant’s last IMPs 
administration for all events. 
­ After the participant’s last IMP administration: 
 Up to 30 calendar days after the participant’s last IMPs administration for all AEs, 
regardless of the supposed role of the research. 
 Irrespective of the time of onset in case of serious AE related to the research. 
Of note, events occurring between the signature of the ICF and the first administration of the 
IMP for which the investigator does not consider an association with the research must be 
reported as medical history or as signs or symptoms related to the studied disease in the 
dedicated form of the e-CRF.  
Fatal events, related or not to the research, occurring after ICF signature and before first IMP 
administration, must be reported on AE form. 
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Figure (8.9.1) 1 - Rules for Adverse Event reporting 
 
8.9.2. 
Responsibilities of the investigator 
For any AE and special situation mentioned above the investigator must: 
­ Note in the participant's medical file the date on which he/she learned of the event (at a 
follow-up visit or a telephone contact with the participant or a third person, …) and any other 
relevant information which he/she has learned of the event. 
­ Assess the event in terms of seriousness, severity and causality. 
­ Report the event to the sponsor using the AE form (in case of ERIN, the reporting should 
be done immediately). 
­ Document the event with additional useful information. 
­ Ensure the follow-up of the event. 
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IRB/IEC, 
in accordance with local regulations. 
Moreover, the investigator must report to the sponsor and/or to the IRB/IEC and/or to the 
Competent Authorities in accordance with the local regulation, any new information that might 
materially influence the benefit-risk assessment of the IMP or that would be sufficient to 
consider changes in the IMP administration or in the overall conduct of the clinical 
investigation. 
8.9.2.1. 
Documentation of the event 
The investigator must ensure that all events are well documented. He/she should provide the 
sponsor on request, with anonymized copies of relevant documents (e.g. autopsy report and 
terminal medical reports [ICH E6 R2]).35  
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8.9.2.2. 
Follow-up of adverse events 
The investigator must ensure that follow-up of the participant is appropriate to the nature of the 
event, and that it continues until resolution if deemed necessary. 
Any change in terms of diagnosis, intensity, seriousness, measures taken, causality or outcome 
regarding an AE already reported must be written up in a new complete evaluation of the event 
documented on the “Adverse event” page previously created for the event. 
If the AE has not resolved at the participant's final visit, the participant must be followed up 
suitably and any information on the outcome of the event will be noted on the “Adverse Event” 
page previously created for the event. 
If the follow-up of the participant is not done by the investigator him/herself (hospitalisation, 
followed by a specialist or the participant's general practitioner, …), the investigator will do 
everything to establish/maintain contact with the person/department in charge of follow-up of 
the participant. 
8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP/NIMP by a person 
around the participant) 
Pregnancy  
If a female participant in the study becomes pregnant, the investigator must: 
­ Stop immediately the study treatments. 
­ Report it on an “Adverse Event” page as well as on the specific paper pregnancy form 
(1st page) to be notified immediately (ERIN). 
­ Contribute to the follow-up of this pregnancy and provide the sponsor with information 
concerning this follow-up (notably using the 2nd page of the specific paper pregnancy form). 
If the partner of a participant becomes pregnant during the study, the pregnancy should not be 
reported in the e-CRF. The investigator should immediately contact the sponsor (contact details 
provided in the investigator’s study file) who will inform him/her about the procedure to be 
followed. 
Overdose of IMP or NIMP 
­ In case of overdose, the investigator should report it on an “Adverse Event” page to be 
notified immediately (ERIN). 
­ Overdose should be followed-up to ensure that the information is as complete as possible 
with regards to:  
 Dose details (number of units, duration, …) and, if multiple overdose, details regarding 
other medicinal products or substance. 
 Context of occurrence, i.e. intentional (suicide attempt, other reason) or accidental (error 
in prescription, administration, dispensing, dosage). 
 Related signs and symptoms (“No related adverse events” to be reported otherwise). 
 Outcome. 
­ Insofar as possible, a blood sample should be collected for assay of the IMP taken. 
Intake of IMP or NIMP by a person around the participant This event should not be 
reported in the e-CRF. The investigator should immediately contact the sponsor (contact details 
provided in the investigator’s study file) who will inform him/her about the procedure to be 
followed. 
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8.9.2.4. 
Recording Methods in the e-CRF 
Adverse events must be documented on the “Adverse Event” page of the e-CRF. 
In case of chronic disease: 
­ If the disease is known when the participant enters in the study, only worsening (increased 
frequency and/or intensity of the episodes/attacks) will be documented as an adverse event. 
­ If a disease is detected during the study and if repeated episodes enable diagnosis of a chronic 
disease, the episodes will be grouped on the “Adverse Event” page previously created for 
the event which will clearly describe the diagnosis. 
8.9.2.5. 
Procedure for an event requiring an immediate notification 
In case of an event requiring an immediate notification, the investigator must: 
­ Immediately after being informed of this event, fill in the participant's medical file as well 
as the “Adverse Event” page of the e-CRF according to the general instructions available 
in the e-CRF, without waiting for the results of the clinical outcome or of additional 
investigations. When data will be submitted into the e-CRF system, an e-mail will be 
immediately and automatically sent to the sponsor. 
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IRB/IEC, in 
accordance with local regulations. 
Moreover, on request, the investigator should provide the sponsor with the documents required 
in Section 8.9.2.1. 
If an adverse event initially non-serious worsens and becomes a serious adverse event, this must 
be reported immediately on an “Adverse event” page of the e-CRF. 
In case the e-CRF is unavailable when the investigator was informed of the ERIN, he/she 
should: 
­ Immediately fill in a paper “Adverse event” page: 
 For serious event on a paper “Adverse event – Initial information” page. 
 For event initially non-serious on a paper “Adverse event – Initial information” page, and 
the worsening leading to seriousness on a paper “Adverse event – Additional 
information” page. 
­ Immediately send the page(s) by fax or a scan of them by e-mail to the person(s) designated 
in the contact details provided in the investigator’s study file or outside working hours, the 
24-hour phone line. 
­ As soon as the e-CRF becomes available, the investigator should enter these data in the 
“Adverse Event” page of the e-CRF.  
8.9.3. 
Responsibilities of the sponsor 
In accordance with international guidance, the assessment of the seriousness and the causality 
of adverse events are usually made by the investigator but falls also under sponsor’s duties, 
who is responsible for ensuring that all suspected unexpected serious adverse reactions are 
reported to Competent Authorities and Ethics Committees.  
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The sponsor will review the seriousness of the adverse events and the causality of (at least) the 
serious adverse events, whether reported by the investigator or upgraded by the sponsor. The 
causality and the seriousness may be upgraded (but never downgraded). Anonymized copies of 
relevant documents may be asked for the event assessment. If the assessments of the 
investigator and the sponsor are different, both will be reported in the clinical study report. 
In addition, the sponsor is responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the IMP. 
Independently of the regulatory obligations of the investigator, the sponsor must report the 
pharmacovigilance data and any new safety finding likely to affect the benefit /risk balance of 
the product, required in ICH GCP guidelines and local regulations, to the appropriate 
Authorities, to all the investigators involved and to the trial participants involved - through the 
investigators - as mentioned in Section 13.4.  
The concerned authorities will be notified as soon as possible by the sponsor of the DMC 
recommendations if any, where relevant for the safety of subjects (i.e. modification or 
termination of the study). 
8.10. Responsibilities of Data Monitoring Committee 
In accordance with the DMC charter and the rules for DMC functioning, the DMC is 
responsible for reviewing the efficacy (including disease-related events) and safety data on a 
regular basis and providing written recommendations to the International Coordinator and the 
sponsor regarding the conduct of the study (modification or termination). For more detail refer 
to Section 12.4. 
8.11. Management of treatment dose adaptations due to toxicities 
For participants who have experienced a dosing modification, reasons for dose modifications 
or delays, the supportive measures taken, and the outcome will be documented in the 
participant's source documents and recorded in the e-CRF. 
In 
the 
futuximab/modotuximab 
plus 
trifluridine/tipiracil 
arm 
doses 
of 
either 
futuximab/modotuximab, or trifluridine/tipiracil, or both drugs can be modified, depending on 
the toxicity observed.  
General rules: 
Before starting a new treatment cycle, toxicity must have resolved as specified in the 
Sections 8.11.1 and 8.11.2 and the safety criteria to be met as specified in the Section 6.1.5. 
­ If toxicity due to any of the IMPs does not resolve during the given cycle to Grade 1 or 
baseline, the start of the next cycle will be delayed for a maximum of 30 days for 
trifluridine/tipiracil and 21 days for futuximab/modotuximab (see Sections 8.11.1 and 
8.11.2). If more than the maximum delay period is needed for recovery, the next cycle should 
be started with the IMP not concerned by the toxicity.  
­ If, in the opinion of the investigator, the toxicity is clearly related to one of the treatments, 
reduction of one and not the other agent is appropriate. If, in the opinion of the investigator, 
the toxicity is related to the futuximab/modotuximab only futuximab/modotuximab should 
be reduced according to recommended dose modifications. If, in the opinion of the 
investigator, the toxicity is related to the trifluridine/tipiracil only trifluridine/tipiracil should 
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be reduced according to recommended dose modifications. If the toxicity is related to the 
combination of two agents, both agents should be reduced (if applicable), interrupted or 
discontinued according to the recommended dose modifications.  
­ Participants 
may 
have 
trifluridine/tipiracil 
discontinued 
and 
continue 
on 
futuximab/modotuximab 
alone. 
Similarly, 
participants 
may 
discontinue 
futuximab/modotuximab and continue on trifluridine/tipiracil alone if appropriate.   
8.11.1. Management of treatment dose adaptations due to trifluridine/tipiracil toxicities 
All toxicities related to trifluridine/tipiracil must have resolved to Grade 1 or baseline before 
the start of a new treatment cycle. 
In the event of haematological and/or non-haematological toxicities, rules for 
trifluridine/tipiracil dose interruption and resumption are provided in Table (8.11.1) 1; rules for 
dose modifications are provided in Table (8.11.1) 2 and Table (8.11.1) 3.  
Treatment interruptions are regarded as lost treatment days and missed doses should not be 
replaced; the planned treatment schedule should be maintained. 
A new treatment cycle with trifluridine/tipiracil can be started only if neutrophils count is ≥ 1.5 
x 109/L and platelets count is ≥ 75 x 109/L. 
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Table (8.11.1) 1 - Dose interruption and resumption criteria for haematological toxicities 
related to myelosuppression 
Parameter 
Interruption criteria* 
Resumption criteria** 
Neutrophils 
< 0.5 × 109/L 
≥ 1.5 × 109/L 
Platelets 
< 50 × 109/L 
≥ 75 × 109/L 
* Interruption criteria apply only during active treatment intake period (i.e., D1-5 and D8-12) based on an unscheduled laboratory 
assessment.  
**Resumption criteria apply to the start of the next cycle for all participants regardless of whether or not the interruption criteria were met. 
Table (8.11.1) 2 - Recommended dose modifications in case of haematological adverse event 
related to myelosuppression 
Adverse event related to myelosuppression 
Recommended dose modifications 
Febrile neutropenia 
Don’t start a new treatment cycle until the resumption criteria 
are met (Table (8.11.1) 1) 
When resuming dosing, decrease the dose level by 5 mg/m² 
from the previous dose level (Table (6.1.3.2) 2) 
Dose reductions are permitted to a minimum dose of 
20 mg/m²/dose twice daily 
Do not increase dose after it has been reduced 
NCI-CTCAE 
Grade 4 
neutropenia 
count 
< 0.5 × 109/L that results in more than 1 week’s 
delay in start of next cycle 
NCI-CTCAE 
Grade 4 
thrombocytopenia 
< 25 × 109/L that results in more than 1 week’s 
delay in start of next cycle 
Table (8.11.1) 3 - Recommended dose modifications in case of non-haematological adverse event 
related to trifluridine/tipiracil 
Adverse event related to trifluridine/tipiracil 
Recommended dose modifications 
NCI-CTCAE non-haematologic grade 3 or 4 
adverse reaction; except for grade 3 nausea and/or 
vomiting controlled by antiemetic therapy or 
diarrhoea responsive to antidiarrheal medicinal 
products. 
Don’t start a new treatment cycle until toxicity resolves to 
Grade 1 or baseline 
When resuming dosing, decrease the dose level by 5 mg/m² 
from the previous dose level (Table (6.1.3.2) 2) 
Dose reductions are permitted to a minimum dose of 
20 mg/m²/dose twice daily 
Do not increase dose after it has been reduced 
If the participant recovers from toxicities requiring treatment interruption: 
­ During the 2-week active treatment intake period of a cycle (treatment D1-D12): 
 If no dose reduction is required, trifluridine/tipiracil may be resumed during that cycle. 
Missed doses must not be caught up. 
 If a dose reduction is required, trifluridine/tipiracil should be resumed at the start of the 
next treatment cycle at the appropriate dose level. 
­ During the rest period (D13-28): 
 Start the next cycle on schedule at the appropriate trifluridine/tipiracil dose level.  
If the toxicity does not resolve during the given cycle to Grade 1 or baseline, the start of the 
next cycle may be delayed by a maximum of 30 days from the last dose of trifluridine/tipiracil 
administered to allow the initiation of both IMPs at the same time in the next cycle. If more 
than 30 days from the last dose administered are needed for recovery, the next cycle should be 
started by omitting trifluridine/tipiracil doses as needed (i.e. next cycle is started with only 
S95026 and trifluridine/tipiracil is reintroduced later) or the participant may have 
trifluridine/tipiracil discontinued, according to investigator’s judgement. 
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Note: 
Interruption/resumption 
criteria 
and 
recommended 
dose 
modifications 
of 
trifluridine/tipiracil could be done in accordance with the local SmPC (Summary of Product 
Characteristics)). 
8.11.2. Management of treatment dose adaptations due to futuximab/modotuximab 
toxicities 
Anticipated AEs that may be experienced with futuximab/modotuximab are detailed in this 
protocol (Section 2.6 and Section 2.8), as well as in the Investigator's Brochure (IB). 
Participants will be evaluated throughout the course of the trial for acute as well as delayed 
and/or cumulative toxicities.  
If a significant toxicity thought to be related to futuximab/modotuximab is experienced at any 
point during the participant’s participation in the study, the investigator will determine 
appropriate management, including determining whether that toxicity warrants a change in 
premedication (Section 6.1.2), or a dose modification such as infusion prolongation (in the 
event of an IRR) (Section 8.11.2.1), temporary dose delay (Section 8.11.2.2), or dose reduction 
(Section 8.11.2.3).  
8.11.2.1. Decrease of infusion rate 
For IRRs, infusion prolongation instructions are provided in Section 8.12.4.1. 
To enhance participant safety following an infusion prolongation, subsequent infusions will be 
administered with a lower infusion rate at the prolonged rate. 
8.11.2.2. Dose Delay 
Toxicities may be managed by delay in dosing, provided they do not meet the criteria for IMP 
discontinuation (Section 5.8.1). In such cases, the period between any 2 scheduled doses may 
be extended up to 3 days (inclusive) to allow an improvement of the toxicity. Such delays will 
be considered an extension within the current cycle. If a delay of more than 3 days from the 
schedule dose date is necessary, the dose should be omitted and proceed to the next scheduled 
dose (i.e. 14 days from the last dose).  
If 3 consecutive doses are needed to be omitted (i.e. more than 21 days from the last dose of 
futuximab/modotuximab), 
the 
participant 
should 
be 
discontinued 
from 
futuximab/modotuximab. All delays of futuximab/modotuximab must be documented on the 
appropriate page of the participant’s e-CRF. 
If toxicity does not resolve during the given cycle to Grade 1 or baseline, the start of the next 
cycle may be delayed by a maximum of 21 days from the last dose of futuximab/modotuximab 
administered to allow the initiation of both IMPs at the same time in the next cycle. If more 
than 21 days from the last dose administered are needed for recovery, futuximab/modotuximab 
should be discontinued and the next cycle will start with only trifluridine/tipiracil. 
Dosing may be restarted at the same dose, as clinically indicated. However, administration of 
futuximab/modotuximab may only be restarted provided retreatment criteria are met 
(Section 6.1.5). 
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For treatment restart with no dose reduction:  
- 
If treatment restart after the omission of 1 dose (i.e. treatment delay up to 14 days from 
the last dose), it is recommended that dosing restart with maintenance dose of 6 mg/kg;  
- 
If treatment restart after the omission of 2 consecutive doses (i.e. treatment delay up to 
21 days from the last dose), it is recommended that dosing re-start with the re-
administration of a loading dose of 9 mg/kg followed by weekly maintenance doses of 
6 mg/kg. 
For treatment restart with dose reduction, see Section 8.11.2.3. 
8.11.2.3. Dose Reduction 
In the event of Grade 3 treatment-related AEs, the participant may continue on study if there is 
evidence of clinical benefit as judged by the treating physician, but could do so at a reduced 
dose of futuximab/modotuximab once retreatment criteria are met (Section 6.1.5) (specific 
instructions for dose reduction linked to IRR, dermatologic AEs, and hypomagnesemia, are 
provided in Appendices 9, 10 and 11, respectively). All dose reductions of 
futuximab/modotuximab must be documented on the appropriate page of the participant’s 
e-CRF.  
If toxicity is to be managed by dose reduction, the futuximab/modotuximab dose will be 
decreased as shown in (Table (8.11.2.3) 1). Dose reduction may occur either during treatment 
cycles, or between cycles, as clinically indicated. 
Table (8.11.2.3) 1 - Dose reduction of futuximab/modotuximab 
 
Starting dose (Dose level 0) 
Dose level -1 
Dose level -2 
Futuximab/modotuximab* 
6 mg/kg 
4.5 mg/kg 
3 mg/kg 
*Note: Dose Reductions for 9 mg/kg loading dose not applicable. The number of dose reductions allowed is limited to 2  
Abbreviations (in alphabetical order): kg, kilogram; mg, milligram 
A maximum of 2 dose reductions for futuximab/modotuximab-related toxicity are allowed (to 
a minimum dose of 3 mg/kg). Do not re-escalate dose after it has been reduced. 
8.12. Recommendations regarding treatment of toxicities 
8.12.1. Management of nausea and vomiting 
Trifluridine/tipiracil has emetogenic potential. 
­ A single antiemetic agent, such as dexamethasone, a 5-HT3 receptor antagonist or a 
dopamine receptor antagonist, such as metoclopramide may be considered for prophylaxis. 
­ If a participant experiences acute or delayed nausea or vomiting due to trifluridine/tipiracil, 
it is advised that, at the next cycle, a higher antiemetic regimen may be given. 
­ In case a participant experiences of anticipatory nausea and vomiting, benzodiazepines are 
recommended. The above is based on Multinational Association of Supportive Care in 
Cancer (MASCC) and European Society for Medical Oncology (ESMO) guidelines36 and 
Hesketh et al. (2016).37 
8.12.2. Management of diarrhoea 
Educate both participants and participants’ families regarding the potential seriousness of 
chemotherapy-induced diarrhoea. Instruct participants to immediately contact the study site 
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staff at the first sign of loose stool. The participant should be instructed to record the number 
of stools and report symptoms indicating a complicated diarrhoea (see list below). 
­ Educate the participant regarding the dietary measures to be taken in case of diarrhoea. 
­ Provide participants with loperamide (or other standard antidiarrheal therapy) and instruct 
the participant on how to use it at the first sign of diarrhoea. 
­ Monitor the participant’s fluid and electrolyte balance, with appropriate intervention as 
clinically indicated with fluids and electrolyte replacement.38  
Mild to moderate diarrhoea (Grade 1 or 2 according to NCI-CTCAE without complications): 
­ It is recommended to start dietary modifications and standard antidiarrheal therapy for 
example loperamide at an initial dose of 4 mg followed by 2 mg every 4 hours or after every 
unformed stool (not to exceed 16 mg/day). 
­ If diarrhoea resolves with antidiarrheal therapy, the dietary modifications should be 
continued (with a gradually addition of solid foods). Antidiarrheal therapy may be 
discontinued when the participant has been diarrhoea-free for at least 12 hours. 
­ If diarrhoea persists for more than 24 hours, the dose of antidiarrheal therapy should be 
increased (for loperamide increase to 2 mg every 2 hours), and oral antibiotics may be started 
as prophylaxis for infection. 
­ If diarrhoea has not resolved after 48 hours on initial treatment, the participant should be 
started on a second-line antidiarrheal agent. 
Complicated diarrhoea: 
­ Any Grade 3 or 4 diarrhoea is classified as “complicated”. In addition, Grade 1 or 2 diarrhoea 
and at least one of the following symptoms are also considered as complicated: 
 Fever, sepsis, moderate to severe cramping. 
 Grade 2 nausea/vomiting. 
 Decreased performance status. 
 Neutropenia. 
 Frank bleeding. 
 Dehydration. 
­ Aggressive management of complicated cases should involve:  
 Intravenous (IV) fluids. 
 Octreotide at a starting dose of 100 to 150 µg subcutaneous tid or IV (25 to 50 µg/h) if 
the participant is severely dehydrated, with dose escalation up to 500 µg until diarrhoea 
is controlled. 
 Administration of antibiotics (e.g., fluoroquinolone). 
­ Stool work-up (evaluation for blood, faecal leukocytes, C difficile, Salmonella, E coli, 
Campylobacter, and infectious colitis), complete blood count, and electrolyte profile should 
be performed. 
­ Continue intervention as described until the participant has been diarrhoea-free for 24 hours. 
8.12.3. Management of febrile neutropenia and anaemia 
Administer haematologic support as medically indicated (e.g., blood transfusions, granulocyte 
colony-stimulating factor [G-CSF], erythropoietin, etc.) according to the institutional site 
standards.  
If there are no standard procedures for the use of growth factors, follow Recommendations for 
the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
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Guideline Update, available at http://www.instituteforquality.org/practice-guidelines; or the 
European Organization for Research and Treatment of Cancer (EORTC) update to 2010 
guidelines for the use of G-CSF, available at https://www.eortc.org/guidelines/. 
8.12.4. Management of Infusion related reactions 
There is an inherent risk for IRRs with the administration of mAbs, therefore premedication for 
prophylaxis of IRRs will be mandatory prior to each dose of futuximab/modotuximab. All 
participants will be premedicated with standard therapies that include a glucocorticoid and an 
H1 antagonist. Where indicated, consideration may be given to include an H2 antagonist and/or 
acetaminophen. Recommended premedication doses are provided (Section 6.1.2.1 and 
Appendix 9). 
Should a participant experience an IRR while in the study, guidelines for premedication 
following an IRR are provided (Section 6.1.2.1.3). Guidelines for the grading and management 
of IRRs of all severities are also provided (Section 8.11.2.1 and Appendix 9). 
Instructions for the grading and management of IRRs are provided. In all cases the investigator 
should use best clinical judgment in managing such reactions. 
­ For Grade 3 reactions, the infusion will be STOPPED. The participant will be either 
discontinued from treatment or must receive subsequent treatments at a reduced dose and at 
a prolonged infusion rate. 
­ For Grade 4 reactions, the infusion will be STOPPED and the participant will be permanently 
discontinued from treatment. 
8.12.4.1. Decrease of infusion rate 
For IRRs, the following infusion prolongation instructions are provided: 
­ For mild IRR (Grade 1), the infusion rate must be decreased by 50% from the prior rate. This 
lower infusion rate must be maintained in all subsequent infusions.  
­ For moderate IRR (Grade 2), interrupt the infusion for a minimum of 30 minutes, and at least 
until there is either amelioration to ≤ Grade 1 severity or return to baseline status. Administer 
supportive care, as medically indicated. Restart the infusion with an infusion rate decreased 
by 50% from the prior rate. This lower infusion rate must be maintained in all subsequent 
infusions.  
­ For Grade 3 reactions, STOP the infusion. Administer supportive care. The participant will 
be either discontinued from treatment or must receive subsequent treatments at a reduced 
dose and with a decreased infusion rate (≥ 50% of decrease). 
­ For Grade 4 reactions, STOP the infusion. Administer supportive care. The participant will 
be permanently discontinued from treatment. 
­ All infusion interruptions and subsequent prolongations, including modified infusion times, 
as well as the toxicity that necessitated them, will be clearly documented on the appropriate 
page of the participant’s e-CRF. 
Note: Any assessments to be performed or samples to be collected (e.g., vital signs, PK) at the end of or following 
the EoI will still be performed or collected beginning at the delayed EoI timepoint. 
To enhance participant safety following an infusion prolongation, subsequent infusions will be 
administered with a lower infusion rate. 
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8.12.5. Management of dermatologic toxicity 
Participants who received futuximab/modotuximab will be monitored weekly for evidence of 
dermatologic AEs. Dose delay and/or intrapatient dose-reduction(s) will be required upon 
occurrence of Grade 3 AEs and may be implemented in the event of a Grade 2 dermatologic 
reaction that is debilitating for the participant. 
Recommendations for management of Grade 1 to 3 dermatologic AEs are provided. Participants 
must be withdrawn from IMP treatment in the event of a Grade 4 dermatologic AE. Guidelines 
for grading and management of dermatologic AEs and dose reductions to be implemented in 
the event of such reactions are also provided (Appendix 10). 
8.12.6. Management of hypomagnesemia, hypocalcemia, and hypokalemia 
Participants will be monitored weekly for hypomagnesemia, hypocalcemia, and hypokalemia. 
In the event of Grade 3-4 hypomagnesemia, repletion is required as well as predosing 
electrocardiograms (ECG) to monitor for corrected QT (QTc) prolongation. For Grade 4 
hypomagnesemia that is refractory to IV magnesium-replacement therapy, dosing with 
futuximab/modotuximab should be delayed or reduced. Full management instructions are 
provided in Appendix 11. 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY OR 
SAFETY 
9.1. Assessments related to screening/inclusion criteria 
9.1.1. 
Assessments related to inclusion criteria 
9.1.1.1. 
Informed consent 
Obtain signed and dated ICF from the patient during the screening visit prior to the 
implementation of study procedures required by the protocol. Please refer to Section 13.3. 
 
9.1.1.2. 
Histological/Cytological Confirmation 
Histological confirmation of adenocarcinoma of the colon or rectum should be documented in 
the patient’s source documents. The pathology report should be available in the patient’s source 
documents. 
9.1.1.3. 
KRAS/NRAS/BRAF status 
Genomic analysis from peripheral whole blood sample for defining patient eligibility and 
stratification will be based on assessment of ctDNA in plasma with an oncogene panel. The 
sample will be submitted for mutation analysis prior to first administration of first IMP (for 
Safety Lead-In part) and to randomisation. The genomic analysis includes a series of genes 
frequently mutated in cancer, but will be focused on the following genes: 
­ BRAF 
 
­ KRAS & NRAS 
 
 
 
­ EGFR-ECD mutation analysis (for stratification purpose: "WT" if no mutation and 
"mutated" if one or more 
 mutations are detected). 
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Backup DNA extracts from included participants and screened participants non included will 
be stored, with the consent of the participant, for a maximum of 25 years after the end of the 
study according to local regulation for retrospective analysis restricted to the study of the 
pathology and the response to the treatment. All samples may be destroyed at any time on 
participant’s or sponsor’s request. 
Additional details and the sample collection instructions are provided in laboratory manual. 
9.1.2. 
Assessments not related to inclusion criteria 
9.1.2.1. 
Patient Numbering (Only for Randomised part) 
Once the patient has signed ICF, the study site will connect to the IWRS for patient’s 
registration and to obtain a patient's number (see the IWRS manual for details). Each patient 
will be assigned a unique patient number. This patient number will be maintained throughout 
the study and will not be reassigned. Participants who withdraw consent or discontinue from 
the study after being assigned a patient number will retain their initial number. 
9.1.2.2. 
ECOG performance status 
Collect ECOG performance status score (Appendix 2). 
9.1.2.3. 
Medical history 
Obtain a complete medical history. 
Of note, events occurring between the signature of the ICF and the first study treatments 
administration for which the investigator does not consider an association with any 
procedure/condition required by the study protocol must be reported as medical history in the 
dedicated form of the e-CRF. 
9.1.2.4. 
Previous surgery, radiotherapy and treatments related to the colorectal cancer 
Collect previous surgery, radiotherapy and treatments related to the colorectal cancer. 
9.1.2.5. 
Baseline Signs and Symptoms 
Signs and symptoms related to the colorectal cancer present following ICF signature and before 
the first study treatments administration should be recorded in the patient’s source documents. 
9.1.2.6. 
MMR/MSI status  
MMR/MSI status will be collected in the e-CRF if available. 
9.1.2.7. 
Demography 
Collect demography data (age, sex, ethnic origin).  
9.2. Measurement of drug concentration  
9.2.1. 
Sample Collection Timepoints 
Blood samples for the evaluation of PK are to be collected at the timepoints listed in 
Table (9.2.1) 1 and Table (9.2.1) 2. The accurate sampling dates and times must be recorded in 
the e-CRF. 
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Table (9.2.1) 1 - Sample collection timepoints for futuximab/modotuximab and trifluridine/tipiracil 
(Pharmacokinetics during the Safety Lead-In and Arm A of Randomised part) 
 
Futuximab and modotuximab assessment 
Trifluridine and tipiracil assessment 
C1D1 
Pre-dose* 
Pre-dose*  
End of infusion** 
End of infusion**  
1-2 hours after end of infusion  
1-2 hours after end of infusion 
C1D8 
Pre-dose* 
Pre-dose* 
End of infusion** 
End of infusion** 
30 min-1 hour after end of infusion  
30 min-1 hour after end of infusion  
C1D15 
Pre-dose* 
 
End of infusion** 
 
30 min-1 hour after end of infusion  
 
C1D22 
Pre-dose* 
 
End of infusion** 
 
30 min-1 hour after end of infusion 
 
C2D1 
Pre-dose* 
Pre-dose* 
End of infusion** 
End of infusion** 
30 min-1 hour after end of infusion  
30 min-1 hour after end of infusion  
C2D8 
Pre-dose* 
Pre-dose* 
End of infusion** 
End of infusion** 
30 min-1 hour after end of infusion  
30 min-1 hour after end of infusion  
C2D15 
Pre-dose* 
 
End of infusion** 
 
30 min-1 hour after end of infusion  
 
C2D22 
Pre-dose* 
 
End of infusion** 
 
30 min-1 hour after end of infusion  
 
CXD1 
Pre-dose* 
 
WV 
During the visit 
During the visit 
*i.e. 5-60 minutes before infusion of futuximab/modotuximab 
**i.e. within 10 minutes before to the end of infusion of futuximab/modotuximab 
Table (9.2.1) 2 - Sample collection timepoints for trifluridine/tipiracil 
(Pharmacokinetics in Arm B of Randomised part) 
 
Trifluridine and tipiracil assessment 
C1D1 
At the beginning of the visit  
At the end of the visit 
C1D15 
During the visit   
C2D1 
During the visit   
C2D15 
During the visit   
WV 
During the visit 
9.2.2. 
Sampling Methods 
For Trifluridine and tipiracil assessment, 4 mL of blood will be taken at each timepoint 
(Appendix 12). Concentrations of trifluridine and tipiracil will be determined in sodium 
heparinised plasma, using a mass spectrometry, validated according to current regulatory 
guidelines. 
For Futuximab and modotuximab assessment, 2.5 mL of blood will be taken at each 
timepoint (Appendix 12). Futuximab/modotuximab will be determined in serum, using an 
enzyme-linked immunosorbant assay, and validated according to current regulatory guidelines. 
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Preparation and management of the bioanalytical samples will be described in a separate 
document. 
9.3. Pharmacodynamic measurements 
Not applicable. 
9.4. Assessment of biomarkers  
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a sampling collection, or not 
perform or discontinue an analysis due to either practical or strategic reasons (e.g. inadequate 
sample number, issues related to the quality of the sample or issues related to the assay that 
preclude analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on 
the results obtained during the study, sample collection analysis may be omitted at the discretion 
of the sponsor. 
Peripheral whole blood (20 mL) will be collected pre-dose on C1D1, C2D1, C3D1 then every 
2 cycles along with tumour assessment and at withdrawal visit, and analysed centrally for 
ctDNA monitoring. Potential predictors of response as well as mechanisms of resistance could 
be explored. The collection is mandatory for all participants. Backup DNA extracts will be 
stored, with the consent of the participant, for a maximum of 25 years after the end of the study 
according to local regulation for retrospective analysis restricted to the study of the pathology 
and the response to the treatment. All samples may be destroyed at any time on participant’s or 
sponsor’s request. 
Additional details and the sample collection instructions are provided in laboratory manual. 
9.4.1. 
Mandatory assessment 
Participation in the study implies a systematic participation in the mandatory investigation. All 
participants will have to consent to this investigation by signing the main information and 
consent form for participation in the study. In addition, in case of consent withdrawal, related 
samples will be destroyed after mandatory assessment is completed and in any case before the 
clinical study report final version is made available. 
Overall results of the genomics biomarkers assessment may be transmitted to the participant 
upon his/her request through the investigator, according to local regulations if applicable.  
9.4.1.1. 
Sampling, processing and storage 
In all participants, 20 mL of blood will be taken at each timepoint.  
The plasma will be separated by centrifugation and stored at < -70°C in appropriate labelled 
storage cryotubes and sent on dry ice. DNA will be extracted from plasma sample and subjected 
to genomic analysis for circulating tumour DNA monitoring. Preparation and management of 
the samples will be described in a separate document. 
These samples are dedicated to retrospective analysis if participants consent and will be 
destroyed at the end of the storage period. If participants withdrawn his/her Informed consent 
form, please refer to Section 9.4.1. 
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Table (9.4.1.1) 1 - Biomarker(s) experimental conditions 
Biomarker(s) assessed 
Experimental conditions 
 
Sampling time points 
Matrix 
Purpose 
Circulating tumour DNA 
C1D1, C2D1, C3D1 
CxD1 (every 2 cycles) 
Withdrawal visit 
Blood 
ctDNA monitoring 
9.4.1.2. 
Labelling and transfer to analytical centre 
Samples will be single coded with a unique number and thus will not carry any personal 
identifiers. 
Samples collection information must be entered as required on the appropriate sample 
collection e-CRF page(s) and requisition form(s). 
Detailed instructions for the samples labelling and shipments are outlined in the laboratory 
manual (or equivalent) for the study. 
The randomisation list will be sent to the analytical centre in order to select the samples to be 
analysed.  
9.4.1.3. 
Transfer of analytical results 
Final analytical results will be transferred to Data Management according to Section 14.2.  
9.4.2. 
Retrospective analysis 
Retrospectives analyses involving human biological samples are considered as optional 
assessments and are performed after the end of the study (planned or not in the clinical study 
protocol). 
Participation in these retrospective analyses is optional and is not mandatory for the inclusion 
of a given participant in the study.  
If the participant agrees, some additional samples / remaining biomarker samples may be stored 
after the end of the study.  
They could be further analysed to address scientific questions related to the product or disease 
including research related to improvements or enhancements in the development of 
bioanalytical methods.  
A decision to perform such exploratory biomarker research studies will be based on outcome 
data from this study or from new scientific findings related to the drug class or disease, as well 
as reagent and assay availability.  
Samples will be kept in suitable conditions in a central bio-repository specialized in storage of 
biological samples until further notification from the sponsor and may be retained stored up to 
25 years after study closure completion. 
9.4.3. 
Transfer of pharmacogenomics results  
If the analysis is required during the study, final analytical results will be transferred to Data 
Management at the end of the study. 
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9.4.4. 
Interpretation 
If relevant for the project, an evaluation will be carried out and reported in a separate document.  
This evaluation will be performed by analysing the associations between polymorphisms in 
relevant absorption, distribution, metabolism, and excretion (ADME) genes and the 
pharmacokinetics of futuximab/modotuximab. 
9.5. Immunogenicity 
Blood samples (2.5 mL) for the evaluation of immunogenicity will be collected at the 
timepoints listed in Table (9.5) 1. The accurate sampling dates and times must be recorded in 
the e-CRF. 
Table (9.5) 1 - Sample Collection Timepoints for futuximab/modotuximab (during the Safety Lead-In 
and Arm A of Randomised part) 
 
Futuximab/modotuximab assessment 
C1D1 
Pre-dose* 
C1D15 
Pre-dose* 
C2D1 
Pre-dose* 
C2D15 
Pre-dose* 
CXD1 
Pre-dose*,** 
WV 
During the visit 
*i.e. 5-60 minutes before infusion of futuximab/modotuximab 
**The frequency of futuximab/modotuximab immunogenicity assessments will be reduced to every 2 months after the first 6 months in the 
first year and every 4 months after the first year.  
In all participants, 2.5 mL of blood will be taken at each timepoint (Appendix 12). ADA will 
be determined in serum, using an Immunoassay method, validated according to current 
regulatory guidelines.  
ADA Backup samples will be stored, for a maximum of 3 years after the end of the study, to 
allow additional analyses related to immunogenicity assessment to be performed in case of 
agencies’ request during their review process. All samples will be destroyed at the latest at the 
end of the storage period or at any time on participant’s or sponsor’s request. 
9.6. Quality of Life Assessments (Only for Randomised part) 
EORTC Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) (Appendix 6) 
and EQ-5D-5L (Appendix 5) will be completed by the participant on an e-PRO, independently 
of the study personnel at the following time points, at the beginning of each visit at the following 
time point: 
­ Inclusion. 
­ After the end of cycle 1 (C2D1) 
­ Every 2 cycles during the treatment period (C3D1, C5D1…). 
­ WV. 
­ Every 2 months during the follow-up period, until death or until end of the study is reached 
(whichever occur first).  
 
Participants will be provided with specific instructions in order to be comfortable with the 
e-PRO device and enhance the quality of the data. In case the participant is not able to use e-
PRO, a caregiver (not a medical/investigator staff) will be allowed to read the questions to the 
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participant and to collect the answer without any interpretation of the questions and the answers. 
Data entered by the participant will be sent to a central database via a secured transfer. 
10. STATISTICS 
10.1. Statistical analysis 
A Statistical Analysis Plan (SAP), and associated templates for Tables, Listings and Graphs, 
will be written and completed before database lock. These specifications will detail the 
implementation of all the planned statistical analyses in accordance with the main 
characteristics stated in the protocol.  
10.1.1. Analysis sets / Treatment groups 
10.1.1.1. Analysis sets 
Full Analysis Set (FAS): In accordance with the ITT principle and Section 5.2.1 of ICH E9 
guideline,39 all participants to whom a therapeutic unit was randomly assigned using IWRS. 
Participants in the FAS will be analysed in the arm they were assigned by randomisation. FAS 
will be used in all efficacy analyses of Randomised part, unless otherwise specified. 
Safety Set (SS): All participants having taken at least one dose of IMPs. Participants will be 
analysed according to the treatment actually received. SS will be used in all analyses of Safety 
Lead-In part and safety analyses of Phase 3 part.  
Per-Protocol Set (PPS): all participants in the FAS who do not violate the terms of the protocol 
in a way that would affect the study outcome significantly. Participants not fulfilling one of the 
following criteria will not be included in the PPS: 
­ Must have histologically or cytologically confirmed adenocarcinoma of mCRC [Screening 
criterion #2]. 
­ Should be without RAS (KRAS and NRAS) mutations and without BRAF mutation 
[Screening criterion #3]. 
­ Must have received at least 2 prior regimens of standard chemotherapy for mCRC and had 
demonstrated progressive disease or intolerance to their last regimen [Screening criterion 
#5]. 
­ Should have received previous treatment with commercially available anti-EGFR mAbs for 
≥ 16 weeks [Screening criterion #6]. 
­ ECOG performance status 0 or 1 [Screening criterion #9]. 
­ Currently receiving or having received anticancer therapies within 4 weeks prior to first IMP 
administration [Non-screening criterion #14]. 
PRO Analysis Set: All participants from the FAS who have completed screening and at least 
one post baseline assessment. Quality of life (QoL) endpoints will be evaluated on PRO 
Analysis Set. 
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10.1.1.2. Treatment groups 
Treatment considered for the analysis of Safety Lead-In part will be the following:  
­ Futuximab/modotuximab + trifluridine/tipiracil. 
Treatment groups considered for the analysis of Randomised part will be the following:  
­ Futuximab/modotuximab + trifluridine/tipiracil (Arm A). 
­ Trifluridine/tipiracil (Arm B). 
10.1.2. Statistical methods 
10.1.2.1. General considerations 
The data from Safety Lead-In part and Randomised part will summarized, analysed and listed 
separately. 
The following descriptive statistics will be provided depending on the nature of considered 
data:  
­ Qualitative data: number of observed values, number and percentage of participants per 
class. 
­ Quantitative data: number of observed values, mean and standard deviation, median, first 
and third quartiles, minimum and maximum. 
­ Survival data (time to event occurrence or to censoring): total number of participants, total 
number and percentage of participants having an event overall, number of participants at 
risk, number of participants with censored data, number of participants with event of interest. 
10.1.2.2. Disposition and baseline characteristics 
The participants’ disposition and baseline characteristics will be described in SS for Safety 
Lead-In part and in the FAS by treatment arms and overall for Randomised part.  
The number of participants in each study population and the reasons for exclusion, along with 
any randomisation and/or stratification errors will be summarized as well as the disposition of 
participants, including reasons for discontinuation and protocol deviations at baseline and 
during study.  
Characteristics of participants including demography, characteristics of the disease at diagnosis 
and study entry, medical history, prior therapy and concomitant medication at baseline will be 
summarised.  
10.1.2.3. Treatments of participants 
Extent of exposure and treatment compliance, as well as concomitant medication during 
treatment period will be described in the SS. Extent of exposure includes number of cycles, 
cumulative dose, dose intensity, relative dose intensity, dose modifications.  
The follow-up duration will be calculated overall and in each arm with the reverse Kaplan-
Meier method.  
The non-study cancer treatment after study treatment discontinuation will be summarized. Any 
use of non-study cancer treatment during the study treatment period will also be presented as 
protocol deviation.  
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10.1.2.4. Efficacy analysis 
10.1.2.4.1. Safety Lead-In part 
The proportion of participants with objective evidence of CR or partial response (PR) (ORR) 
according to RECIST version 1.1 criteria and using investigator’s tumour assessment will be 
summarized descriptively. 
The proportion of participants with BOR according to RECIST version 1.1 criteria and using 
investigator’s tumour assessment will be summarized descriptively. 
The proportion of participants with objective evidence of CR or PR or stable disease (SD) 
(DCR) according to RECIST version 1.1 criteria and using investigator’s tumour assessment 
will be summarized descriptively. 
PFS is defined as the time from the first administration of IMP date until the date of the 
investigator-assessed radiological disease progression according to RECIST version 1.1 or 
death, whichever occurs first. PFS will be summarized using Kaplan Meier curve and further 
characterised in terms of the median and survival probabilities at 2, 4, 6 and 8 months along 
with the corresponding 2-sided 95% CI for the estimates.  
OS is defined as the time from the first administration of IMP date until the date of death due 
to any cause. OS will be summarized using Kaplan Meier curve and further characterised in 
terms of the median and survival probabilities at 6, 12 and 18 months along with the 
corresponding 2-sided 95% CI for the estimates.  
10.1.2.4.2. Randomised Part 
Primary objective 
The primary objective is to demonstrate the superiority of futuximab/modotuximab in 
combination with trifluridine/tipiracil over trifluridine/tipiracil monotherapy in terms of OS in 
participants with chemotherapy pre-treated (including oxaliplatin, irinotecan and 
5-fluorouracil, anti-VEGF agents, and anti-EGFR mAb therapy for ≥ 16 weeks) metastatic 
colorectal cancer that are KRAS/NRAS and BRAF WT (Double negative [DN]).  
Key secondary objective 
The key secondary objective is to demonstrate the superiority of futuximab/modotuximab in 
combination with trifluridine/tipiracil over trifluridine/tipiracil monotherapy in terms of OS in 
participants with chemotherapy pre-treated (including oxaliplatin, irinotecan and 
5-fluorouracil, anti-VEGF agents, and anti-EGFR mAb therapy for ≥ 16 weeks) metastatic 
colorectal cancer that are KRAS/NRAS, BRAF WT and EGFR-extracellular domain WT 
(Triple negative [TN]). 
Secondary objectives 
Secondary objectives are to estimate the effect of futuximab/modotuximab in combination with 
trifluridine/tipiracil versus trifluridine/tipiracil monotherapy in terms of PFS, OR, DC, DoR, 
TTNT, TTR, and TtPS2 in participants with chemotherapy pre-treated (including oxaliplatin, 
irinotecan and 5-fluorouracil, anti-VEGF agents, and anti-EGFR mAb therapy for ≥ 16 weeks) 
metastatic colorectal cancer. 
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Other secondary objectives are to compare the safety and tolerance, and the impact on QoL of 
futuximab/modotuximab in combination with trifluridine/tipiracil to trifluridine/tipiracil 
monotherapy in participants with chemotherapy pre-treated metastatic colorectal cancer.  
Intercurrent events  
During the study the following intercurrent events could occur:  
­ Administration of further anti-cancer therapy. 
­ Treatment discontinuation. 
­ Treatment switch (from futuximab/modotuximab in combination with trifluridine/tipiracil 
to trifluridine/tipiracil monotherapy and from trifluridine/tipiracil monotherapy to 
futuximab/modotuximab in combination with trifluridine/tipiracil). 
Estimands of interest  
The attribute treatment will be the same for all estimands of interest:  
­ Treatment: Futuximab/modotuximab + trifluridine/tipiracil versus trifluridine/tipiracil 
monotherapy. 
The following estimands will be studied: 
Table (10.1.2.4.2) 1 - Studied estimands 
Estimand  
Variable 
Population 
level 
summary 
Handling 
intercurrent 
events (IEs) 
Population 
Primary estimand: effect of the randomised treatments 
on the survival duration in all subjects that are 
KRAS/NRAS and BRAF WT (Double negative [DN]) 
regardless of whether or not intercurrent events occur 
OS 
HR 
Treatment 
policy 
strategy 
FAS 
Key secondary estimand: effect of the randomised 
treatments on the survival duration in all subjects that 
are KRAS/NRAS, BRAF WT and EGFR-extracellular 
domain WT (Triple negative [TN]) regardless of 
whether or not intercurrent events occur 
OS 
HR 
Treatment 
policy 
strategy 
FAS 
restricted to 
Triple 
negative 
[TN] subjects 
Effect of the randomised treatments on the survival 
duration in all subjects that are KRAS/NRAS and 
BRAF WT (Double negative [DN]) before participants 
receive further anti-cancer therapy 
OS 
HR 
While on 
treatment 
strategy 
FAS 
Effect of the randomised treatments on the survival 
duration in all subjects that are KRAS/NRAS, BRAF 
WT and EGFR-extracellular domain WT (Triple 
negative [TN]) before participants receive further anti-
cancer therapy 
OS 
HR 
While on 
treatment 
strategy 
FAS 
restricted to 
Triple 
negative 
[TN] subjects 
Effect of the randomised treatments on progression-
free survival before participants receive further anti-
cancer therapy 
PFS 
HR 
While on 
treatment 
strategy 
FAS 
Effect of the randomised treatments on progression-
free survival regardless of whether or not intercurrent 
events occur 
PFS 
HR 
Treatment 
policy 
strategy 
FAS 
Effect of the randomised treatments on response 
before participants receive further anti-cancer therapy 
OR 
DC 
Risk 
difference 
While on 
treatment 
strategy 
FAS 
 
 
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Table (10.1.2.4.2) 1 (Cont’d) - Studied estimands 
Estimand  
Variable 
Population 
level 
summary 
Handling 
intercurrent 
events (IEs) 
Population 
Effect of the randomised treatments on the response 
duration before participants receive further anti-cancer 
therapy 
DoR 
HR 
While on 
treatment 
strategy 
FAS 
Effect of the randomised treatments on the time from 
the randomisation to initiation of the next systemic 
anti-cancer therapy 
TTNT 
HR 
While on 
treatment 
strategy 
FAS 
Effect of the randomised treatments on the time from 
randomisation until first radiologically confirmed 
tumour response (CR or PR) before participants 
receive further anti-cancer therapy 
TTR 
HR 
While on 
treatment 
strategy 
FAS 
Effect of the randomised treatments on the time from 
the date of randomisation to the date when ECOG PS 
score of ≥ 2 is observed for the first time before 
participants receive further anti-cancer therapy 
TtPS2 
HR 
While on 
treatment 
strategy 
FAS 
With:  
­ OS: overall survival defined as the time from date of randomisation into the study to death 
from any cause.  
­ PFS: progression-free survival defined as the time from date of randomisation until the date 
of the investigator-assessed radiological disease progression or death, whichever occurs first. 
­ OR: overall response defined as the achievement of confirmed CR or PR according to 
RECIST version 1.1 criteria and using investigator’s tumour assessment. 
­ DC: disease control defined as the achievement of best response of CR or PR or SD 
according to RECIST version 1.1 criteria and using investigator’s tumour assessment. 
­ DoR: duration of response defined as the time from the first documentation of confirmed 
tumour response (CR or PR) according to RECIST version 1.1 criteria and using 
investigator’s tumour assessment to the first documentation of objective tumour progression 
or to death due to any cause. 
­ TTNT: time to next treatment defined as the time from the randomisation to initiation of the 
next systemic anti-cancer therapy. 
­ TTR: time to response defined as the time from randomisation until first radiologically 
confirmed tumour response (CR or PR) according to RECIST version 1.1 criteria and using 
investigator’s tumour assessment. 
­ TtPS2: time to ECOG performance status ≥ 2 defined as the time from the date of 
randomisation to the date when ECOG PS score of ≥ 2 is observed for the first time. 
Estimands and the way for handling IEs will be detailed in the following paragraphs. 
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10.1.2.4.2.1. Primary estimand based on the OS 
The primary estimand of interest is the effect of the randomised treatments on the survival 
duration in all subjects that are KRAS/NRAS and BRAF WT (Double negative [DN]) 
regardless of whether or not intercurrent events occur (treatment policy strategy). The 
motivation for this choice is to assess the efficacy of the futuximab/modotuximab in 
combination with trifluridine/tipiracil compared to trifluridine/tipiracil monotherapy under the 
ITT principle (intercurrent events are considered to be part of the treatments being compared).  
All data collected during the trial regardless of occurrence of an IE will be used. This is aligned 
with the treatment policy strategy. 
Primary analysis  
The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS data).  
OS for each arm will be summarized using Kaplan Meier curves and further characterised in 
terms of the median and survival probabilities at 6, 12 and 18 months along with the 
corresponding 2-sided 95% CI for the estimates.  
The hazard ratio of OS with its 95% confidence interval will be estimated with a stratified Cox 
proportional hazard model (stratification factors based on IWRS data).  
For missing data (not linked to intercurrent events), i.e. participants without documentation of 
death (lost to follow-up, withdrawal of consent, administrative end of study), the OS will be 
censored on the last contact date the participant was known to be alive or the cut-off date, 
whichever is earlier.  
Sensitivity analyses  
As sensitivity analyses, the following analyses will be done:  
­ The proportional hazards assumption will be checked. If relevant, other statistical method 
could be used. 
­ OS analysis based on PPS. 
Other sensitivity analyses will be defined in the SAP if necessary.  
Supplementary analyses  
Subgroup analyses  
OS subgroup analyses are planned to further explore the homogeneity of the treatment effect 
across participant subsets. Depending on the sample size, the following subgroups will be 
examined: ECOG PS (0, 1), extracellular domain EGFR mutations (ECD) (presence, absence), 
previous regimens of treatment (2, ≥ 3), region (North America, European Union, Asia, Rest of 
the World), time since diagnosis of 1st metastasis (< 18, ≥ 18 months), location of primary 
disease (right, left), gender (female, male), age (< 70, ≥ 70 years), prior surgical resection (yes, 
no), number of metastatic sites (1-2, ≥ 3), neutrophils to lymphocytes ratio (NLR < 3, NLR ≥ 3), 
neutrophils to lymphocytes ratio (NLR < 5, NLR ≥ 5), response to previous treatment with anti-
EGFR (CR/PR, SD), last previous regimen (anti-EGFR, no anti-EGFR), previously treated with 
anti-VEGFs treatment (yes, no), skin toxicity with previous anti-EGFR (yes, no), skin toxicity 
with previous anti-EGFR (Grade 1-2, Grade 3-4, no toxicity), duration of previous anti-EGFR 
(< 8, ≥ 8 months), Race (White, American Indian/Alaska native, Asian, Black/African 
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American, Native Hawaiian/Other pacific islander), Premedication with antibiotics for skin 
toxicity (yes, no).  
A stratified Cox-regression model with treatment arm as predictor variable will be fitted 
separately for each subgroup category. The hazard ratio for treatment along with the associated 
95% confidence interval will be provided.  
Exploratory analysis  
A multivariate OS analysis will be performed using a stratified Cox proportional hazard model 
(3 stratification factors (ECOG PS (0 versus 1), extracellular domain EGFR mutations (ECD) 
(presence versus absence) and previous regimens of treatment (2 versus ≥ 3)). Treatment will 
be included in the model and a stepwise selection process (p-value to enter < 0.15, p-value to 
remain < 0.10) will be applied to identify potential additional prognostic factors among the 
following covariates: region (North America, European Union, Asia, Rest of the World), time 
since diagnosis of 1st metastasis (< 18, ≥ 18 months), location of primary disease (right, left), 
gender (female, male), age (< 70, ≥ 70 years), prior surgical resection (yes, no), number of 
metastatic sites (1-2, ≥ 3), neutrophils to lymphocytes ratio (NLR < 3, NLR ≥ 3), neutrophils 
to lymphocytes ratio (NLR < 5, NLR ≥ 5), response to previous treatment with anti-EGFR 
(CR/PR, SD), last previous regimen (anti-EGFR, no anti-EGFR), previously treated with anti-
VEGFs treatment (yes, no), skin toxicity with previous anti-EGFR (yes, no), skin toxicity with 
previous anti-EGFR (Grade 1-2, Grade 3-4, no toxicity), duration of previous anti-EGFR (< 8, 
≥ 8 months), Race (White, American Indian/Alaska native, Asian, Black/African American, 
Native Hawaiian/Other pacific islander), Premedication with antibiotics for skin toxicity (yes, 
no).  
10.1.2.4.2.2. Key secondary estimand based on the OS 
The key secondary estimand of interest is the effect of the randomised treatments on the survival 
duration in all subjects that are KRAS/NRAS, BRAF WT and EGFR-extracellular domain WT 
(Triple negative [TN]) regardless of whether or not intercurrent events occur (treatment policy 
strategy). The motivation for this choice is to assess the efficacy of the futuximab/modotuximab 
in combination with trifluridine/tipiracil compared to trifluridine/tipiracil monotherapy under 
the ITT principle (intercurrent events are considered to be part of the treatments being 
compared). 
All data collected during the trial regardless of occurrence of an IE will be used. This is aligned 
with the treatment policy strategy. 
The following analyses will be done as primary analyses:  
­ The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS 
data). 
­ OS for each arm will be summarized using Kaplan Meier curves and further characterised 
in terms of the median and survival probabilities at 6, 12 and 18 months along with the 
corresponding 2-sided 95% CI for the estimates.  
­ The hazard ratio of OS with its 95% confidence interval will be estimated with a stratified 
Cox proportional hazard model (stratification factors based on IWRS data).  
As OS in TN population is identified as the key secondary estimand, closed sequential testing 
procedure will be used to statistically evaluate and interpret OS in TN population only if the 
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primary estimand, OS in DN population, is statistically significant. Therefore, the family-wise 
error rate is strongly controlled. 
The following analyses will be done as sensitivity analyses:  
­ The proportional hazards assumption will be checked. If relevant, other statistical method 
could be used. 
­ OS analysis based on PPS. 
Other sensitivity analyses will be defined in the SAP if necessary. 
For missing data (not linked to intercurrent events), i.e. participants without documentation of 
death (lost to follow-up, withdrawal of consent, administrative end of study), the OS will be 
censored on the last contact date the participant was known to be alive or the cut-off date, 
whichever is earlier. 
The same subgroup analyses as used for the primary estimand will be done. 
10.1.2.4.2.3. Supplementary estimand based on OS 
One supplementary estimand based on OS is defined in order to assess the effect of the 
randomised treatments on the survival time in all subjects who are KRAS/NRAS and BRAF 
WT (Double negative [DN]) before participants receive further anti-cancer therapy (while on 
treatment strategy).  
The other estimand based on OS is defined in order to assess the effect of the randomised 
treatments on the survival time in all subjects who are KRAS/NRAS, BRAF WT and EGFR-
extracellular domain WT (Triple negative [TN]) before participants receive further anti-cancer 
therapy (while on treatment strategy). 
The aim of this estimand is to evaluate the effect of the study treatment without a potential 
effect of another therapy. 
The use of data post intercurrent events will be different according to the IE:  
­ For IE “administration of further anti-cancer therapy” and “treatment switch”: data obtained 
post IE will not be used for the analysis. OS will be censored at the time of administration 
of further anti-cancer therapy. 
­ For IE “treatment discontinuation”: time of death for any cause after treatment 
discontinuation will be taken into account. 
These strategies are aligned with those estimands.  
The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS data).  
For missing data (not linked to intercurrent events), i.e. participants without documentation of 
death (lost to follow-up, withdrawal of consent, administrative end of study), the OS will be 
censored on the last contact date the participant was known to be alive or the cut-off date, 
whichever is earlier.  
Other estimands will be defined in the SAP if necessary. 
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10.1.2.4.2.4. Secondary estimands based on PFS, OR, DC, DoR, TTNT, TTR and TtPS2 
Secondary estimand based on PFS  
One secondary estimand of interest is the effect of the randomised treatments on progression-
free survival in all subjects before participants receive further anti-cancer therapy (while on 
treatment strategy). For participants who start the subsequent anti-cancer therapy before disease 
progression or death will be censored at the date of last evaluable tumour assessment prior to 
the date of any subsequent anti-cancer therapy. This is aligned with the estimand and the while 
on treatment strategy.  
The other secondary estimand of interest is the effect of the randomised treatments on 
progression-free survival in all subjects regardless of whether or not intercurrent events occur 
(treatment policy strategy). All data collected during the trial regardless of occurrence of an IE 
will be used. This is aligned with the treatment policy strategy. 
The following analyses will be done as primary analyses:  
­ The distribution of PFS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS 
data). 
­ PFS for each arm will be summarized using Kaplan Meier curves and further characterised 
in terms of the median and survival probabilities at 2, 4, 6 and 8 months along with the 
corresponding 2-sided 95% CI for the estimates.  
­ The hazard ratio of PFS with its 95% confidence interval will be estimated with a stratified 
Cox proportional hazard model (stratification factors based on IWRS data).  
The following analyses will be done as sensitivity analyses:  
­ An analysis that considers clinical progression and administration of further anti-cancer 
therapy as PFS events in addition to the radiological progression or death.  
­ PFS analysis based on PPS. 
For missing data (not linked to intercurrent events), i.e. participants who were lost to follow-up 
or who have withdrawn their consent without radiological progression or reached the time point 
of analysis without a known record of death or radiological progression, the PFS will be 
censored at the date of last evaluable tumour assessment or the cut-off date, whichever is earlier.  
The same subgroup analyses as used for the primary estimand will be done for PFS.  
Secondary estimands based on ORR and DCR  
Other secondary estimand of interest are the effect of the randomised treatments on response in 
all subjects before participants receive further anti-cancer therapy. 
Responses recorded after intercurrent event will be excluded. This is aligned with the estimand 
and the treatment while on treatment strategy. 
The following analyses will be done:  
­ OR based on the investigator’s tumour assessment will be compared in the FAS between 
treatment arms using a stratified Cochran-Mantel-Haenszel (CMH) test. A 2-sided 95% CI 
for the difference in ORR between the two treatment arms will also be provided based on 
the normal approximation. If required, a Fisher’s exact test and 2-sided 95% Clopper-
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Pearson CIs will be used. A 2-sided 95% CI for the difference in ORR between the two 
treatment arms will also be provided based on the normal approximation. 
­ DC based on the investigator’s tumour assessment will be compared in the FAS between 
treatment arms using a stratified CMH test. A 2-sided 95% CI for the difference in DCR 
between the two treatment arms will also be provided based on the normal approximation. 
If required, a Fisher’s exact test and 2-sided 95% Clopper-Pearson CIs will be used. A 2-
sided 95% CI for the difference in DCR between the two treatment arms will also be 
provided based on the normal approximation.  
Secondary estimands based on DoR, TTNT, TTR and TtPS2 
Responses recorded after intercurrent event will be excluded. This is aligned with the estimand 
and the treatment while on treatment strategy. 
The following analyses will be done:  
­ The distribution of DoR per investigator’s tumour assessment will be compared between the 
two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance 
(stratification factors based on IWRS data). 
­ DoR per investigator’s tumour assessment for each arm will be summarized using Kaplan 
Meier curves and further characterised in terms of the median along with the corresponding 
2-sided 95% CI for the estimate. 
­ The distribution of TTNT will be compared between the two treatment groups using a 
stratified log-rank test at one-sided 2.5% level of significance (stratification factors based on 
IWRS data). 
­ TTNT for each arm will be summarized using Kaplan Meier curves and further characterised 
in terms of the median along with the corresponding 2-sided 95% CI for the estimate. 
­ The distribution of TTR per investigator’s tumour assessment will be compared between the 
two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance 
(stratification factors based on IWRS data). 
­ TTR per investigator’s tumour assessment for each arm will be summarized using Kaplan 
Meier curves and further characterised in terms of the median along with the corresponding 
2-sided 95% CI for the estimate. 
­ The distribution of TtPS2 will be compared between the two treatment groups using a 
stratified log-rank test at one-sided 2.5% level of significance (stratification factors based on 
IWRS data). 
­ TtPS2 for each arm will be summarized using Kaplan Meier curves and further characterised 
in terms of the median along with the corresponding 2-sided 95% CI for the estimate. 
10.1.2.5. Quality of Life analysis 
Endpoints:  
­ EORTC QLQ-C30 questionnaire. 
­ EORTC EQ-5D-5L questionnaire. 
10.1.2.5.1. Analysis 
10.1.2.5.1.1. EORTC QLQ-C30 
The raw QoL data will be scored according to the EORTC scoring manual and the change in 
score from baseline in the global health status (GHS) scale is identified as the primary QoL 
variable of interest.  
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The completion and compliance rates will be summarised by treatment group for each 
scheduled assessment timepoints.  
The completion rate is defined as the rate of participants who completed the QoL instrument 
among participants in the QoL analysis set.  
The compliance rate is defined as the rate of participants who completed the QoL instrument 
among participants still on treatment at each visit. 
Baseline values and changes in scores from baseline (GHS and each sub-scale score) will be 
summarized at each scheduled assessment time point descriptively.  
A repeated-measures mixed-effects model (SAS PROC MIXED) that includes terms for 
treatment arms, baseline stratification factors, baseline sub-scale score and time of visit will be 
used to compare the two treatment groups with respect to changes from baseline in the GHS 
and each sub-scale score longitudinally over time. 
Time to definitive ≥ 10 points deterioration from baseline in the GHS and in each sub-scale, 
will be compared between the two treatment arms in the QoL analysis set using the stratified 
log-rank test at a 2-sided 5% level of significance (strata based on IWRS data). Death will be 
considered to be a deterioration event of QoL. Participants receiving any further anti-neoplastic 
therapy before definitive worsening will be censored at the date of their last QoL assessment 
before starting this therapy. Participants who have not worsened as of the cut-off date for the 
analysis will be censored at the date of their last assessment (questionnaire) before the cut-off. 
Participants without evaluable questionnaire at baseline will be censored at their randomisation 
date + 1 day. The distributions will be described using Kaplan-Meier curves including the 
median time to definitive 10 points deterioration. 
10.1.2.5.1.2. EORTC EQ-5D-5L 
The dimensional 5-level system will be converted into a single index utility score: the utility 
index will be derived according to specific country algorithms.  
The completion and compliance rates will be summarised by treatment group for each 
scheduled assessment timepoints.  
The completion rate is defined as the rate of participants with evaluable EQ-5D-5L assessment 
among participants of the EQ-5D-5L analysis set.  
The compliance rate is defined as the rate of participants with evaluable EQ-5D-5L assessment 
among participants still on treatment at each visit.  
A breakdown table to include the proportions of reported problems (no problems, slight 
problems, moderate problems, severe problems, or extreme problems) at baseline versus each 
scheduled assessment timepoint will be presented in each dimension of EQ-5D-5L by treatment 
arms in the EQ-5D-5L analysis set.  
Baseline values and changes in score from baseline in EQ-5D-5L VAS and EQ-5D-5L health 
utility index will be presented by treatment arms at each scheduled assessment timepoint by 
descriptive statistics (N, mean/proportion median, SD, Q1, Q3).  
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A repeated-measures mixed-effects model (SAS PROC MIXED) that includes terms for 
treatment, baseline stratification factors, baseline score and time of visit will be used to compare 
the two treatment groups in the EQ-5D-5L analysis set with respect to changes from baseline 
in the EQ-5D-5L VAS and EQ-5D-5L health utility index.  
10.1.2.6. Safety analysis 
All participants included in the Safety set (SS) will be evaluated by treatment arms unless 
otherwise specified.  
10.1.2.6.1. Adverse events 
Treatment-emergent adverse events are defined as any AEs reported from the date of first 
administration of IMP to 30 days after the last date of IMP. Frequency and percentages of 
participants will be summarized for: any grade TEAE, Grade 3 or higher TEAE, IMP related 
TEAE, serious TEAE, TEAE leading to dose modification, TEAE leading to IMP 
discontinuation, death and TEAE leading to death. Adverse events will be summarized by SOC 
and preferred term. All AE data will be listed by participant. 
Of note, the seriousness and the relationship to the IMP of the adverse event correspond to the 
investigator opinion or, in case of events upgraded by the sponsor for seriousness or for 
causality in case of SAE, to the sponsor opinion.  
Number and percentage of participants who experienced a DLT will be summarized and listed 
for Safety Lead-In part. 
10.1.2.6.2. Clinical laboratory evaluation 
For haematological, biochemistry, urinary and coagulation parameters, descriptive statistics on 
value at baseline, on value at each post-baseline visit under treatment, on last post-baseline 
value under treatment and, on change from baseline to last post-baseline value under treatment 
will be provided.  
For all clinical laboratory parameters (except urinary parameters), the following analysis will 
be performed: Laboratory parameters classified (number and percentage of participants in each 
class) according to these reference ranges and using shift tables from baseline to the worst (high 
and/or low) values under treatment.  
10.1.2.6.3. Vital signs, clinical examination and other observations related to safety 
10.1.2.6.3.1. Vital signs and clinical examination 
Vital signs and clinical examination will be described, in terms of value at baseline, value at 
each post-baseline visit under treatment and last post-baseline value under treatment; as well as 
in terms of change from baseline to each post baseline visit under treatment and to last post-
baseline value under treatment.  
10.1.2.6.3.2. Electrocardiogram 
ECG parameters will be described, in terms of value at baseline, value at each post-baseline 
visit under treatment and last post-baseline value under treatment; as well as, for quantitative 
endpoints, in terms of change from baseline to each post baseline visit under treatment and to 
last post-baseline value under treatment. Moreover, values and changes form baseline of 
corrected QT interval will be described in classes, considering thresholds defined in ICH E14 
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(i.e., ≤ 450,] 450; 480],] 480; 500] and > 500 ms for values, and ≤ 30,] 30; 60] and > 60 ms for 
changes).  
10.1.2.7. Biomarkers analysis 
Based on ctDNA, pharmacodynamic biomarkers, potential predictors of response as well as 
mechanisms of resistance could be explored. More details will be described in the SAP. 
10.1.2.8. Interim analysis 
There are 3 planned interim analyses: an early futility interim analysis (interim 0) will be 
triggered when ~83 PFS events have observed in DN population which is designed under a 
hypothetical Phase 2 study that would have 95% power to detect a true hazard ratio for PFS of 
HR ≤ 0.525 (assumptions of mPFS 4 months versus 2.1 months) with a one-sided alpha level 
of 0.10. This futility analysis will use both PFS and OS data to calculate the Predictive 
Probability of Success incorporating historical data based on an extension of the methodology 
proposed by Saint Hilary et al.40 for decision making. More details on the methodology and 
PPoS calculation will be provided in SAP. Study will be stopped for futility if the calculated 
PPoS < 10%.  If the study proceeds, an interim OS analysis for futility (interim 1) will be 
conducted when approximately 33.3% of the planned final number of OS events in DN 
population (i.e. 128 of 383 OS events) have been observed. If the study proceeds, a second 
interim analysis will occur to evaluate futility and efficacy (interim 2) when 255 events (66.7% 
of the planned final number of OS events) have occurred in DN population. 
10.2. Determination of sample size 
Approximately 25 participants will be evaluated in Safety Lead-In part. The DMC will initially 
determine tolerability after 6 evaluable participants have been treated. If ≤ 2 participants out of 
the first 6 experience a DLT, and the DMC based on the totality of safety data determines the 
doses to be tolerable, then the Safety Lead-In will be expanded by an additional cohort of 
6 participants. The DMC will again assess the tolerability when 12 participants have been 
enrolled and the 12th participant has completed the first treatment cycle. If ≤ 3 participants 
experience a DLT, and the DMC based on the totality of safety data determines the doses to be 
tolerable, the Safety Lead-In will be expanded to add another 13 participants, for a total of 
25 participants. The DMC will meet again at the end of the Safety Lead-In part when 
approximately 25 participants have been treated.  
The primary endpoint of Randomised part will be OS in DN population, the key secondary 
endpoint will be OS in TN population. The primary hypothesis will test whether treatment with 
trifluridine/tipiracil 
in 
combination 
with 
futuximab/modotuximab 
compared 
with 
trifluridine/tipiracil alone leads to OS prolongation in DN population. A total of 500 patients 
will be randomised in a 1:1 ratio to the 2 treatment arms and followed-up until at least 383 OS 
events are observed across the 2 treatment arms will provide 90% power to detect a true hazard 
ratio (HR) ≤ 0.71 (median OS: 8.5 vs 12 months) using a stratified log-rank test (stratified by 
Performance Status [PS] [0 vs 1], extracellular domain EGFR mutations [extracellular domain 
(ECD)] [presence vs absence] and previous regimens of treatment [2 vs ≥ 3]), with an overall 
1-sided significance level of 0.025 for the primary endpoint (adjusted for OS interim analyses). 
Assuming enrolment over 21 months with a ramp-up to a maximum of 30 patients per month 
and a lost-to-follow-up rate of 7% across both treatment arms, the timing of the primary analysis 
is expected to be at 37.5 months after 1st randomisation.  
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To control type I and type II errors, the planned interim analyses for OS will utilise O’Brien 
Fleming alpha spending function (the Lan-DeMets method)41 for efficacy boundaries 
determination and Hwang-Shih-Decani (non-binding)42 beta spending function with γ 
parameter equal to -1.5 for futility boundary determination. If OS in DN population is 
significant at final analysis when 383 OS events have occurred in the DN population, OS in the 
TN population will be tested at the full alpha level, i.e., 0.025. The OS testing plan for the 
primary endpoint has 90% power conditional on passing the early futility interim analysis 
(interim 0). 
Since the boundary is dependent on the number of OS events, the actual boundary used will be 
re-calculated, incorporating the spending function as defined, based on the number of actual 
OS events analysed at the time of the interim analysis relative to the planned 383 events. The 
boundary for the final analysis will similarly be adjusted in accordance with the amount of 
remaining alpha. The interim analysis specifications per the plan are provided in Table (10.2) 1. 
Table (10.2) 1 - Interim analysis specifications 
Analysis  
IF  
# OS 
Events 
Efficacy 
Futility 
Zboundary Pboundary  α spend HRcrit Zboundary 
Pboundary β  spend 
HRcrit 
Interim 1  0.334 
128 
NA 
NA 
NA 
NA 
-0.132 
0.553 
0.019 
1.024 
Interim 2  0.666 
255 
2.511 
0.006 
0.006 
0.73 
0.997 
0.159 
0.049 
0.883 
Final  
1 
383 
1.993 
0.023 
0.025 
0.816 
1.993 
0.023 
0.1 
0.816 
IF = information fraction. Zboundary is the critical test statistic value at which futility (< Z) or efficacy (> Z) would be concluded. Pboundary is 
the critical one-sided p-value threshold for the comparison (> p for futility, < p for efficacy). α spend and β spend are the amount of type I 
and type II error spent at each analysis, respectively. HRcrit is the observed hazard ratio threshold (> HR for futility, < HR for efficacy).  
The DMC will be responsible for evaluating the interim futility and efficacy analysis and 
making a recommendation about early termination due to observed study results. 
10.3. Pharmacokinetic analyses and PK/PD analysis 
10.3.1. Safety Lead-In part 
In order to inspect the pharmacokinetic profiles of futuximab/modotuximab and 
trifluridine/tipiracil when given in combination, external Visual Predictive Check on the 
individual serum for futuximab/modotuximab and plasma for trifluridine/tipiracil 
concentrations will be performed. For this, previously developed population PK models for 
futuximab/modotuximab, and trifluridine/tipiracil, will be used to perform simulations 
(1000 replicates) of the expected concentration-time profile of these compounds administered 
as monotherapies. The [P5; P95] prediction interval (i.e. encompassing 90% of overall 
predicted concentrations) and the median of the overall simulated plasma/serum concentration-
time curves will be calculated and will be graphically superimposed with observed 
concentration-time data. 
10.3.2. Randomised Part 
Concentrations of futuximab/modotuximab and trifluridine/tipiracil will be analysed by a 
population modelling approach, described in a separated Data Analysis Plan (DAP). 
This analysis will provide pharmacokinetic parameters (such as Cmax and AUC) and their 
associated variability in participants and will be the object of a separate report. Interim analyses 
using this approach could be performed if required. 
Exploratory assessment of the relationship between exposure and pharmacodynamics (as safety 
and 
efficacy) 
will 
be 
performed 
and 
if 
applicable, 
population 
pharmacokinetic-pharmacodynamic (PK/PD) models will be developed and a DAP will be set 
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up and reported separately. The pharmacometrics analysis may require other model-based 
approaches to better describe the PK/PD of the compound. In this case a description of these 
methods would be included in a specific DAP. 
The data of the present study could be pooled with data from previous or future clinical studies, 
if relevant. It could also be combined with literature data if required. 
11. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will allow the monitors, the persons responsible for the audit, the 
representatives of the IRB/IEC, and of the Competent Authorities to have direct access to source 
data / documents. 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. Study monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by the structure mentioned in document entitled 
Administrative part of clinical study protocol.  
If on-site monitoring cannot be accomplished, remote Source Data Verification may be 
performed in accordance with local regulations 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The 
CMP describes in detail who will conduct the monitoring, at what frequency monitoring will 
be done, at what level of detail monitoring will be performed, and the distribution of monitoring 
reports.  
12.1.1. Before the study 
The investigator will allow the monitor to visit the site and facilities where the study will take 
place to ensure compliance with the protocol requirements. 
Training sessions may be organised for the investigators and/or instruction manuals may be 
given to the investigators. 
12.1.2. During the study 
The investigator will allow the monitor to: 
­ Review of the study site’s processes and procedures. 
­ Verify appropriate clinical investigator supervision of study site staff and third-party 
vendors. 
­ Inspect the site, the facilities and the material used for the study. 
­ Meet all members of his/her team involved in the study. 
­ Consult the documents relevant to the study. 
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­ Have access to the e-CRF (i.e. Access to an analogic phone line or his/her computer) and/or 
to the e-PRO service provider’s database to check that they been filled out correctly. 
­ Check that the e-CRF and e-PRO have been filled out correctly. 
­ Directly access source documents for comparison of data therein with the data in the 
electronic case report forms and/or to the e-PRO/e-COA service provider’s database. 
­ Verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
The study monitoring will be carried out at regular intervals, depending on the recruitment rate 
and / or the investigation schedule, and arranged between the investigator and monitor. 
All information dealt with during these visits will be treated as strictly confidential. 
12.2. Computerised medical file 
If computerised medical files are used, and if the computer system allows, no change made in 
the medical files by the investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the prior 
information (i.e. audit trail). The investigator will save data at regular intervals. 
The investigator must guarantee the integrity of the study data in the medical files by 
implementing security measures to prevent unauthorised access to the data and to the computer 
system. 
If the computerised medical files are considered as not validated by the sponsor, the investigator 
undertakes: 
­ At the start of the study, to print the medical files of all participants allowing a reliable 
verification of the study criteria (e.g. Medical history/previous treatments/ characteristics of 
the studied disease documented within the period of time defined by the study protocol). 
­ During the study, to print in real time each data entry and each data change. 
The investigator or designated person of the site team will personally sign, date and give the 
number of pages on the first or last page of each print-out. At each visit by the monitor, the 
investigator will provide all the print-outs of the medical files of the participants. The monitor 
will personally sign and date the first (or last) page then initial all pages in each paper print-out. 
If the computer system allows the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the medical files of the 
participants and the records of the changes made. Each print-out will be personally dated and 
signed, by the investigator and the monitor on the first page. The number of pages will also be 
indicated by the investigator and the monitor on the first page. 
If the computerised medical files are considered as validated by the sponsor, the investigator 
undertakes to give access to the monitor to the computerised medical files of all participants. If 
the monitor cannot access to the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the records of the changes 
made to the medical files of the participants. Each print-out will be personally dated and signed, 
by the investigator and the monitor on the first page. The number of pages will also be indicated 
by the investigator and the monitor on the first page. 
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The investigator undertakes to keep: 
­ All medical file print-outs signed and dated by him/her and by the monitor when the 
computer system is considered as not validated by the sponsor. 
­ If the computer system used allows changes to be made, the print-outs of the audit trail when 
the computer system is considered as not validated by the sponsor or when the monitor 
cannot access to the audit trail in the computer system. 
­ All original source-documents (originals of specific examinations, informed consent forms, 
therapeutic unit tracking form...). 
12.3. Audit - Inspection 
The investigator should be informed that an audit may be carried out before, during or after the 
end of the study. 
If on-site auditing cannot be accomplished, remote audit may be performed in accordance 
with local regulations. 
The investigator should be informed that the Competent Authorities may also carry out an 
inspection in the facilities of the sponsor and/or the study centre(s). The sponsor will inform 
the investigators concerned immediately upon notification of a pending study centres 
inspection. Likewise, the investigator will inform the sponsor of any pending inspection. 
The investigator must allow the representatives of the Competent Authorities and persons 
responsible for the audit:  
­ To inspect the site, facilities and material used for the study. 
­ To meet all members of his/her team involved in the study. 
­ To have direct access to study data and source documents. 
­ To consult all the documents relevant to the study. 
If the computerised medical file is considered as not validated, the investigator undertakes to 
provide all the source-documents and the print-outs of the medical files of the participants and, 
if the computer system used allows, the record of the changes made during the study. 
If the computerised medical file is considered as validated, the investigator undertakes to: 
­ Give access to the representatives of the Competent Authorities and persons responsible for 
the audit to the computerised medical files of all participants. 
­ Provide the print-outs of the changes made during the study, if the tracking of the changes 
made to the medical files cannot be accessed in the computer. 
12.4. Supervisory committees 
12.4.1. Steering Committee 
The Steering Committee (SC) members will be appointed by the sponsor prior to the initiation 
of the study. The SC will comprise experts in colorectal cancer and sponsor representatives. 
The SC will be involved in the overall supervision of the study, will implement measures if 
needed to reduce deviations from the protocol to a minimum and will be involved in periodic 
reviews of the progress of the study. Details on the role of the SC and working procedures will 
be defined in the SC Charter. 
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12.4.2. Data Monitoring Committee 
Safety data collected during the Safety Lead-In part will be reviewed by a DMC to assess if 1) 
the drug combination is tolerable, 2) if the MTD has been exceeded, and 3) if the randomised 
portion of the study may proceed. 
During the Safety Lead-In part, the DMC will initially determine tolerability after 6 evaluable 
participants, then after 12 participants treated and finally when all 25 participants will have 
been enrolled. 
Throughout the Safety Lead-in part DLT occurrence will be followed on a continuous base and 
if the number of participants who experienced at least one DLT in each cohort exceeds the 
maximum number of DLTs that is considered safe (≥ 3/6 evaluable participants, ≥ 4/12 
evaluable participants, ≥ 6/18 evaluable participants and ≥ 8/25 evaluable participants), at any 
time during the Safety Lead-In part the enrolment will be halted, an urgent DMC meeting will 
be organized and DMC will provide recommendations on study continuation, modification or 
discontinuation. 
For Safety Lead-In safety and tolerability evaluation process see Section 4.1.3.4. 
During the Randomised part the DMC will meet approximately every 4 months in the first year 
and approximately twice a year thereafter and at the planned interim analysis as well.  
The composition and role of the DMC will be described in a charter finalised before the trial is 
initiated. 
DMC recommendations will be forwarded to the IRB/IEC / Competent Authorities only if 
relevant for the safety of participants. 
12.4.3. Blinded Independent Central Review (only for Randomised part) 
All imaging data acquired for efficacy purposes (e.g., CT/MRI scans) will be transmitted to an 
imaging vendor for quality check and storage. Image transmission to the imaging vendor should 
be performed according to the imaging vendor manual. BICR review of stored imaging data 
will be performed only if needed, retrospectively, and will not be provided to investigators for 
decisions regarding patient treatment. Should BICR be needed, the images will be read by 
readers who are blinded to treatment assignment and to other clinical data as specified in the 
BICR charter.  
13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the "Participant information and consent form" document, the list of 
investigators, the insurance certificate, the futuximab/modotuximab Investigator’s Brochure, 
the Product Information of trifluridine/tipiracil will be submitted to IRB(s)/IEC(s) by the 
investigator(s) or the national coordinator(s) or the sponsor in accordance with local 
regulations. 
The study will not start in a centre before written approval by corresponding IRB/IEC(s) has 
been obtained, the local regulatory requirements have been complied with, and the signature of 
the clinical study protocol of each contractual party involved has been obtained. 
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13.2. Study conduct 
The study will be performed in accordance with the ethical principles stated in the Declaration 
of Helsinki 1964, as revised in Fortaleza, 2013 (Appendix 1), with the GCP and with the 
applicable regulatory requirements. 
13.3. Participant information and informed consent 
In any case, the participant (and/or his/her legal representative, when required) must be 
informed that he/she is entitled to be informed about the outcome of the study by the 
investigator. 
The investigator or a person designated by him/her is required to collect written consent from 
each participant before his/her participation in the study. Prior to this, the investigator or his/her 
delegate must inform each participant of the objectives, benefits, risks and requirements 
imposed by the study, as well as the nature of the IMPs. 
The participant will be provided with an information and consent form in clear, simple 
language. He/she must be allowed ample time to inquire about details of the study and to decide 
whether or not to participate in the study. 
One, or two if required by local regulation, original information and consent form(s)must be 
completed, dated and signed personally by the participant and by the person responsible for 
collecting the informed consent. ICF will be available electronically if requested by the patient 
in the randomised part only. The electronic signature for the ICF will not be available. 
If the participant is unable to read, an impartial witness should be present during the entire 
informed consent discussion. The participant must give consent orally and, if capable of doing 
so, complete, sign and personally date the information and consent form. The witness must then 
complete, sign and date the form together with the person responsible for collecting the 
informed consent. 
The participant will be given one signed copy (or original if required by local regulation) of the 
information and consent form. A signed original will be kept by the investigator. 
A copy of the information and consent form in the language(s) of the country is given in the 
“Participant information and consent form” document attached to the protocol. 
13.4. Modification of the information and consent form 
Any change to the information and consent form constitutes an amendment to this document 
and must be submitted for approval to the IRB/IEC(s), and if applicable to the Competent 
Authorities. 
A copy of the new version(s) of the information and consent form(s) in the language(s) of the 
country will be given in the amendment to the “Participant Information and consent form”. 
Such amendments may only be implemented after written approval of the IRB/IEC has been 
obtained and compliance with the local regulatory requirements, except for an amendment 
required to eliminate an immediate risk to the study participants. 
Each participant affected by the amendment and/or his/her legal representative must complete, 
date and co-sign one, or two if required by local regulation, original(s) of the new version of 
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the information and consent form together with the person who collected the informed consent 
(and an independent witness, if applicable). He/She/They will receive one signed copy (or 
original, if required by local regulation) of the amendment to the information and consent 
form(s). The signed original(s) will be kept by the investigator. 
14. DATA HANDLING AND RECORD KEEPING 
14.1. Study data 
A 21 CFR Part 11-compliant electronic data capture system will be used in this study. An 
electronic case report form (e-CRF) is designed to record the data required by the protocol and 
collected by the investigator. 
The e-CRF will be produced by I.R.I.S. in compliance with its specifications. The investigator 
or a designated person from his/her team will be trained for the use of the e-CRF by the sponsor. 
Data entry at the investigator’s site will be performed by the investigator or by the designated 
person from his/her team after completion of the participant’s Medical File. 
Upon entry, data will be transmitted via the Internet from the study centre to the study database. 
The investigator or the designated person from his/her team agrees to complete the e-CRF, at 
each participant visit, and all other documents provided by the sponsor (e.g. documents relating 
to the IMP management…). 
Data recorded directly on e-CRF and considered as source data (Section 4.5) must be collected 
immediately in the e-CRF. The other e-CRF forms must be completed as soon as possible 
following each visit. 
All corrections of data on the e-CRF must be made by the investigator or by the designated 
person from his/her team using electronic data clarifications according to the provided 
instructions. All data modification will be recorded using the audit trail feature of the e-CRF 
software, including date, reason for modification and identification of the person who has made 
the change. 
To ensure confidentiality and security of the data, usernames and passwords will be used to 
restrict system access to authorised personnel only, whether resident within the investigator’s 
sites, the sponsor or third parties. 
Data will be verified in accordance with the monitoring strategy defined for the study. After 
comparing these data to the source documents, the monitor will request correction / clarification 
from the investigator using electronic data clarifications that should be answered and closed as 
quickly as possible. 
Data can be frozen during the study after their validation. However, the investigator has the 
possibility to modify a data if deemed necessary via a request to the sponsor. 
The investigator or authorised member for sign-off must confirm the authenticity of the data 
recorded in the e-CRF by signing the e-CRF in a timely manner as defined in the e-CRF 
completion guide.  
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After the last visit of the participant, the investigator or co-investigator must attest the 
authenticity of the data collected in the e-CRF by entering his/her username and password. 
After the data base lock, the investigator or an authorised member of his/her team will have to 
download from the e-CRF an electronic file containing participant data from his/her centre for 
archiving it in the study file (Section 14.3). 
14.2. Data management 
Data are collected via an e-CRF and stored in a secured database. 
For data collected on the e-CRF, the Clinical Data Management of I.R.I.S. is responsible for 
data processing including data validation performed according to a specification manual 
describing the checks to be carried out. As a result of data validation, data may require some 
changes. An electronic data clarification form is sent to the investigator who is required to 
respond to the query and make any necessary changes to the data. 
For data transferred from e-PRO, the Clinical Data Management of I.R.I.S. is responsible for 
data transfer: e-PRO provider provides electronic transfer of computerised data to the Clinical 
Data Management of I.R.I.S. Data are transferred according to a transfer protocol issued by the 
I.R.I.S. data manager. 
For data transferred from IWRS, the Clinical Data Management of I.R.I.S. is responsible for 
data transfer: IWRS provider provides electronic transfer of computerised data to the Clinical 
Data Management of I.R.I.S. Data are transferred according to a transfer protocol issued by the 
I.R.I.S. data manager. 
For data transferring from central reading, the Clinical Data Management of I.R.I.S. is 
responsible for data transfer: central reading provider provides electronic transfer of 
computerised data to the Clinical Data Management of I.R.I.S. Data are transferred according 
to a transfer protocol issued by the I.R.I.S. data manager. 
The Medical Data Department of I.R.I.S. is responsible for data coding including: 
­ medical / surgical history, adverse events and procedures using MedDRA. 
­ medications using World Health Organization, Drug Dictionary (WHO-Drug). 
The coding process is described in a specification manual. 
The investigator ascertains he/she will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact the sponsor or its representatives monitoring 
the study, if any, to request approval of a protocol deviation, as no deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the sponsor 
and approved by the IRB/IEC it cannot be implemented. All important protocol deviations will 
be recorded and reported in the clinical study report. 
When data validation is achieved, a review of the data is performed according to the sponsor 
standard operating procedure. When the database has been declared to be complete and 
accurate, it will be locked, and the study treatments codes will be unblinded and made available 
for data analysis. 
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14.3. Archiving 
The investigator will keep all information relevant to the study for at least 25 years after the 
end of the study, or more if specified by the local regulation.  
At the end of the study, the investigator or an authorised member of his/her team will download 
an electronic copy of each participant’s data from the e-CRF and should keep it in a reliable, 
secure and durable location. The file includes all data and comments reported in the e-CRF, the 
history of all queries and signatures and the full audit trail reports.  
The file must include appropriate restrictions (password protection) and adequate protection 
from loss, physical damage or deterioration for the duration of the archiving period.  
All data reported in e-COA, e-PRO will be provided to the investigator’s site. 
15. INSURANCE 
I.R.I.S., or any parent company of SERVIER GROUP in charge of the management of clinical 
trials, is insured under the liability insurance program subscribed by LES LABORATOIRES 
SERVIER to cover its liability as sponsor of clinical trials on a worldwide basis. 
Where an indemnification system and/or a mandatory policy are in place, I.R.I.S. or any parent 
company of SERVIER GROUP will be insured under a local and specific policy in strict 
accordance with any applicable law.  
All relevant insurance documentation is included in the file submitted to any authorities’ 
approval of which is required. 
16. OWNERSHIP OF THE RESULTS - DATA SHARING POLICY AND 
PUBLICATION POLICY 
I.R.I.S., acting as the study sponsor, assumes full responsibilities relating to this function and 
retains exclusive property rights over the results of the study, which it may use as it deems fit.  
I.R.I.S. will ensure that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalisation of the study report, the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
Any project of publication and/or communication relative to the study and/or relative to the 
obtained results during the study or after the study end shall be submitted to the sponsor. in 
accordance with the guidelines set forth in the applicable publication policy or financial 
agreement. 
The investigator, who submitted the project, shall take the sponsor's comments into due 
consideration.  
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As the study is a multicentre one, the first publication must be performed only with data 
collected from several study sites and analysed under the responsibility of I.R.I.S. The 
investigator commits himself not to publishing or communicating data collected in only one 
centre or part of the centres before the publication of the complete results of the study, unless 
prior written agreement from the other investigators and I.R.I.S. has been provided. 
Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. 
Researchers can ask for a study protocol, participant-level and/or study-level clinical trial data 
including clinical study report. 
They can ask for all interventional clinical studies: 
­ submitted for new medicines and new indications approved after 1 January 2014 in the 
European Economic Area (EEA) or the US. 
­ Where Servier or an affiliate are the Marketing Authorisation Holders. The date of the first 
Marketing Authorisation of the new medicine (or the new indication) in one of the EEA 
Member States will be considered within this scope. 
In addition, Servier’s data sharing policy includes all interventional clinical studies in 
participants: 
­ Sponsored by Servier. 
­ With a first participant enrolled as of 1 January 2004 onwards. 
­ For New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for 
which development has been terminated before any marketing authorisation approval. 
The datasets generated and/or analysed during the current study will be available upon request 
from www.clinicaltrials.servier.com after the Marketing Authorisation has been granted. 
Summary results and a lay summary will be published on clinicaltrials.servier.com within 
12 months after the end of the study.  
The results will be submitted for publication in scientific literature within 18 months after the 
end of the study.  
17. ADMINISTRATIVE CLAUSES 
17.1. Concerning the sponsor and the investigator 
17.1.1. Persons to inform 
In accordance with local regulations, the investigator and/or the sponsor will inform, the 
Director of the medical institution, the pharmacist involved in the study and the Director of the 
analysis laboratory. 
With the agreement of the participant, the investigator will inform the participant’s general 
practitioner about his/her participant’s participation in a clinical study. 
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17.1.2. Substantial protocol amendment and amended protocol 
If the protocol must be altered after it has been signed, the modification or substantial 
amendment must be discussed and approved by and approved by the International Coordinator 
and the sponsor. 
The substantial protocol amendment must be drafted in accordance with the sponsor standard 
operating procedure and an amended protocol must be signed by both parties. Both documents 
must be kept with the initial protocol. 
All substantial amendments and corresponding amended protocols must be sent by the 
investigator(s) or the coordinator(s) or the sponsor, in accordance with local regulations, to the 
IRB/IEC that examined the initial protocol. They can only be implemented after a favourable 
opinion of the IRB/IEC has been obtained, local regulatory requirements have been complied 
with, and the amended protocol has been signed, except for a measure required to eliminate an 
immediate risk to the study participants. 
When the submission is performed by the investigator or the International Coordinator, the 
latter must transmit a copy of IRB/IEC’s new written opinion to the sponsor, immediately upon 
receipt. 
Furthermore, the substantial amendment and amended protocol are to be submitted to the 
competent authorities in accordance with local regulations. 
17.1.3. Final study report 
The study report(s) will be drafted by Biostatistics - Centre of Excellence Methodology and 
Valorisation of Data of I.R.I.S. in compliance with I.R.I.S. standard operating procedure. 
The sponsor’s representative and International Coordinator must mutually agree on the final 
version. One copy of the final report must be dated and signed by the International Coordinator 
and by the Director of the Therapeutic Area. 
The clinical study report, the summary of the results of the clinical trial together with a summary 
that is understandable to a layperson will be submitted where applicable within 1 year after the 
end of the clinical trial worldwide. 
If the clinical trial is still on-going but ended in the European countries, the statistical analysis 
will not be relevant before the end of the study worldwide. Therefore, the timelines defined 
above still apply. 
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17.2. Concerning the sponsor 
The sponsor undertakes to: 
­ Supply the investigator with adequate and sufficient information concerning the IMP and 
the NIMP administered during the study to enable him/her to carry out the study. 
­ Supply the investigator with the trifluridine/tipiracil Product Information. 
­ Supply the investigator with the futuximab/modotuximab Investigator’s Brochure, the one 
best suited to ensure participant safety, and any potential updated version during the study: 
 For the IMP if marketed, to be appended to Investigator’s Brochure (Section 4. Guidance 
for the investigator). 
 For all reference products used in the study. 
 For all NIMPs available on the market. 
­ Obtain any authorisation to perform the study and/or import licence for the IMPs and NIMPs 
administered that may be required by the local authorities before the beginning of the study. 
­ Provide the International Coordinator annually, or with another frequency defined by the 
local regulations, with a document describing study progress which is to be sent to the 
IRB/IEC(s). 
­ Take all the necessary precautions to maintain the safety of the processed data, in particular 
their confidentiality, their integrity and their availability, by assessing risks identified 
concerning personal data protection. The following measures will be implemented (non-
exhaustive): 
 Management of authorisation to access to personal data (e-CRF). 
 Identification and authentication measures before accessing personal data (e-CRF). 
 Traceability measures for the access to and modification of personal data (e-CRF). 
 Secured data transfer. 
 Time limit for storing personal data. 
­ Handle any security breach by implementing an internal committee (including CISO, DPO, 
communication department…) in order to qualify the security incident (Information systems, 
nature and number of personal data impacted), to define an action plan for corrective actions 
and to notify to relevant person (authority and/or if needed individuals). 
17.3. Concerning the investigator 
17.3.1. Confidentiality - Use of information 
All documents and information given to the investigator by the sponsor with respect to 
futuximab/modotuximab and trifluridine/tipiracil and study CL3-95026-001 are strictly 
confidential. 
The investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the sponsor on paper and computer and stored for its sole use relating to its 
activities as the sponsor of clinical trials, in accordance with GCP.  
He/she has a right to access, modify, and delete his/her own personal data by applying to the 
sponsor. 
In case participant wants to exercise his/her rights regarding personal data protection, he/she 
will contact the investigator. The investigator will forward the request to the sponsor (Appendix 
8). 
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The investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this study, for carrying out the protocol. This agreement is binding as 
long as the confidential information has not been disclosed to the public by the sponsor. The 
clinical study protocol given to the investigator may be used by him/her or his/her colleagues 
to obtain the informed consent of study participants. The clinical study protocol as well as any 
information extracted from it must not be disclosed to other parties without the written 
authorisation of the sponsor. 
The investigator must not disclose any information without the prior written consent from 
I.R.I.S., except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the investigator commits himself/herself to informing I.R.I.S. prior to 
disclosure of information to these authorities. 
A participant screening log and a full identification and enrolment list of each participant will 
be completed and kept in a safe place by the investigator who should agree to provide access 
on site to the auditor and/or the representatives of the Competent Authorities. The information 
will be treated in compliance with professional secrecy. 
The participant screening log must be completed from the moment the investigator checks that 
a participant could potentially take part in the study (by assessment of participant medical 
history during a visit or by examination of the medical file). 
17.3.2. Organisation of the centre 
Every person to whom the investigator delegates under his/her responsibility a part of the 
follow-up of the study (co-investigator, nurse…) and any other person involved in the study for 
this centre (cardiologist, pharmacist…) must figure in the "Organisation of centre" document. 
This document should be filled in at the beginning of the study and updated at any change of a 
person involved in the study in the site. 
17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 
­ To provide his/her dated and signed English Curriculum Vitae (CV) (maximum 2 pages) or 
to complete in English the CV form provided by the sponsor and to send it to the sponsor, 
together with that of his/her co-investigator(s). 
­ To provide a detailed description of the methods, techniques, and investigational equipment, 
and the reference values for the parameters measured. 
­ To provide any other document required by local regulation. 
­ To send a copy of the IRB/IEC’s opinion with details of its composition and the 
qualifications of its constituent members. 
The CV of other members of the team involved in the study (if possible, in English) will be 
collected during the course of the study (at least, members involved in the participants’ medical 
follow-up/study-related decision process and persons involved in the measurement of main 
assessment criteria). 
 
 
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18. REFERENCES 
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EGFR Extracellular Domain Mutations in Colorectal Cancer. Clin Cancer Res. 
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Petrelli F, Borgonovo K, Barni S. The predictive role of skin rash with cetuximab and 
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Price T, Kim TW, Li J, et al. Final results and outcomes by prior bevacizumab exposure, 
skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-
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KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016;68:51-9. [PE0161037] 
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with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal 
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trifluridine/tipiracil in combination with cetuximab in RAS wild-type metastatic 
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in Colorectal Cancer. Am Soc Clin Oncol Educ Book. 2015:e149-56. [PE0161362] 
27. 
Baba Y, Tamura T, Satoh Y, et al. Panitumumab interaction with TAS-102 leads to 
combinational anticancer effects via blocking of EGFR-mediated tumor response to 
trifluridine. Mol Oncol. 2017;11(8):1065-77. [PE0141603] 
28. 
Tsukihara H, Nakagawa F, Sakamoto K, et al. Efficacy of combination chemotherapy 
using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, 
cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep. 
2015;33(5):2135-42. [PE0121009] 
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Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in 
BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019;381(17):1632-43. 
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and weight be known. 1916. Nutrition. 1989;5(5):303-11; discussion 12-3. 
[PE0167388] 
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31. 
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;45(2):228-47. 
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Schwartz LH, Litiere S, de Vries E, et al. RECIST 1.1-Update and clarification: From 
the RECIST committee. Eur J Cancer. 2016;62:132-7. [PE0131860] 
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Expedited Reporting, issued as CPMP/ICH/377/95. 1995 
34. 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 4 April 2001 on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of good 
clinical practice in the conduct of clinical trials on medicinal products for human use. 
2001 
35. 
ICH E6 (R2), Integrated Addendum to Good Clinical Practice (GCP), Step 5, Adopted 
by CHMP, 15 December 2016, issued as EMA/CHMP/ICH/135/1995. 2016 
36. 
Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update 
for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and 
of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-
v33. [PE0142471] 
37. 
Hesketh PJ, Bohlke K, Lyman GH, et al. Antiemetics: American Society of Clinical 
Oncology Focused Guideline Update. J Clin Oncol. 2016;34(4):381-6. [PE0166904] 
38. 
Benson AB, 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the 
treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22(14):2918-26. 
[PE0125149] 
39. 
ICH Topic E9 – Statistical Principles for Clinical Trials: Adopted by CPMP, March 
1998, issued as CPMP/ICH/363/96/step 5. 1998. [PE0124379] 
40. 
Saint-Hilary G, Barboux V, Pannaux M, et al. Predictive probability of success using 
surrogate endpoints. Stat Med. 2019;38(10):1753-74. [PE0150724] 
41. 
Lan KKG, DeMets DL. Discrete Sequential Boundaries for Clinical Trials. Biometrika. 
1983;70(3):659-63. [PE0161044] 
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Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Statistics in Medicine. 1990;9(12):1439-45. 
[PE0161042] 
 
 
 
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19. APPENDICES 
 
 
 
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Appendix 1: World Medical Association Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington DC, USA, 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of participants, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
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7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
participants or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. 
Physicians who combine medical research with medical care should involve their 
participants in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the participants 
who serve as research subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risk, Burdens and Benefits 
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
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17. 
All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. 
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
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Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration. 
The committee must have the right to monitor on-going studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without consideration 
and approval by the committee. After the end of the study, the researchers must submit a 
final report to the committee containing a summary of the study’s findings and 
conclusions. 
Privacy and Confidentiality 
24. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
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27. 
When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious participants, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research group. In such circumstances the physician must seek informed consent from the 
legally authorised representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
31. 
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
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Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention 
and the participants who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
Unproven Intervention in Clinical Practice 
In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorised representative, may use an unproven 
intervention if in the physician's judgment it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
 
 
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Appendix 2: Patient performance status 
Status 
Karnofsky 
Grade 
Status 
ECOG* - ZUBROD / WHO 
Normal, no complaints; no evidence of 
disease. 
100 
0 
Fully active, able to carry on all pre-
disease performance without 
restriction. 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
90 
Normal activity with efforts; some signs or 
symptoms of disease. 
80 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature, e.g., light house work, office 
work. 
Cares for self; unable to carry on normal 
activity or to do active work. 
70 
Requires occasional assistance, but is able to 
care for most of his personal needs. 
60 
2 Ambulatory and capable of all selfcare 
but unable to carry out any work 
activities. Up and about more than 
50% of waking hours. 
Requires considerable assistance and 
frequent medical care. 
50 
Disabled; requires special care and 
assistance. 
40 
3 
Capable of only limited self-care,  
confined to bed or chair more than 
50% of waking hours. 
Severely disabled; hospital admission is 
indicated although death not imminent. 
30 
Very sick; hospital admission necessary; 
Active supportive treatment necessary. 
20 
4 
Completely disabled.  
Cannot carry on any self-care.  
Totally confined to bed or chair. 
Moribund; fatal processes progressing 
rapidly. 
10 
Dead 
0 
5 
Dead 
* As published in Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response Criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
 
 
 
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Appendix 3: Cockroft formula 
 
Cockroft formula (Cockroft et al., 1976)  
 
CreatClear [mL/min] = ((140 – Age [years]) / SerumCreat [µmol/L]) * Weight [kg]* Sex 
 
Male = 1.23 
Female = 1.04 
 
 
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Appendix 4: New York Heart Association (NYHA) classification 
The Stages of Heart Failure NYHA Classification 
In order to determine the best course of therapy, physicians often assess the stage of heart failure 
according to the NYHA functional classification system. This system relates symptoms to 
everyday activities and the patient's quality of life. 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is increased. 
 
 
 
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Appendix 5: EQ-5D-5L 
 
 
 
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Appendix 6: EORCT QLQ-C30 
 
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As published in Aaronson NK, et al. "The European Organization for Research and Treatment of Cancer QLQ-
C30: a quality of life instrument for use in international clinical trials in oncology." Journal of the national cancer 
institute, 1993:365-376. 
 
 
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Appendix 7: New Response Evaluation Criteria in Solid Tumours: 
Revised RECIST guideline (version 1.1), Eisenhauer, 2009 
Measurability of tumour at baseline 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
­ 10 mm by CT-scan (CT-scan slice thickness no greater than 5 mm), 
­ 10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable), 
­ 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT-scan (CT-scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
­ Bone scan, PET-scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions, 
­ Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above, 
­ Blastic bone lesions are non-measurable. 
Cystic lesions: 
­ Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts, 
­ ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
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Lesions with prior local treatment: 
­ Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
Tumour response evaluation 
Assessment of overall tumour burden and measurable disease 
To assess OR or future progression, it is necessary to estimate the overall tumour burden at 
baseline and use this as a comparator for subsequent measurements. 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumour response is the primary endpoint. Measurable disease is defined by the 
presence of at least one measurable lesion. In studies where the primary endpoint is tumour 
progression (either time to progression or proportion with progression at a fixed date), the 
protocol must specify if entry is restricted to those with measurable disease or whether patients 
having non-measurable disease only are also eligible. 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline (this 
means in instances where patients have only one or two organ sites involved a maximum of two 
and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumour. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumour. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, saggital or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterise any objective tumour regression 
in the measurable dimension of the disease. 
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All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumour response 
for target lesions. 
Evaluation of target lesions: 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT-scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’. When this occurs it is important that a value be recorded on the case report form. 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. 
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To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumour response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumour burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the patient has only non-measurable disease. This circumstance arises in some Phase 3 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumour burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localised to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that disease makes 
it impossible to do so, therefore the increase must be substantial. 
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New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment 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 (a ‘positive’ FDG-PET scan lesion 
means one which is FDG avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image) at follow-up is a sign of PD 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 PD. 
 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 PD 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 PD. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the protocol 
requirements, it may also require confirmatory measurement. Specifically, in non-randomised 
trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the ‘best overall response’. 
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Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
Table 1: Time point response: patients with target (+/- non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = Not evaluable 
When patients have non-measurable disease only (therefore non-target), Table 2 is to be used. 
Table 2: Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
on-CR/non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = Not evaluable. 
1 = ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response is not 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it must 
also meet the protocol specified minimum time from baseline. If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments. 
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For example, a patient who has SD at first assessment, PD at second and does not meet 
minimum duration for SD, will have a best response of PD. The same patient lost to follow-up 
after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or PR 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 3. 
Table 3: 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 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = Not evaluable. 
1 = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum 
duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and 
in fact the patient had 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. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may 
not have a total sum of ‘zero’ on the case report form (e-CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response. 
Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an OR: 
it is a reason for stopping study therapy. The OR status of such patients is to be determined by 
evaluation of target and non-target disease as shown in Tables 1–3. 
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Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fineuneedle aspirate/biopsy) before assigning a status of CR. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
at the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
Frequency of tumour re-evaluation 
Frequency of tumour re-evaluation while on treatment should be protocol specific and adapted 
to the type and schedule of treatment. However, in the context of Phase 2 studies where the 
beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with 
the end of a cycle) is reasonable. Smaller or greater time intervals than these could be justified 
in specific regimens or circumstances. The protocol should specify which organ sites are to be 
evaluated at baseline (usually those most likely to be involved with metastatic disease for the 
tumour type under study) and how often evaluations are repeated. Normally, all target and non-
target sites are evaluated at each assessment. In selected circumstances certainnon-target organs 
may be evaluated less frequently. For example, bone scans may need to be repeated only when 
CR is identified in target disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumour evaluations depends on whether 
the trial has as a goal the response rate or the time to an event (progression/death). If ‘time to 
an event’ (e.g. time to progression, disease-free survival, progression-free survival) is the main 
endpoint of the study, then routine scheduled re-evaluation of protocol specified sites of disease 
is warranted. In randomised comparative trials in particular, the scheduled assessments should 
be performed as identified on a calendar schedule (for example: every 6–8 weeks on treatment 
or every 3–4 months after treatment) and should not be affected by delays in therapy, drug 
holidays or any other events that might lead to imbalance in a treatment arm in the timing of 
disease assessment. 
Confirmatory measurement/duration of response 
Confirmation 
In non-randomised trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e. in 
randomised trials (Phase 2 or 3) or studies where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of trial 
results. However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not 
blinded. 
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In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. 
If the proportion of patients achieving stable disease for a minimum period of time is an 
endpoint of importance in a particular trial, the protocol should specify the minimal time 
interval required between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard 
practice. However, these limitations of the precision of the measured endpoint should be taken 
into account if comparisons between trials are to be made. 
 
 
 
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Appendix 8: DATA PROTECTION / GDPR (General Data Protection Regulation of 27 
April 2016 n°2016/679) -  
INSTRUCTIONS TO INVESTIGATOR FOR HANDLING DATA RIGHTS 
REQUESTS 
In the framework of a research study/clinical trial, a participant to the study may exercise his/her 
rights, i.e. may ask I.R.I.S. (as data controller) for:  
­ Access to his/her data. 
­ Rectification of inaccurate/incomplete information. 
­ Restriction of processing of data. 
­ Objection to processing of data. 
­ Data portability (receiving his/her data in a readable format). 
In accordance with the Informed Consent Form and information notice provided to participant, 
we requested participant to contact you first for exercising their rights.  
Request for exercise of rights: 
­ Has to be a written one (either originating from an (e)-mail from a participant or from request 
expressed orally to you and put in written). 
­ Has to be sent by you by e-mail or by mail to I.R.I.S. (as data controller) to central address 
dataprivacy@servier.com or local Servier address as mentioned in ICF/information notice 
provided/available. 
 
DO 
Instructions to be followed by you 
DON’T 
What you should not do 
E-mail title: Data protection rights 
Do not forward participant e-mail (if applicable) 
Study name/number 
 
Participant number 
No information regarding participant identity:  
No participant’s name, e-mail address, participant’s 
signature 
As soon as possible without exceeding a week 
 
I.R.I.S. and INVESTIGATOR responsibilities 
GDPR requirement:  
It is mandatory for I.R.I.S. as data controller to provide an answer to 
participant/volunteer within 1 month following the request (article 12 of GDPR) 
Clinical trials requirements:  
It is prohibited for I.R.I.S. as a sponsor to know the identity of the 
participants/volunteer participating to studies  
 
 
I.R.I.S. responsibility 
Investigator responsibility 
Forward/inform I.R.I.S.  
of the request 
 
YES 
Timelines  
Answer within 1 month once 
expressed by the participant 
Request: transmitted to I.R.I.S.  as soon 
as expressed by the participant 
Answer: transmitted by you to 
participant as soon as sent by I.R.I.S.  
Answer the request 
YES 
 
 
 
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Appendix 9: Management of Infusion-related Reactions 
A. Prophylaxis for Infusion-Related Reactions 
Premedication for prophylaxis of IRRs will be mandatory prior to each dose of 
futuximab/modotuximab. All participants must be premedicated with standard therapies that 
include a glucocorticoid and an H1 antagonist. Where indicated, consideration may be given to 
include an H2 antagonist and/or acetaminophen. 
Required and optional agents, as well as recommended doses, are provided bellow  
Premedications for Infusion-Related Reactions 
Drug Class  
Recommended Dose  
When to Administer prior 
Required Agents 
Glucocorticoid  
80-100 mg IV methylprednisolone 
or equivalent* 
approximately 0.5 to 2 hours 
Antihistamine (H1 antagonist)  
25-50 mg IV diphenhydramine or 
equivalent** 
approximately 0.5 hours 
Optional Agents 
Antihistamine (H2 antagonist)  
50 mg IV ranitidine or equivalent, 
or 
20 mg IV famotidine or equivalent 
approximately 0.5 hours 
Acetaminophen 
1000 mg IV (where available, or 
PO) or equivalent 
approximately 0.5 hours 
Abbreviations (in alphabetical order): IV, intravenous; mg, milligram 
*Glucocorticoid premedication may be omitted in participants with insulin-dependent diabetes. 
**Oral H1 antagonists could be used but they should be given 1 hour prior to infusion. 
Note: Doses may be adjusted based on institutional practices. Administration of oral dexamethasone, 10 mg po, (or equivalent) 
12 hours and 6 hours prior to administration of futuximab/modotuximab is permissible in participants experiencing IRRs or if an increased 
incidence or severity of IRRs are observed.  
For IRRs while in the study, the following premedication instructions are provided: 
­ For Grade 1, Grade 2, or Grade 3 reactions, consider additional premedication or adjustment 
to premedications for subsequent infusions. 
­ For Grade 4 reactions, not applicable as no further treatment with IMP is allowed. 
B. Grading of Infusion-Related Reactions 
The NCI-CTCAE v5* definition of IRRs (General Disorders and Administration Site 
Conditions) is shown below. Symptoms occurring during or following infusion of 
investigational therapy may also be defined according to AE categories such as allergic 
reaction, anaphylaxis, or cytokine release syndrome. In the setting of symptoms occurring 
during or following infusion of investigational therapy, investigators are encouraged to use the 
AE term “Infusion-Related Reaction” and any additional terms (including those not listed here) 
that best describe the event. Those described should be graded as follows. 
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Grading of Infusion-Related Reactions 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion 
related 
reaction 
Mild transient 
reaction; 
infusion 
Interruption not 
indicated; 
intervention not 
indicated 
Therapy or 
infusion 
interruption 
indicated but 
responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤ 24 hours 
Prolonged (e.g., 
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterised by adverse reaction to the infusion of pharmacological or biological 
substances. 
Allergic 
reaction 
Systemic 
intervention not 
indicated    
Oral intervention 
indicated 
Bronchospasm; 
hospitalization 
indicated for 
clinical sequelae; 
intravenous 
intervention 
indicated 
      
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterised by an adverse local or general response from exposure to an allergen. 
Anaphylax
is 
- 
- 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
intervention 
indicated; 
allergy-related 
edema/angioede
ma; hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterised by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it 
presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to 
death. 
Cytokine 
release 
syndrome 
Fever with or 
without 
constitutional 
symptoms    
Hypotension 
responding to 
fluids; hypoxia 
responding to 
<40% O2        
Hypotension 
managed with 
one pressor; 
hypoxia requiring 
≥ 40% O2         
Life-
threatening 
consequences; 
  
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterised by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or 
hypoxia caused by the release of cytokines. 
C. Guidelines for Management of Infusion-Related Reactions 
Consistent with usual medical practice, selected parenteral medications may be utilised for 
Grade > 2 allergic/hypersensitivity reactions. The sponsor should be contacted immediately if 
questions arise concerning the grade of the reaction. The following are recommended 
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management guidelines for IRRs associated with IMP administration. In all cases the 
investigator should use best clinical judgment in managing such reaction. 
 
Management of Infusion-Related Reactions 
Grade 1 
­ Consider slowing the infusion to 50% of the prior rate 
­ Monitor the patient for worsening condition 
­ If the infusion is extended, administer subsequent infusions at the prolonged rate 
­ Consider additional premedication or adjustment to premedications for 
subsequent infusions 
Grade 2 
­ Interrupt the infusion for a minimum of 30 minutes 
­ Administer 
additional 
pharmacologic 
therapy 
(e.g., 
diphenhydramine, 
acetaminophen) and appropriate supportive care (e.g., oxygen), as medically 
indicated 
­ Resume the infusion at 50% of the prior rate once the infusion-related reaction 
has resolved or decreased to ≤ Grade 1 
­ Monitor the patient for worsening condition 
­ Administer subsequent infusions at the prolonged rate 
­ Consider additional premedication or adjustment to premedications for 
subsequent infusions 
Grade 3 
­ Stop the infusion 
­ Administer 
additional 
pharmacologic 
therapy 
(diphenhydramine, 
dexamethasone) and appropriate supportive care (e.g., oxygen), as medically 
indicated 
­ Administer epinephrine or bronchodilators as medically indicated 
­ Hospital admission for observation may be indicated 
­ Do not resume infusion after a ≥ Grade 3 reaction 
­ Participants who have a Grade 3 infusion-related reaction will be either 
discontinued from treatment, or must receive subsequent treatments at a reduced 
dose and a prolonged infusion rate (slowed to 50% of the prior rate or longer) 
­ Consider additional premedication or adjustment to premedications for 
subsequent infusions 
­ Participants who have a > Grade 3 infusion-related reaction will be discontinued 
from treatment 
In the Event of Infusion Prolongation 
Any assessments to be performed or samples to be collected (e.g., vital signs, PK) at the end of 
or following EoI will still be performed or collected beginning at the delayed EoI timepoint. 
All infusion interruptions and subsequent prolongations, including modified infusion times, as 
well as the toxicity that necessitated them, will be clearly documented on the appropriate page 
of the patient’s e-CRF. 
 
 
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Appendix 10: Management of Dermatologic Adverse Events 
A. Grading and Management of futuximab/modotuximab-Related Dermatologic AEs 
Recommendations for management of Grade 1 to Grade 3 futuximab/modotuximab-induced 
dermatologic AEs (i.e., rash, xerosis, paronychia, pruritus, photosensitivity, and fissures) are 
summarized below. If a patient experiences any Grade 4 dermatologic AE, the patient must be 
withdrawn from futuximab/modotuximab treatment. It is strongly recommended that a 
dermatologist is consulted in the event of Grade 3 or Grade 4 dermatologic AE. 
Futuximab/modotuximab - Management of Rash 
NCI-CTCAE Grade 
Action 
with 
futuximab/modotuximab 
Treatment- Rash 
1 
Papules and/or pustules covering 
< 10% body surface area 
(BSA), which may or may not be 
associated with symptoms of 
pruritus or tenderness 
Continue at the same dose 
Topical: Face and Chest Steroid 
creams of low potency; 
alclometasone 0.05% or desonide 
0.05% or fluocinolone 0.01%; 
2 × daily  
Topical: Rest-of-body moisturizers; 
2 × daily  
Systemic1: minocycline 100 mg/day 
or doxycycline 200 mg/day; for at 
least 4 weeks 
2 
Papules and/or pustules covering 
10-30% BSA, which may or may 
not be associated with symptoms 
of pruritus or tenderness; 
associated with psychosocial 
impact; limiting instrumental 
activities of daily living (ADL); 
papules and/or pustules covering 
> 30% BSA with or without mild 
symptoms 
Continue at the same dose 
 
If locally debilitating for 
the patient, consider 
following guidelines for 
dose-delay and dose 
reduction as outlined in 
the Dose Reduction for 
Grade 3 Dermatologic 
AEs table in Section B 
below 
Topical: See Grade 1 
Systemic1: 
­ minocycline 100 mg/day or 
doxycycline 200 mg/day; for at 
least 4 weeks 
­ 1 week course of oral steroid: 
methylprednisolone 4 mg tablets: 
 Day 1: 2-1-1-2 
 Day 2: 1-1-1-2 
 Day 3: 1-1-1-1 
 Day 4: 1-1-1 
 Day 5 1-0-1 
 Day 6: 1 
3 
Papules and/or pustules covering 
> 30% BSA, with moderate or 
severe symptoms; limiting 
selfcare ADL; IV antibiotics 
indicated 
 
Delay dose of 
futuximab/modotuximab, 
continue skin treatment 
and re-assess. 
Refer to the Dose 
Reduction for Grade 3 
Dermatologic AEs table 
in Section B below for 
further guidelines on dose 
reduction 
Topical: 
See Grade 1 
Systemic1: 
See Grade 2 
 
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; NCI-CTCAE, Common Terminology 
Criteria for Adverse Events v5.0 
1. Alternatives in case of intolerance: First generation cephalosporins, amoxicillin, erythromycin or limecycline. 
If infection is suspected (yellow crusts, purulent discharge, painful skin/nares): Obtain culture and change to oral antibiotic based on 
sensitivity 
 
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Futuximab/modotuximab - Management of Xerosis 
NCI-CTCAE Grade 
Action 
with 
futuximab/modotuximab 
Treatment- Xerosis 
1 
< 10% BSA and no 
associated erythema or 
pruritus 
Continue at the same dose 
Topical: Face 
moisturizing cream or ointment1; 
2 × daily 
and 
Topical: Body 
ammonium lactate 6-12% cream; 
2 × daily 
2 
10-30% BSA and associated 
with erythema or pruritus; 
limiting instrumental ADL 
Continue at the same dose 
If locally debilitating for 
the patient, consider 
following guidelines for 
dose-delay and dose 
reduction as outlined in the 
Dose Reduction for Grade 3 
Dermatologic AEs table in 
Section B below 
Topical: Face 
moisturizing cream or ointment1; 
2 × daily 
and 
Topical: Body 
ammonium lactate 12% cream or 
salicylic acid 3-6% cream or urea 10-
20% cream; 2×daily 
3 
> 30% BSA and associated 
with pruritus; 
limiting self-care ADL 
Delay dose of 
futuximab/modotuximab, 
continue skin treatment and 
re-assess. 
Refer to the Dose Reduction 
for Grade 3 Dermatologic 
AEs table in Section B 
below for further guidelines 
on dose reduction 
Topical: Face 
moisturizing cream or ointment1; 
2 × daily 
and 
Topical: Body 
ammonium lactate 12% cream or 
salicylic acid 3-6% cream or urea 10-
20% cream; 2 × daily 
and 
Topical: Eczematous areas 
topical steroid (e.g., triamcinolone 
acetonide 0.025% or desonide 0.05% or 
alclometasone 0.05% or fluticasone 
propionate 0.05%); 2 × daily  
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; NCI-CTCAE, Common Terminology 
Criteria for Adverse Events v5.0 
1. If prescription is not available, recommendation by pharmacist/dermatologist is acceptable 
 
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Futuximab/modotuximab Management of Paronychia 
NCI-CTCAE Grade 
Action 
with 
futuximab/modotuximab 
Treatment- Paronychia 
1 
Nail fold edema or erythema; 
disruption of the cuticle 
Continue at the same dose 
Topical:  
antibiotics (e.g., clindamycin 1% or 
erythromycin 1%) 
and 
vinegar soaks (i.e., soaking fingers or 
toes in a 1:1 solution of white vinegar 
in water for 15 min daily 
2 
Localized intervention 
indicated; oral intervention 
indicated (e.g., antibiotic, 
antifungal, antiviral); nail fold 
edema or erythema with pain; 
associated with discharge or 
nail plate separation; limiting 
instrumental ADL 
Continue at the same dose 
If locally debilitating for 
the patient, consider 
following guidelines for 
dose-delay and dose 
reduction as outlined in the 
Dose Reduction for 
Grade 3 Dermatologic AEs 
table in Section B below 
Same as for Grade 1 
and 
Topical:  
silver nitrate application weekly 
(consultation with dermatologist or 
surgeon is recommended) 
and 
Systemic: 
bacterial culture, oral antibiotic if 
infection confirmed 
3 
Operative intervention 
indicated; IV antibiotics 
indicated; limiting self-care 
ADL 
Delay dose of 
futuximab/modotuximab, 
continue skin treatment 
and re-assess. Refer to the 
Dose Reduction for 
Grade 3 Dermatologic AEs 
table in Section B below 
for further guidelines on 
dose reduction 
Same as for Grade 1 
and 
Topical: 
silver nitrate application weekly 
(consultation with dermatologist or 
surgeon is recommended) 
and 
consider nail avulsion (consultation 
with dermatologist or surgeon is 
recommended) 
and 
Systemic: 
bacterial culture, oral antibiotic if 
infection confirmed 
Abbreviations (in alphabetical order): ADL, activities of daily living; NCI-CTCAE, Common Terminology Criteria for Adverse Events 
v5.0; IV, intravenous 
 
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Futuximab/modotuximab Management of Pruritus 
NCI-CTCAE Grade 
Action 
with 
futuximab/modotuximab 
Treatment- Pruritus 
1 
Mild or localized; topical 
intervention indicated 
Continue at the same dose 
Topical:  
steroid (e.g., triamcinolone acetonide 
0.025%, desonide 0.05%, 
alclometasone 0.05%, Fluticasone 
propionate 0.05%); 2 × daily 
or 
anti-pruritics (e.g., pramoxine 1%, 
doxepin 5% cream); 2 × daily 
2 
Widespread and intermittent; 
skin changes from scratching 
(e.g., edema, papulation, 
excoriations, lichenification, 
oozing/crusts); oral 
intervention indicated; 
limiting instrumental ADL 
Continue at the same dose 
If locally debilitating for 
the patient, consider 
following guidelines for 
dose-delay and dose 
reduction as outlined in the 
Dose Reduction for 
Grade 3 Dermatologic AEs 
table in Section B below 
Same as for Grade 1 
and 
Systemic: 
oral antihistamines (diphenhydramine 
25-50 mg; hydroxyzine 25 mg; 
fexofenadine 60 mg; 3 × daily 
3 
Widespread and constant; 
limiting self care ADL or 
sleep; systemic corticosteroid 
or immunosuppressive therapy 
indicated 
Delay dose of 
futuximab/modotuximab, 
continue skin treatment 
and re-assess. Refer to the 
Dose Reduction for 
Grade 3 Dermatologic AEs 
table in Section B below 
for further guidelines on 
dose reduction 
Same as for Grade 2 
 
Abbreviations (in alphabetical order): ADL, activities of daily living; NCI-CTCAE, Common Terminology Criteria for Adverse Events 
v5.0 
 
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Futuximab/modotuximab Management of Photosensitivity 
NCI-CTCAE Grade 
Action 
with 
futuximab/modotuximab 
Treatment- Photosensitivity 
1 
Painless erythema and 
erythema covering <10% 
BSA 
Continue at the same dose 
Topical:  
broad spectrum sunscreen with an SPF 
of at least 15; reapplied every 2 hours 
or more frequently if swimming or 
perspiring 
and 
Systemic: 
bacterial culture, oral antibiotic if 
infection confirmed 
2 
Tender erythema covering 10-
30% BSA 
Continue at the same dose 
If locally debilitating for 
the patient, consider 
following guidelines for 
dose-delay and dose 
reduction as outlined in the 
Dose Reduction for 
Grade 3 Dermatologic AEs 
table in Section B below 
Same as for Grade 1 
and 
Topical: 
corticosteroids (e.g., triamcinolone 
acetonide 0.025% or desonide 0.05% or 
alclometasone 0.05% cream or 
fluticasone propionate 0.05%); 
2 × daily 
3 
Erythema covering > 30% 
BSA and erythema with 
blistering; photosensitivity; 
oral corticosteroid therapy 
indicated; pain control 
indicated (e.g., narcotics or 
NSAIDs) 
Delay dose of 
futuximab/modotuximab, 
continue skin treatment 
and re-assess. Refer to the 
Dose Reduction for 
Grade 3 Dermatologic AEs 
table in Section B below 
for further guidelines on 
dose reduction 
Same as for Grade 2 
 
Abbreviations (in alphabetical order): BSA, body surface area; NCI-CTCAE, Common Terminology Criteria for Adverse Events v5.0; 
NSAID, nonsteroidal anti-inflammatory drug; SPF, sun protection factor 
 
Futuximab/modotuximab Management of Fissures 
NCI-CTCAE Grade 
Action 
with 
futuximab/modotuximab 
Treatment- Fissures 
1 
Initiated at first occurrence 
No action 
Topical: 
­ thick moisturizers of zinc oxide (13-
40%) cream 
­ liquid glues of cyanoacrylate to seal 
cracks 
2 
If no improvement after 
2 weeks from initiation of 
Step 1 
No action 
Topical: 
­ thick moisturizers of zinc oxide (13-
40%) cream under occlusion at night 
­ salicylic 
acid 
6% 
cream 
or 
ammonium lactate/lactic acid 12% 
3 
If no improvement after 
2 weeks from initiation of 
Step 2 
Delay dose of 
futuximab/modotuximab, 
and 
re-assess. Discuss need for 
dose reduction and/or 
further dose omissions 
with sponsor or designee 
Continue local treatment as described 
in Step 2 
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Prophylaxis for fissures includes careful use of moisturizing creams and/or ointments 3 times a 
day and after handwashing, using only fragrance-free soaps. Should fissures begin to form, a 
stepwise approach outlined above should be followed. Topical application of cyanoacrylate 
tissue adhesive (i.e., surgical glue) products may be considered to promote wound repair. 
If fissures occur which are unresponsive to intensive therapeutic treatment as specified above, 
futuximab/modotuximab dosing should be delayed. The need for dose-reduction and/or 
continued dose-delays should be discussed with the sponsor or designee, if adequate 
improvement is not seen after the initial dose-delay. 
B. Dose Reduction Guidelines for futuximab/modotuximab-Related Dermatologic AEs 
Dose delay and/or intrapatient dose reduction(s) will be required upon occurrence of Grade 3 
anti-EGFR associated dermatologic AE, and should be implemented according to Table Dose 
Reduction for Grade 3 Dermatologic AEs 
Futuximab/modotuximab Dose Reduction for Grade 3 Dermatologic AEs 
Dermatologic 
AE Grade 3 
Futuximab/modotuximab 
Immediate 
Action 
Outcome 
Improvement 
Futuximab/modotuximab 
First occurrence 
Delay dose 
Grade ≤ 1 
Continue at same dose 
Grade 2  
Reduce to 4.5 mg/kg 
No improvement 
Discontinue 
Second occurrence 
Delay dose 
Grade ≤ 1 
Continue at same dose 
Grade 2  
At dose of 6.0 mg/kg: Reduce to 4.5 mg/kg 
At dose of 4.5 mg/kg: Reduce to 3.0 mg/kg 
No improvement 
Discontinue 
Third occurrence 
Delay dose 
Grade ≤ 1 
Continue at same dose 
Grade 2  
At dose of 6.0 mg/kg: Reduce to 4.5 mg/kg 
At dose of 4.5 mg/kg: Reduce to 3.0 mg/kg 
At dose of 3.0 mg/kg: discontinue  
No improvement 
Discontinue 
Fourth occurrence 
Discontinue 
Any 
Discontinue 
Abbreviations (in alphabetical order): AE, adverse event; kg, kilogram; mg, milligram 
Note: Dose reductions for 9 mg/kg loading not applicable. For dose delays, re-assess after < 2 weeks. Longer delays are allowed 
if no recovery to < Grade 2 after 2 weeks 
In each case, the next treatment should be delayed, and the patient’s condition should be 
reassessed after 1 week, and if necessary, 2 weeks. Treatment should be delayed further if the 
AE remains at Grade 3 after 2 weeks. 
In the case of a Grade 2 dermatologic AE which is locally debilitating for the patient, the 
guidelines outlined above may be followed at the investigator’s discretion. 
Participants must be withdrawn from futuximab/modotuximab treatment in the event of 
a Grade 4 dermatologic AE. 
 
 
 
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Appendix 11: Management of Hypomagnesemia 
A. NCI-CTCAE Grading of Hypomagnesemia and QTc Prolongation 
Grading of Hypomagnesemia and QTc Prolongation 
Event 
1 
2 
3 
4 
5 
Hypomagnesemia 
< LLN-1.2 mg/dL 
< LLN-0.5 mmol/L 
< 1.2-0.9 mg/dL 
< 0.5-0.4 mmol/L 
< 0.9-0.7 mg/dL 
< 0.4-0.3 mmol/L 
< 0.7 mg/dL 
< 0.3 mmol/L 
life-threatening 
consequences 
Death 
ECG QTc Interval 
prolonged 
Average QTc 450-
480 ms 
Average QTc 
481-500 ms 
Average QTc >= 
501 ms; >60 ms 
change from 
baseline 
Torsade de 
pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms 
of serious 
arrhythmia 
- 
Abbreviations (in alphabetical order): NCI-CTCAE, Common Terminology Criteria for Adverse Events v5.0; dL, deciliter; ECG, 
electrocardiogram; L, liter; LLN, lower limit of normal; mg, milligram; mmol, millimole; ms, millisecond; QTc, corrected QT interval 
 
B. Management of Hypomagnesemia 
Participants receiving futuximab/modotuximab will be monitored weekly for 
hypomagnesemia, which should be managed as follows 
 
Management of Hypomagnesemia and QTc Prolongation 
Grade 
Action 
Grade 1 
No replacement therapy required, but may be administered at treating physician’s 
discretion, weekly monitoring to continue 
Grade 2 or higher 
Use of concomitant QTc-prolonging drugs* should be discontinued unless urgently 
needed for medical care and no alternative therapy is available 
Grade 3-4 
Administer MgSO4 (6g to 10g IV) at minimum 2 times per week until ≤ Grade 1 
Perform predosing ECG (required) to monitor for QTc prolongation** 
In the event of Grade 3 QTc prolongation potentially due to hypomagnesemia, 
futuximab/modotuximab administration should be delayed while magnesium 
repletion is undertaken 
futuximab/modotuximab may be restarted with continued intensive magnesium 
therapy at the same dose or at a reduced dose once hypomagnesemia returns to ≤ 
Grade 1 severity, and once the QTc returns to WNL or baseline status 
In the event of TdP or other life-threatening arrhythmias discontinue 
futuximab/modotuximab 
Grade 4 
For Grade 4 hypomagnesemia that is refractory to IV magnesium-replacement 
therapy, dosing with futuximab/modotuximab should be delayed or reduced. 
Abbreviations (in alphabetical order): g, gram; IV, intravenous; MgSO4, magnesium sulfate; QTc, corrected QT interval; TdP, Torsade 
de pointes; WNL, within normal limits 
* Listings of QTc prolonging drugs may be found at: <https://crediblemeds.org/index.php?cID=222> 
** ECG is required before futuximab/modotuximab administration to monitor QT prolongation that may result in severe arrhythmias 
such as TdP. 
 
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Appendix 12: Maximum Total Blood Collection Volumes 
  
Treatment period 
Volume/ 
sample 
Screening 
/Inclusion  
Cycle 1 
Cycle 2 
Cycle 3 
Further from 
Cycle 4 
Withdrawal 
Visit 
Total (ml) 
# Volume mL  # 
Volume mL  # 
Volume mL 
# 
Volume mL  # 
Volume mL  # 
Volume mL 
Volume mL  
Genomic analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for ctDNA 
20 
1 
20 
 
0 
 
0 
 
0 
 
0 
 
0 
20 
Biomarker  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood exploratory 
biomarkers* 
20 
0 
0 
1 
20 
1 
20 
1 
20 
0 
0 
1 
20 
80 
Safety assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology  
5 
1 
5 
2 
10 
2 
10 
2 
10 
2 
10 
1 
5 
50 
Biochemistry  
10 
1 
10 
2 
20 
2 
20 
2 
20 
2 
20 
1 
10 
100 
Additional 
Biochemistry 
for Mg, Ca, K 
5 
0 
0 
2 
10 
2 
10 
2 
10 
2 
10 
0 
0 
40 
Coagulation  
5 
1 
5 
1 
5 
1 
5 
1 
5 
1 
5 
1 
5 
30 
β hCG test 
5 
1 
5 
1 
5 
1 
5 
1 
5 
1 
5 
1 
5 
30 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK evaluation for 
futuximab/modotuximab 
2.5 
0 
0 
12 
30 
12 
30 
1 
2.5 
1 
2.5 
1 
2.5 
67.5 
PK evaluation for T/T 
4 
0 
0 
6 
24 
6 
24 
0 
0 
0 
0 
1 
4 
52 
ADA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (2.5 mL) for 
futuximab/modotuximab** 
2.5 
0 
0 
2 
5 
2 
5 
1 
2.5 
1 
2.5 
1 
2.5 
17.5 
TOTAL volume (mL)  
 
 
45 
 
129 
 
129 
 
75 
 
55 
 
54 
487 
Abbreviations (in alphabetical order): #, number of samples; ADA, anti-drug antibody; Ca, calcium; K, potassium; Mg, magnesium; mL, millilitre; PK, pharmacokinetic; T/T, trifluridine/tipiracil  
* C1D1, C2D1, C3D1 then every 2 cycles 
** The frequency of ADA assessments will be reduced to every 2 months after the first 6 months in the first year and every 4 months after the first year. 
If sites can perform haematology, serum chemistry, and coagulation studies with smaller volumes of blood per sample, they are encouraged to do so. Required PK, ADA, and PD/biomarker volumes are fixed and 
should not be reduced. 
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16.1.9. Documentation of statistical methods 
Hardware and software tools 
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Statistical analyses were performed using SAS®/PC Software version 9.2.  
 
Coding was performed using Medical Dictionary for Regulatory Activities for the medical 
events and World Health Drug Dictionary for the treatments. 
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Follow up of versions 
Version 
Release date 
(dd/mm/yyyy) Key modifications(*) 
Impact 
V1.0 
04/02/2022 
Not applicable. 
V2.0 
15/03/2023 
As the Randomized part has been 
cancelled due to study 
discontinuation during the Safety 
Lead-In part, all the methods and 
analyses related to Randomized part 
have been removed.  
-
In addition:Section 3.2.4:
deletion of some descriptive
tables of baseline
characteristics
-
Section 3.3: deletion by
class analyses
-
Section 3.4: deletion of
efficacy analyses, except the
BOR analysis
-
Section 3.5.1: addition of
related TEAE leading to
death description
-
Section 3.5.2: deletion of
descriptive tables for deaths
-
Section 3.5.3: descriptive
tables by visit restricted to
cycle 1 and addition of shift
tables for baseline vs last
values under treatment
-
Section 3.5.4: descriptive
tables by visit restricted to
last value
-
Section 3.5.5: descriptive
tables by visit restricted to
last value
-
Section 5.1: update of the
first and last IMP intakes
definitions
-
Section 7.3 update Table -
Gradable and non-gradable
laboratory parameters
(*) Main changes as compared to the statistical analyses planned in the protocol for the first 
SAP signed version (1.0). Main changes from the previous signed version for the other SAP 
signed version(s). 
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Table of contents 
Table of contents ........................................................................................................................ 4
List of tables ............................................................................................................................... 6
List of figures ............................................................................................................................. 7
List of abbreviations ................................................................................................................... 8
1. INTRODUCTION ............................................................................................................. 11
1.1.
Study objectives .............................................................................................................. 11
1.2.
Study design .................................................................................................................... 11
1.2.1. Study plan ..................................................................................................................... 11
1.2.2. Randomisation .............................................................................................................. 15
1.3.
Determination of sample size ......................................................................................... 15
2. ANALYSIS SETS AND SUBGROUPS / TREATMENT GROUPS ............................ 16
2.1.
Analysis sets ................................................................................................................... 16
2.2.
Treatment groups ............................................................................................................ 16
2.3.
Subgroups ....................................................................................................................... 16
3. STATISTICAL METHODS ............................................................................................. 16
3.1.
General considerations .................................................................................................... 16
3.2.
Disposition and baseline characteristics ......................................................................... 16
3.2.1. Disposition of patients .................................................................................................. 17
3.2.2. Protocol deviations ....................................................................................................... 17
3.2.3. Study population ........................................................................................................... 17
3.2.4. Demographic data and other baseline characteristics ................................................... 17
3.2.4.1.
Demographic characteristics .................................................................................... 17
3.2.4.2.
History of cancer   .................................................................................................... 17
3.2.4.3.
Signs and symptoms related to colorectal cancer   .................................................. 18
3.2.4.4.
Medical and surgical history not related to colorectal cancer   ............................... 18
3.2.4.5.
Previous therapies related to colorectal cancer   ...................................................... 18
3.2.4.6.
Vital signs and clinical examination at baseline ...................................................... 18
3.2.4.7.
ECG at baseline ....................................................................................................... 19
3.2.4.8.
Clinical laboratory at baseline ................................................................................. 19
3.3. Treatments ...................................................................................................................... 19
3.3.1. Extent of exposure and treatment compliance .............................................................. 19
3.3.1.1.
Trifluridine/tipiracil   ............................................................................................... 19
3.3.1.2.
Futuximab/modotuximab    ...................................................................................... 20
3.3.2. Concomitant treatments and new anti-cancer therapies   ............................................. 20
3.4. Efficacy analysis ............................................................................................................. 20
3.5. Safety analysis ................................................................................................................ 21
3.5.1. Adverse events.............................................................................................................. 21
3.5.2. Death  ........................................................................................................................... 21
3.5.3. Clinical laboratory evaluation ...................................................................................... 22
3.5.4. Vital signs, clinical examination and other observations related to safety ................... 22
3.5.5. ECG   ............................................................................................................................ 22
3.6. QoL ................................................................................................................................. 22
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4. INTERIM ANALYSIS ...................................................................................................... 23
5. APPENDIX A: DATA HANDLING AND PROGRAMMING
SPECIFICATIONS ........................................................................................................... 23
5.1. General analytic definitions ............................................................................................ 23
5.1.1. Expressions ................................................................................................................... 23
5.1.2. Value prior to treatment / under treatment ................................................................... 24
5.1.3. General duration derivation and conversion ................................................................. 24
5.1.4. Analysable value .......................................................................................................... 25
5.1.5. First and last IMP intake dates ..................................................................................... 25
5.1.6. Other dates .................................................................................................................... 26
5.2. Specific analytic definitions and data handling conventions .......................................... 26
5.2.1. Study patients: Disposition, baseline characteristics and follow-up ............................ 26
5.2.1.1. 
Disposition of patients ............................................................................................. 26
5.2.1.2. 
Protocol deviations .................................................................................................. 26
5.2.1.3. 
Demographic data and other baseline characteristics .............................................. 27
5.2.1.3.1. Demographic data .................................................................................................. 27
5.2.1.3.2. History of Colorectal cancer  ................................................................................. 27
5.2.1.3.3. Previous therapies for colorectal cancer   .............................................................. 29
5.2.1.3.4. Initial tumour assessment ...................................................................................... 29
5.2.1.4. 
Extent of exposure and treatment compliance ......................................................... 30
5.2.1.5. 
Concomitant treatments ........................................................................................... 33
6. APPENDIX B: EFFICACY .............................................................................................. 36
6.1. Non-confirmed Best overall response ............................................................................. 36
7. APPENDIX C: SAFETY .................................................................................................. 37
7.1. Adverse events ................................................................................................................ 37
7.2. Death ............................................................................................................................... 39
7.3. Clinical laboratory evaluation ......................................................................................... 39
7.4. Vital signs and clinical examination ............................................................................... 43
7.5. Electrocardiogram ........................................................................................................... 44
8. APPENDIX D: QUALITY OF LIFE ............................................................................... 45
9. APPENDIX E: SOFTWARE AND PROGRAMMING CODES .................................. 46
10.
APPENDIX F: EARLY FUTILITY (INTERIM 0) ................................................... 48
11.
REFERENCES .............................................................................................................. 61
CL3-95026-001 -   Statistical Analysis Plan | VV-TMF-130355 | 1.0
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List of tables 
Table (5.1.2) 1 - Time frame .................................................................................................... 24
Table (5.1.2) 2 - Time frame of cycle n ................................................................................... 24
Table (5.1.4) 1 - Definition of analysable value ...................................................................... 25
Table (5.1.5) 1 - Substitution rules of tIMP intake dates ......................................................... 25
Table (5.1.6) 1 - Substitution rules of death date ..................................................................... 26
Table (5.1.6) 2 - Substitution rules of dates if no specific management is defined ................. 26
Table (5.2.1.3.2) 1 - Substitution rules of History of colorectal cancer ................................... 28
Table (5.2.1.5) 1 - Substitution rules of concomitant treatments intake dates ......................... 34
Table (5.2.1.5) 2 - Substitution rules of further anti-tumour therapy intake dates ................... 35
Table (6.1) 1 - BOR when confirmation of CR and PR not required ...................................... 36
Table (7.1) 1 - Treatment-emergence of adverse events in case of missing severity/grade 
(if any) ...................................................................................................................................... 38
Table (7.1) 2 - Substitution rules of AE dates .......................................................................... 39
Table (7.1) 3 - Substitution rules of recovery date ................................................................... 39
Table (7.3) 1 - Gradable and non-gradable laboratory parameters .......................................... 40
Table (7.3) 2 - Definition of CTCAE grade - Version 5.0 - Gradable parameters 
according to baseline value ...................................................................................................... 41
Table (7.4) 1 - Patient Performance Status .............................................................................. 44
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List of figures 
Figure (1.2.1) 1 - CL3-95026-001 Study Design ..................................................................... 12
Figure (1.2.1) 2 - Study plan for the Safety Lead-In Part ........................................................ 13
Figure (1.2.1) 3 - Study plan for the randomised Part .............................................................. 14
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List of abbreviations 
ADA 
: Anti-drug Antibody 
AE 
: Adverse Event 
ALT 
: ALanine (Amino)Transferase 
ALP 
: ALkaline Phosphatase 
ANCOVA 
: Analysis of Covariance  
AST 
: ASpartate (Amino)Transferase 
AUC 
: Area Under the Plasma Concentration-Time Curve  
BID 
: Twice Daily 
BOR 
: Best Overall Response 
BPM 
: Beats per Minute 
BSA 
: Body Surface Area 
CI 
: Confidence Interval 
CLcr 
: Creatinine clearance 
cm 
: Centimetre 
CMH 
: Cochran-Mantel-Haenszel 
CR 
: Complete Response 
CRF 
: Case Report Form 
CTCAE 
: Common Terminology Criteria for Adverse Events 
ctDNA 
: Circulating tumour DNA 
DAP 
: Data Analysis Plan 
DBP 
: Diastolic Blood Pressure 
DCR 
: Disease Control Rate 
DI 
: Dose Intensity 
DLT 
: Dose-Limiting Toxicity 
DMC 
: Data Monitoring Committee 
DN 
: Double-Negative 
DoR 
: Duration of Response 
ECD 
: Extracellular Domain  
ECG 
: ElectroCardioGram 
ECOG PS 
: Eastern Cooperative Oncology Group Performance Status 
e-CRF
: Electronic Case Report Form 
EGFR
: Epidermal Growth Factor Receptor 
EORTC
: European Organisation for Research and Treatment of Cancer 
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FAS 
: Full Analysis Set 
GCP 
: Good Clinical Practice 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
GHS 
: Global Health Status 
HR 
: Heart Rate 
HR 
: Hazard Ratio 
ICF 
: Informed Consent Form 
ICH 
: International Conference on Harmonization 
IE 
: Intercurrent Event  
IMP 
: Investigational Medicinal Product 
INR 
: International Normalized Ratio 
I.R.I.S.
: Institut de Recherches Internationales Servier 
ITT
: Intention-To-Treat  
IU
: International Unit 
IV
: IntraVenous (route) 
IWRS
: Interactive Web Response System 
KRAS
: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LDH
: Lactate DeHydrogenase 
LLN
: Lower Limit of Normal laboratory reference range 
MedDRA
: Medical Dictionary for Regulatory Activities 
MMRM
: Mixed-effects Model Repeated Measures 
NCI
: National Cancer Institute 
NCI-CTCAE 
: National Cancer Institute - Common Terminology Criteria For Adverse 
Events  
NLR 
: Neutrophils lymphocytes ratio 
OR 
: Objective Response  
ORR 
: Overall Response Rate 
OS 
: Overall Survival 
PD 
: Progressive Disease 
PD 
: Pharmacodynamics  
PFS 
: Progression Free Survival 
PK 
: Pharmacokinetics  
PR 
: Partial Response 
PRO 
: Patient Reported Outcome 
PS 
: Performance Status 
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PT 
: Preferred Term 
PV 
: PharmacoVigilance 
QLQ 
: Quality of Life Questionary 
QoL 
: Quality of Life 
QTc 
: QT interval corrected for heart rate 
QTcB 
: Bazett’s corrected QT interval 
QTcF 
: Fridericia’s corrected QT interval  
RDI 
: Relative Dose Intensity 
RECIST 
: Response Evaluation Criteria In Solid Tumours  
RMST 
: Restricted mean survival time 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SBP 
: Systolic Blood Pressure 
SD 
: Standard Deviation 
SD 
: Stable Disease 
SOC 
: System Organ Class 
SS 
: Safety Set 
TEAE 
: Treatment Emergent Adverse Event 
STEAE 
: Serious Treatment Emergent Adverse Event 
TLG 
: Tables, Listings and Graphs 
TN 
: Triple Negative 
TR 
: Tumour Response  
TtPS2 
: Time to ECOG Performance Status ≥ 2 
TTNT 
: Time to Next Treatment  
TTR 
: Time to Response  
TUDD 
: Time until definitive deterioration 
ULN 
: Upper Limit of Normal laboratory reference range 
VAS 
: Visual Analogue Scale 
VEGF 
: Vascular Endothelial Growth Factor  
WBC 
: White Blood Cells 
WHO 
: World Health Organization 
WT 
: Wild Type 
WV 
: Withdrawal Visit 
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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) details the planned analyses to be performed for the Safety 
Lead-In part, in accordance with the main characteristics of the amended clinical study protocol 
of 16th August 2022. 
The randomised part has been cancelled due to study discontinuation during the Safety Lead-
in part for strategic reasons. All information concerning the randomised part is described in the 
protocol. 
The templates for Tables, Listings and Graphs (TLG) are described in a separate document. 
1.1. Study objectives  
Safety Lead-In part  
Primary 
- To assess safety and tolerability of futuximab/modotuximab in combination with 
trifluridine/tipiracil according to National Cancer Institute Comment Terminology Criteria 
for Adverse Events (NCI-CTCAE) v5.0. 
Secondary 
- To assess anti-tumour activity of futuximab/modotuximab in combination with 
trifluridine/tipiracil per investigator assessment using Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.1 in terms of: 
Objective Response Rate (ORR).
Best Overall Response (BOR).
Disease Control Rate (DCR).
Progression Free Survival (PFS).
- To assess anti-tumour activity of futuximab/modotuximab in combination with 
trifluridine/tipiracil in terms of: 
Overall Survival (OS).
- To characterise the pharmacokinetic (PK) profile of futuximab/modotuximab, trifluridine 
and tipiracil in the combination of futuximab/modotuximab with trifluridine/tipiracil. 
To evaluate the immunogenicity of futuximab/modotuximab (i.e. occurrence of anti-drug 
antibody [ADA]).  
Exploratory  
- To explore biomarkers as potential predictors of response and to track the emergence of 
resistance. 
Thereafter, only the primary analysis and the BOR of the secondary analysis will be assessed. 
1.2. Study design   
1.2.1. 
Study plan  
This is a randomised, open label, multi-centre, two-arm Phase 3 study to evaluate 
futuximab/modotuximab in combination with trifluridine/tipiracil versus trifluridine/tipiracil 
monotherapy in participants ≥ 18 years of age with KRAS/NRAS and BRAF WT mCRC who 
were previously treated by chemotherapy (including oxaliplatin, irinotecan and 5-fluorouracil, 
anti-VEGF agents) and with anti-EGFR mAb therapy for ≥ 16 weeks. 
CL3-95026-001 -   Statistical Analysis Plan | VV-TMF-130355 | 1.0
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Initially, the study comprises two parts a Safety Lead-In part in approximately 25 participants. 
The initial study design is depicted in Figure (1.2.1) 1, Figure (1.2.1) 2 and Figure (1.2.1) 3. 
Figure (1.2.1) 1 - CL3-95026-001 Study Design 
CL3-95026-001 -   Statistical Analysis Plan | VV-TMF-130355 | 1.0
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Figure (1.2.1) 2 - Study plan for the Safety Lead-In Part 
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Figure (1.2.1) 3 - Study plan for the randomised Part 
The study start is defined as the date of the first visit of the first participant. 
The study will be divided into the following periods for each participant: 
- Screening visit/Screening period (maximum 28 days): 
Screening visit: after signature of the Informed Consent Form(s) (ICF) to check screening
criteria and decide if participant can be screened for the study.
Screening period: if the participant is screened in the study, check the inclusion and
exclusion criteria and decide if participant can be included in the study.
- Treatment period: participants will be treated until they meet a discontinuation criterion as 
described in Section 5.8.1 of the protocol. The participants should receive the first dose of 
first IMP (Day 1 of Cycle 1) within 3 days after inclusion.  
- Withdrawal visit (WV): should be conducted within approximately 4 weeks following the 
date of study treatment withdrawal and before the start of a new anticancer therapy. 
CL3-95026-001 -   Statistical Analysis Plan | VV-TMF-130355 | 1.0
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- Follow-up period: after the WV the participant will be followed every 8 weeks (± 10 calendar 
days): 
For survival status until the end of the study. This follow-up can be done remotely by
using various telecommunication technologies including but not limited to phone, internet
and shared electronic medical records.
For tumour assessment (if the patient was withdrawn from the study for another reason
than radiologic disease progression) (compared to the last assessment) until radiologic
progression regardless of initiation of new anticancer therapy.
End of Trial is defined as the date of the last follow-up of the last participant (including a contact 
phone), or the date of last contact attempt if the last participant is declared lost to follow-up, or 
when the target number of OS events is reached, whichever occurs first. 
Any participants still receiving IMPs at the end of the study will be allowed to continue at the 
discretion of the investigator and as long as none of the treatment discontinuation criteria are 
met. 
If some participants are still receiving study treatments when the end of study is met, please see 
Section 6.5 of the protocol for procedures to be followed. 
Due to the exceptional circumstances in relation to the coronavirus disease pandemic, the 
sponsor, in accordance with competent regulatory authority’s guidelines, could decide to 
implement precautionary measures during the study to ensure participants safety, while 
maintaining compliance with GCP and study data integrity. These precautionary measures will 
remain in effect only for the duration of national public health emergency. 
1.2.2. 
Randomisation   
Not applicable due to the cancellation of the randomised part. 
1.3. Determination of sample size  
Approximately 25 participants will be evaluated in Safety Lead-In part. The DMC will initially 
determine tolerability after 6 evaluable participants have been treated. If ≤ 2 participants out of 
the first 6 evaluable participants experience a DLT, and the DMC based on the totality of safety 
data determines the doses to be tolerable, then the Safety Lead-In will be expanded by an 
additional cohort of 6 participants. The DMC will again assess the tolerability when 12 
participants have been enrolled and the 12th participant has completed the first treatment cycle. 
If ≤ 3 participants experience a DLT, and the DMC based on the totality of safety data 
determines the doses to be tolerable, the Safety Lead-In will be expanded to add another 13 
participants, for a total of 25 participants. The DMC will meet again at the end of the Safety 
Lead-In part when approximately 25 participants have been treated. 
CL3-95026-001 -   Statistical Analysis Plan | VV-TMF-130355 | 1.0
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2.
ANALYSIS SETS AND SUBGROUPS / TREATMENT GROUPS
2.1. Analysis sets   
Screened set: All patients screened. 
Safety Set (SS): All participants having taken at least one dose of IMPs.. SS will be used in all 
analyses. 
DLT Evaluable Set (DLTES): all participants in the SS who are evaluable for DLT. DLTES 
will be used in safety analyses, when specified. 
2.2. Treatment groups  
Treatment considered for the analysis will be the following: 
- Futuximab/modotuximab + trifluridine/tipiracil 
2.3. Subgroups  
Not applicable. 
3.
STATISTICAL METHODS
3.1. General considerations  
The following descriptive statistics will be provided depending on the nature of considered 
data: 
Qualitative data: number of observed values, number and percentage of patients per class. 
Quantitative data: number of observed values, mean and standard deviation, median, first and 
third quartiles, minimum and maximum. 
Descriptive summary statistics (n, mean (SD), median, min and max) will be provided for 
variables measured on a continuous scale. 
The frequency distribution (n, %) will be provided for variables measured on a nominal scale. 
3.2. Disposition and baseline characteristics   
The participants’ disposition and baseline characteristics will be described in SS. 
The number of participants in each study population and the reasons for exclusion will be 
summarized as well as the disposition of participants, including reasons for discontinuation and 
protocol deviations at baseline and during study. 
Characteristics of participants including demography, characteristics of the disease at diagnosis 
and study entry, medical history, prior therapy and concomitant medication at baseline will be 
summarized. 
CL3-95026-001 -   Statistical Analysis Plan | VV-TMF-130355 | 1.0
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3.2.1. 
Disposition of patients  
Disposition of patients will be described in the Screened Set before and at inclusion and in the 
SS after the inclusion. 
3.2.2. 
Protocol deviations  
All important protocol deviations before or at inclusion, as well as after inclusion, will be 
described in the SS, by category of deviations based on ICH E3 guideline and ICH E3 Q&A. 
3.2.3. 
Study population  
The number of patients in each study population and the reasons for exclusion will be 
summarized. 
3.2.4. 
Demographic data and other baseline characteristics  
3.2.4.1. 
Demographic characteristics  
The following demographic and baseline variables will be summarized for patients in the SS: 
- Age (years). 
-  
- Gender (Female, Male). 
- Race (White, American Indian or Alaska native, Asian, Black or African American, Native 
Hawaiian/Other Pacific Islander, Other). 
- Ethnicity (Hispanic or Latino, Not Hispanic or Latino). 
-  
- Country. 
- Pregnancy test. 
3.2.4.2. 
History of cancer  
Nature and duration of cancer will be summarized in the SS according to the following 
variables: 
- Primary diagnosis (Adenocarcinoma of colorectal cancer, Other). 
- Primary tumour site (Cecum, Appendix, Ascending colon, Hepatic flexure, Splenic flexure, 
Descending colon, Sigmoid colon, Rectosigmoid segment, Right colon, Left colon, Rectum, 
Transverse colon, Multilocalised right colon, Multilocalised left colon, Other). 
- Primary tumour localisation (Right, Left) (5 Appendix A). 
- Current tumour status: metastasis (Yes, No). 
- Site of metastasis (regional lymph node, distant lymph node, lung, liver, bone, brain, skin, 
peritoneal, soft tissue, other). 
- Number of metastatic sites. 
- Disease duration (years). 
- Time from first metastasis diagnosis to inclusion (months). 
- Progression free interval (months). 
- Treatment free interval (months). 
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A listing of the history of colorectal cancer will also be provided. It will include the following 
information: Disease duration (years), time from first metastasis diagnosis to inclusion 
(months), primary diagnosis, primary tumour site, metastatic sites, progression free interval 
(months) and treatment free interval (months). 
3.2.4.3. 
Signs and symptoms related to colorectal cancer  
Not applicable. 
3.2.4.4. 
Medical and surgical history not related to colorectal cancer  
Not applicable. 
3.2.4.5. 
Previous therapies related to colorectal cancer  
 All previous therapies for the colorectal cancer will be summarized according to the following 
variables for patients in the SS:  
- Previous neo-adjuvant drug treatment (Yes, No). 
- Previous adjuvant drug treatment (Yes, No). 
- Previous adjuvant and neo-adjuvant drug treatment (Yes, No). 
- Previous adjuvant or neo-adjuvant drug treatment (Yes, No). 
- Previous metastatic drug treatment (Yes, No). 
- Previous adjuvant or neo-adjuvant fluoropyrimidine (Yes, No). 
- Previous metastatic fluoropyrimidine (Yes, No). 
- Previous metastatic irinotecan (Yes, No). 
- Previous adjuvant or neo-adjuvant oxaliplatin (Yes, No). 
- Previous metastatic oxaliplatin (Yes, No). 
- Previous metastatic anti-VEGF monoclonal Anti Body (Yes, No). 
- Previous neo-adjuvant anti-EGFR monoclonal Anti Body (Yes, No) in RAS wild type 
patients only as documented in the e-CRF. 
- Previous metastatic anti-EGFR monoclonal Anti Body (Yes, No). 
- Response to previous metastatic regimen containing anti-EGFR monoclonal Anti Body (CR, 
PR, SD). 
- Skin toxicity with previous metastatic regimen containing anti-EGFR monoclonal Anti Body 
(Yes, No). 
- Skin toxicity with previous metastatic regimen containing anti-EGFR monoclonal Anti Body 
(Grade 1-2, Grade 3-4, No skin toxicity). 
- Duration of previous metastatic regimen containing anti-EGFR monoclonal Anti Body. 
- Number of prior regimens for mCRC. 
- Number of prior adjuvant or neoadjuvant regimens. 
- Reason for treatment discontinuation of the last regimen prior to randomisation (Toxicity, 
Progressive disease, Other). 
- Last regimen prior to randomisation containing anti-EGFR monoclonal Anti Body (Yes, 
No). 
3.2.4.6. 
Vital signs and clinical examination at baseline  
Refers to section 3.5.4.. 
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3.2.4.7. 
ECG at baseline  
Refers to section 3.5.5. 
3.2.4.8. 
Clinical laboratory at baseline  
All laboratory data will be analysed using NCI-CTCAE grade criteria. 
Clinical laboratory parameters will be summarized in the SS according to the following classes: 
- For highest and/or lowest gradable parameters at baseline: (Grade 0, Grade 1, Grade 2, 
Grade 3, Grade 4). 
- For non-gradable parameters and gradable parameters without baseline, except for creatinine 
clearance: (< LLN, [LLN, ULN], > ULN). 
- For urinalysis parameters, except for specific gravity and pH: (Absence, Trace, Presence (+, 
More than one +)). 
Creatinine clearance will be categorised in 4 levels of impairment and analysed by classes 
(severe, moderate, mild, normal): 
- Normal renal function (CLcr ≥ 90 mL/min). 
- Mild renal impairment (CLcr 60-89 mL/min). 
- Moderate renal impairment (CLcr 30-59 mL/min). 
- Severe (CLcr < 30 mL/min). 
3.3. Treatments   
3.3.1. 
Extent of exposure and treatment compliance  
3.3.1.1. 
Trifluridine/tipiracil  
Extent of exposure and treatment compliance of trifluridine/tipiracil will be described in the SS 
by patient overall including: 
- Treatment duration (months). 
- Follow-up duration (months) with median based on reverse Kaplan Meier method. 
- Number of cycles per patient. 
- Cumulative dose (mg/m2). 
- Dose intensity (DI) (mg/m2/week). 
- Relative Dose Intensity (RDI) (%). 
- Patients with at least one dose reduction (Yes, No). 
- Number of dose reductions per patient. 
- Number of patients by actual dose level on day 1 of each cycle. 
- Patients with at least one dispensation postponed (Yes, No). 
- Number of dispensations postponed per patient. 
- Patients with at least one unplanned treatment interruption (Yes, No). 
- Number of unplanned treatment interruptions per patient. 
Individual listings by cycle will be provided including: cumulative dose, planned dose intensity, 
DI, RDI, total number of tablets given, estimated and returned (15 or 20 mg for 
trifluridine/tipiracil), cycle duration (weeks), duration of unplanned treatment interruption 
(days), reason for interruption, dispensation postponed (Yes, No), reason for dispensation 
postponed (medical reason, non-medical reason) and dose reduction (Yes, No). 
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Individual listing per patient will be provided including: number of cycles, cumulative dose, 
planned dose intensity, DI, RDI, treatment duration, unplanned treatment interruption (days), 
number of dispensations postponed and number of dose reductions. 
3.3.1.2. 
Futuximab/modotuximab 
Number of infusions per patient, patients with full dose administered, patients with at least one 
missed infusion, number of cycles with at least one missed infusion, patients with infusion 
interrupted, patients with infusion rate decreased, cumulative dose (mg/kg), DI (mg/kg/week) 
and RDI (%)will be described by patient in the SS.  
Individual listing by cycle will be provided including: number of infusions, reason for missed 
infusion (medical reason, non-medical reason), cumulative dose, planned dose intensity, DI, 
RDI, cycle duration (weeks), full dose administered (Yes, No), reason for incomplete volume 
infusion (medical reason, non-medical reason), infusion postponed (Yes, No), reason for 
postponed infusion (medical reason, non-medical reason), reason for infusion interrupted 
(medical reason, non-medical reason) and infusion rate decreased (Yes, No). 
Individual listing per patient will be provided including: number of cycles, number of infusions, 
cumulative dose, planned dose intensity, DI, RDI, treatment duration (months), number of 
cycles with at least one partial dose administered, number of cycles with infusion postponed, 
number of cycles with infusion interrupted and number of cycles with infusion rate decreased. 
3.3.2. 
Concomitant treatments and new anti-cancer therapies  
Drug treatments will be described by pharmacological class, pharmacological sub-class, 
therapeutic class and preferred name (WHO-DD classification, latest available version at the 
analysis date). All concomitant treatments and new anti-cancer therapies will be summarized 
according to the following variables: 
- Concomitant treatment (Yes, No). 
- Received new drug treatment (Yes, No). 
Concomitant treatments taken at inclusion, those taken before, during and after the treatment 
period, as well as new anticancer therapies will be described in the SS. 
For concomitant treatments as well as new drug treatments, individual listing will be provided 
including pharmacological class, pharmacological sub-class, therapeutic class and preferred 
name, medications start and end date, administration schedule and dose unit administered. The 
listing will include medications starting on or after the start of study treatment or medications 
starting prior to the start of study treatment and continuing after the start of study treatment. 
3.4. Efficacy analysis  
The proportion of participants with BOR according to RECIST version 1.1 criteria and using 
investigator’s tumour assessment will be summarized descriptively. 
A waterfall plot displaying the best relative change of the sum of the lesions diameters from 
baseline will be performed. 
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3.5. Safety analysis   
All safety analyses will be performed in the SS unless otherwise specified. 
Calculation rules for safety endpoints and other specific definitions are provided in 
7 Appendix C. 
Adverse events (AEs) will be graded using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events CTCAE version 5.0. 
3.5.1. 
Adverse events  
Treatment-emergent adverse events (TEAE) are defined as any AEs reported from the date of 
first administration of IMP to 30 days after the last date of IMP administration.  
Number of events, number and percentage of patients reporting at least one event, presented by 
SOC and/or PT (depending on the analysis) will be provided for serious adverse events (SAE) 
and TEAE over the study and treatment periods, respectively.  
TEAE and Serious TEAE (STEAE) will be described according to: 
- Worst grade. 
- Severity. 
- Relationship (related to trifluridine/tipiracil, related to Futuximab/modotuximab, related to 
the combination) (8 Appendix D). 
- Outcome (recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not 
recovered/not resolved, fatal, unknown). 
- Leading to drug withdrawal (leading to trifluridine/tipiracil withdrawal, leading to 
Futuximab/modotuximab withdrawal). 
TEAE will be also described according to:  
- Action taken regarding IMPs (drug interrupted, dose reduced, dose delayed, dose reduced or 
delayed, dose reduced and delayed, dose not changed, infusion rate reduced). 
- TEAE related to disease progression.  
- TEAE leading to death. 
- TEAE related (related to trifluridine/tipiracil, related to Futuximab/modotuximab, related to 
the combination) leading to death 
- Requirement of added therapy. 
Non-STEAE (EudraCT analyses) and Non-STEAE related to IMPs will be described by SOC 
and PT. 
Number and percentage of participants who experienced a DLT will be summarized and listed 
in the DLTES. 
3.5.2. 
Death  
Listing of patients who died during the treatment period or during the follow-up period will be 
provided. 
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3.5.3. 
Clinical laboratory evaluation  
For haematological, biochemistry, coagulation and urinary parameters, descriptive statistics on 
value at baseline and on worst value at cycle 1 will be provided. 
Number and percentage of patients for each laboratory parameter classified according to: 
reference ranges (< LLN/≥ LLN or ≤ ULN/> ULN) for non-gradable parameters except 
creatinine clearance, grade (Grade 0, Grade 1, Grade 2, Grade 3, Grade 4) for gradable 
parameters, following classes for proteinuria (Absence, Trace, Presence (+, More than one +)) 
and following classes for creatinine clearance (severe, mild, moderate, normal) and using shift 
tables from baseline to the worst (high and/or low) and last class or value under treatment will 
be described. 
Some parameters with grade dependent on baseline value cannot be computed if there is no 
value at baseline. 
3.5.4. 
Vital signs, clinical examination and other observations related to safety 
Vital signs and clinical examination will be described in the SS, in terms of quantitative values 
for Weight (Kg), and Temperature (°C) and by classes for ECOG, BSA (m2), Heart Rate - HR 
(bpm), Supine Systolic Blood Pressure - SBP (mmHg), Supine Diastolic Blood Pressure - DBP 
(mmHg), Respiratory rate (breaths/min), and Oxygen saturation (%): 
- ECOG (0, 1, 2, 3, 4) documented in the e-CRF. 
- BSA (< 1.07, [1.07,1.23), [1.23, 1.38), [1.38, 1.53), [1.53, 1.69), [1.69, 1.84), [1.84, 1.99), 
[1.99, 2.15), [2.15, 2.30), ≥ 2.30). 
- HR (< 60, [60, 100), ≥ 100 bpm). 
- SBP (< 90, [90, 140), ≥ 140 mmHg). 
- DBP (< 60, [60, 90), ≥ 90 mmHg). 
- Respiratory rate (< 12, [12, 18], > 18 breaths/min). 
- Oxygen saturation (< 90, [90, 95], > 95 %). 
Vital signs and clinical examination will be described, in terms of value at baseline, value at 
cycle 1 (worst value) under treatment, worst value under treatment and last post-baseline value 
under treatment; as well as in terms of change from baseline to cycle 1 (worst value) under 
treatment, to worst value under treatment, to last post-baseline value under treatment.  
3.5.5. 
ECG  
The frequency distribution (n, %) of patients with an ECG performed will be described. ECG 
parameters, as well as heart rate (bpm) (< 60, [60, 100), ≥ 100), will be described by classes, in 
terms of value at baseline and last post-baseline value under treatment. Moreover values and 
changes from baseline of uncorrected and corrected (Fridericia’s correction (𝑄𝑇𝑐𝐹 
=𝑄𝑇/2√𝑅𝑅)) QT intervals, RR interval, PR interval and QRS duration will also be described in 
classes, considering the thresholds defined in 7.5: 
≤ 450, (450, 480], (480, 500] and > 500 msec for values. 
≤ 30, (30, 60] and > 60 msec for changes.  
3.6. QoL  
Not applicable 
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4.
INTERIM ANALYSIS
Not applicable. 
5.
APPENDIX A: DATA HANDLING AND PROGRAMMING SPECIFICATIONS
5.1. General analytic definitions  
5.1.1. 
Expressions   
Reliable value for biological and coagulation samplings is identified in datasets with flag 
BIOFG_parameter name (“Non analysable value”) different from 1 and non-missing result. 
For other panels, reliable value is a non-missing result. 
Value at baseline is defined as the last reliable value prior to treatment intake. 
Note: In case of patient included and/or randomised but not treated (i.e. patients with treatment 
duration equal to 0): value at baseline is defined as the last reliable value.  
Post-baseline value is defined as a reliable value after the first study treatment intake. 
Last value is defined as the last reliable post-baseline value of the criteria of interest during 
treatment period. 
Withdrawal value is defined as the reliable value of the criteria of interest during the 
withdrawal visit. 
Lowest value is defined as the lowest value during the treatment period. 
Highest value is defined as the highest value during the treatment period. 
Worst (lowest/highest) value at cycle i is defined as the worst (lowest/highest) value at cycle. 
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For the description of protocol deviations, the 6 following categories are considered in 
accordance with ICH E3 guideline and ICH E3 Q&A: 
- Selection/inclusion criteria not fulfilled. 
- Patient having withdrawal criteria but not withdrawn. 
- Incorrect treatment or dose received. 
- Forbidden concomitant treatment. 
- Endpoint assessment possibly affected. 
- Safety possibly affected. 
5.2.1.3. 
Demographic data and other baseline characteristics  
5.2.1.3.1. 
Demographic data   
Age is calculated as difference between year of informed consent and year of date of birth. 
5.2.1.3.2. 
History of Colorectal cancer  
Primary tumour localisation:  
- Right if primary tumour site = right colon(1) or transverse or other* 
- Left if primary tumour site = left colon(2) or rectum 
(1) Right colon should include multilocalised right colon, ascending colon, cecum, appendix and hepatic flexure.
(2) Left colon should include multilocalised left colon, descending colon, sigmoid colon, splenic flexure and rectosigmoid segment.
*Other: in the case the patient present multiple tumours in both sides, the disease will be considered as “right-sided”. 
Site of metastasis is defined from History of colorectal cancer e-CRF page. 
Number of metastatic site is defined as the number of distinct site of metastasis (whether the 
site is considered for target or non-target lesion) from History of colorectal cancer e-CRF page. 
Sites filled in ‘Other’ will be counted as 1 site.  
Disease duration 
Disease duration (years) is defined as (Inclusion date – date of the first diagnosis of colorectal 
cancer)/365.25 
Time from first metastasis diagnosis to inclusion   
Time from first metastasis diagnosis to inclusion (months) is defined as (inclusiondate – first 
metastasis diagnosis date)/30.44 
Progression free interval 
Progression free interval (months) is defined as (Date of progression prior to the randomisation 
date – date of end of the last prior anti-cancer therapy*)/30.44. 
The progression free interval of patients progressing during the last regimen is estimated to last 
one day. 
*Including drug treatment, radiotherapy and surgery (whatever the intent). 
Treatment free interval 
Treatment free interval (months) is defined as (date of first IMP intake – date of end of the last 
prior anti-cancer therapy*)/30.44. 
*Including drug treatment, radiotherapy and surgery. 
Of note, in case of partial or incomplete date: 
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Table (5.2.1.3.2) 1 - Substitution rules of History of colorectal cancer 
Missing diagnosis date 
Substituted diagnosis date 
../mm/yyyy 

Diagnosis date = 01/mm/yyyy 
../…/yyyy 

Diagnosis date = 01/01/yyyy 
Missing metastasis date 
Substituted metastasis date 
../mm/yyyy 

Metastasis date = 01/mm/yyyy 
../…/yyyy 

Metastasis date =01/01/yyyy 
Missing start date of the last prior therapy 
Substituted start date of the last prior therapy 
../mm/yyyy 

start date of the last prior therapy = 01/mm/yyyy 
../…/yyyy 

start date of the last prior therapy = 01/01/yyyy 
Missing end date of the last prior therapy 
Substituted end date of the last prior therapy 
../mm/yyyy 

end date of the last prior therapy = start date of the last 
prior therapy + 1day if same month and year 
otherwise: 
end date of the last prior therapy = 01/mm/yyyy 
../…/yyyy 

end date of the last prior therapy = start date of the last 
prior therapy + 1day if same year 
otherwise: 
end date of the last prior therapy = 01/01/yyyy  
../…/… 

end date of the last prior therapy = start date of the last 
prior therapy + 1day   
Missing start date of a previous treatment 
Substituted start date of a previous treatment 
../mmm/yyyy 

01/mmm/yyyy 
../…/yyyy 

01/JAN/yyyy 
../.../…. 

Inclusion date 
Note: 
../mm/yyyy = missing day 
../.../ yyyy = missing day and month 
  ../.../....  = missing date 
RAS status 
Table (5.2.1.3.2) 2 - RAS status 
KRAS 
NRAS 
RAS 
MUTANT 
whatever (mutant, wild, missing) 
MUTANT 
whatever (mutant, wild, missing) 
MUTANT 
MUTANT 
WILD 
WILD 
WILD 
MISSING 
WILD 
NE 
WILD 
MISSING 
NE 
MISSING 
MISSING 
NE 
Stage at diagnosis 
Table (5.2.1.3.2) 3 - Staging based on classification 
Stage in classes 
AJCC stage 
Dukes’ classification 
Astler-Coller modified Dukes’ classification 
Stage 0 
- 
- 
I-II
Stage I 
A 
A 
I-II
Stage I 
A 
B1 
I-II
Stage II-A 
B 
B2 
I-II
Stage II-B 
B
B2 
I-II
Stage II-C 
B 
B3 
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III 
Stage III-A 
C
C1 
Stage III-B 
C
C2 
C 
C1/C2 
C 
C1 
Stage III-C 
C 
C2 
C 
C2/C3 
C 
C3 
IV 
Stage IV-A 
D 
Stage IV-B 
Stage IV-C 
5.2.1.3.3. 
Previous therapies for colorectal cancer  
The existence of a previous drug treatment (Yes, No) is defined from the presence, or not of 
an “anatomical therapeutic chemical classification” and/or a “preferred name” for the previous 
drug treatment at inclusion visit.  
The existence of a previous metastatic drug treatment (Yes, No) is defined from the 
presence, or not of an “anatomical therapeutic chemical classification” and/or a “preferred 
name” for the previous drug treatment after the date of 1st metastasis. 
The existence of a previous adjuvant drug treatment (Yes, No) is defined from the presence 
or not of a previous drug treatment with an adjuvant indication. 
The existence of a previous neoadjuvant drug treatment (Yes, No) is defined from the 
presence or not of a previous drug treatment with a neoadjuvant indication. 
The existence of a previous fluoropyrimidine drug treatment (Yes, No) is defined from the 
presence, or not of a previous drug treatment belonging to the list 3678.0. 
The existence of a previous irinotecan drug treatment (Yes, No) is defined from the 
presence, or not of a previous drug treatment belonging to the list 3674.0. 
The existence of a previous oxaliplatin drug treatment (Yes, No) is defined from the 
presence, or not of a previous drug treatment belonging to the list 3675.0. 
The existence of a previous anti-VEGF monoclonal antibody drug treatment (Yes, No) is 
defined from the presence, or not of a previous drug treatment belonging to the list 4281.0. 
The existence of a previous anti-EGFR monoclonal antibody drug treatment (Yes, No) is 
defined from the presence, or not of a previous drug treatment belonging to the list 4280.0. 
Number of prior regimens for mCRC is calculated as the sum of previous drug treatments 
for mCRC except if reported in a maintenance indication. 
The duration of previous metastatic regimen containing anti-EGFR monoclonal Anti 
Body (months) is defined as (last previous anti-EGFR monoclonal Anti Body drug treatment 
end date – first previous anti-EGFR monoclonal Anti Body drug treatment start date)/30.44. 
5.2.1.3.4. 
Initial tumour assessment  
Not applicable. 
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5.2.1.4. 
Extent of exposure and treatment compliance  
Treatment duration for trifluridine/tipiracil  
Treatment duration (months) for trifluridine/tipiracil is defined as ([min (first intake date of the 
last cycle + 27 days, death date) - first trifluridine/tipiracil intake date] +1)/30.44. 
Treatment duration for futuximab/modotuximab 
Treatment duration (months) for futuximab/modotuximab is defined as [(min (first infusion 
date of the last cycle + 27 days, death date) - first futuximab/modotuximab infusion date) +1] / 
30.44. 
For trifluridine/tipiracil and futuximab/modotuximab, in case of missing or incomplete first 
intake date of the last cycle, the last intake date of the last cycle will be considered. 
Cycle duration for trifluridine/tipiracil 
Duration of cycle i (weeks) for trifluridine/tipiracil is defined as [[first trifluridine/tipiracil 
intake of cycle (i+1)] – [first trifluridine/tipiracil intake of cycle i]] / 7. 
Of note, the duration of the last cycle for trifluridine/tipiracil will be estimated to be 28 days 
for the calculation of Dose Intensity and Relative Dose Intensity at the last cycle. 
Cycle duration for futuximab/modotuximab 
Duration of cycle i (weeks) for futuximab/modotuximab is defined as [[first 
futuximab/modotuximab infusion of cycle (i+1)] – [first futuximab/modotuximab infusion of 
cycle i]] / 7. 
Of note, the duration of the last cycle for futuximab/modotuximab will be estimated to be 
28 days for the calculation of Dose Intensity and Relative Dose Intensity at the last cycle. 
Follow-up duration 
The follow-up duration (months) is calculated as the duration between the last available date 
and the inclusion date [last available date* – inclusion date +1]/30.44. The events of interest 
are being alive or lost to follow-up and death is censored. 
* Last available date is defined as date of death if patient died, and as maximum date among completed dates relative to patient’s information 
otherwise. 
Number of cycles for trifluridine/tipiracil 
The number of cycles with trifluridine/tipiracil will be defined based on trifluridine/tipiracil 
administration page. A patient is considered to enter in a cycle if there is at least one answer 
‘Yes’ to the question ‘Has the patient taken his/her morning (or evening) intake?’. 
Real administrated dose (mg) for trifluridine/tipiracil 
On a time period, real administered dose for trifluridine/tipiracil (mg) = Number of capsules 
15 mg taken*15 + Number of capsules 20 mg taken*20 
With: 
- Number of capsules taken = Number of capsules dispensed - Number of capsules returned 
Else, if Number of capsules returned is missing, Number of capsules taken = Estimated number 
of capsules taken. 
Number of cycles for futuximab/modotuximab 
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The number of cycles with futuximab/modotuximab will be defined based on 
futuximab/modotuximab administration page. A patient is considered to enter in a cycle if the 
answer is "Yes" to the question "Did the patient receive the IMP infusion?’. 
Real administrated dose (mg) for futuximab/modotuximab 
On a time period, real administered dose for futuximab/modotuximab (mg) = sum of total dose 
administrated (full + incomplete doses). 
In case of incomplete dose administered, the real dose administered can be computed as: 
planned dose to be given (mg) * actual volume administered (mL) / infusion volume planned 
(mL)  
Planned dose intensity (PDI) for trifluridine/tipiracil (mg/m²/week) 
10 days of intake 
per cycle 
35 mg/m2 (bid) 
(70 mg/m²/day) 
𝟕𝟎(mg/m²/day) ∗𝟏𝟎
4 (wk)
Planned dose intensity (PDI) for futuximab/modotuximab (mg/kg/week) 
4 weeks of infusion 
per cycle 
9 mg/kg (the first week) then 6 mg/kg (weekly) 
for cycle 1 
𝟗(mg/kg/week) + 𝟔(mg/kg/week) ∗𝟑
4 (wk)
6 mg/kg (weekly) for next cycles 
𝟔(mg/kg/week) ∗4
4 (wk)
Cumulative dose 
The cumulative dose (mg/m²) for trifluridine/tipiracil per patient in a time period (during the 
treatment period or per cycle) is the sum of the total dose that the patient received within that 
period according to the compliance. 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²) = 
∑
(𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝐵𝑆𝐴 (𝑚2)
)
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
Where BSA is calculated in the ClinTrial database by the data management. 
The cumulative dose (mg/kg) for the futuximab/modotuximab per patient in a time period 
(during the treatment period or per cycle) is the sum of the total dose that the patient received 
within that period according to the compliance. 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔) = 
∑
(𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
)
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
Dose intensity (DI) per patient 
The dose intensity (mg/m²/week) for trifluridine/tipiracil per patient is defined as the 
cumulative dose (mg/m²) received during the treatment period divided by the total treatment 
duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑚²/𝑤𝑘) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠)
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The dose intensity (mg/kg/week) for the futuximab/modotuximab per patient is defined as the 
cumulative dose (mg/kg) received during the treatment period divided by the total treatment 
duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑘𝑔/𝑤𝑘) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠)
Dose intensity (DI) per cycle 
The dose intensity (mg/m²/week) for trifluridine/tipiracil per cycle is defined as the cumulative 
dose (mg/m²) received during the cycle divided by the cycle duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑚²/𝑤𝑘) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²) 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑤𝑒𝑒𝑘𝑠)
The dose intensity (mg/kg/week) for the futuximab/modotuximab per cycle is defined as the 
cumulative dose (mg/kg) received during the cycle divided by the cycle duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑘𝑔/𝑤𝑘) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔) 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑤𝑒𝑒𝑘𝑠)
RDI per patient 
The RDI (%) per patient is defined as the ratio of the DI to the initial PDI. 
𝑅𝐷𝐼 (%) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 
𝐷𝐼 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 ∗100
RDI per cycle 
The relative dose intensity (%) per cycle is defined as the ratio of the dose intensity at cycle i 
to the planned dose intensity. 
𝑅𝐷𝐼 (%) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 
𝐷𝐼 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦∗100
Dose reduction for trifluridine/tipiracil 
A cycle with a dose reduction is defined according to the trifluridine/tipiracil dispensing e-CRF 
page (dose modified since the last cycle (Yes, No)). 
Partial dose administered for futuximab/modotuximab  
Partial dose administered for the futuximab/modotuximab is defined by an answer “No” at the 
eCRF interrogation “Was full dose administered?”. 
Dispensation postponed for trifluridine/tipiracil 
A cycle with a dispensation postponed is defined according to the trifluridine/tipiracil 
dispensing e-CRF page (Dispensation postponed (Yes, No)). 
Unplanned treatment interruption for trifluridine/tipiracil 
A treatment interruption is defined according to the number of days between two consecutive 
dates where the answer is ‘Yes’ to the questions ‘Has the patient taken his/her morning intake’ 
or ‘Has the patient taken his/her evening intake’ when this duration is one day or longer 
considering trifluridine/tipiracil administration schedule (5 days on/2 days off, over 14 days 
followed by a 14-day rest). 
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Treatment interruption (days) = (date with an answer ‘Yes’ to the questions ‘Has the patient 
taken his/her morning intake’ or ‘Has the patient taken his/her evening intake’ – following date 
with an answer ‘Yes’ to the questions ‘Has the patient taken his/her morning intake’ or ‘Has 
the patient taken his/her evening intake’) -1  
Note: only intra-cycle interruptions will be considered 
5.2.1.5. 
Concomitant treatments  
The anatomical therapeutic chemical classification (ATC code = 5 digits) is composed of 
4 levels: 
- The first (1 digit) represents the anatomo-physiological class. 
- The second (2 digits) represents the pharmacological class. 
- The third (1 digit) represents the pharmacological sub-class. 
- The last (1 digit) represents the therapeutic class. 
The existence of a concomitant treatment (Yes, No) is defined from the presence, or not, of 
an Anatomical therapeutic chemical classification and/or Preferred name. 
The periods considered for the analysis are: 
At inclusion for which treatments: 
- With start date ≤ inclusion date and stop date ≥ inclusion date or missing are taken into 
account. Inclusion date is equal to the date of inclusion visit, i.e. A000/D000 visit date. 
Before the treatment period for which treatments: 
- With start date < first IMP intake date are taken into account.  
During the treatment period for which treatments: 
- With start date ≥ first IMP intake date and <  (*), or  
- With start date ≤ first IMP intake date and stop date ≥ first IMP intake date or missing 
After the treatment period for which treatments:  
- With start date ≥ (*), or 
- With start date ≤ (*) and stop date > (*) or missing. 
(*)max (first intake date of last cycle + 28 days of trifluridine/tipiracil, first intake date of last cycle + 28 days of futuximab/modotuximab)  
The following rules for substitution of missing or incomplete start and stop dates are so that 
the concomitance period is maximised: 
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7.
APPENDIX C: SAFETY
The periods considered for the analysis of adverse events, deaths and clinical laboratory 
evaluation are: 
- During the treatment period: 
With date ≥ first IMP intake date and <=last IMP intake date as defined in the
Section 5.1.5 + 30 days.
- After the treatment period: 
With date > last IMP intake date as defined in the Section 5.1.5 + 30 days.
7.1. Adverse events  
Each medical concept of adverse events coded according to the internal "multiple medical 
concept" process is taken into account as a single adverse event in the statistical analysis. 
The modalities of the adverse event (onset and end dates, severity, seriousness, action taken, 
additional therapy, relationship, outcome...) replicated by default to each medical concept are 
also taken into account in the statistical analyses. 
Emergent adverse events on treatment are defined as all adverse events: 
- Which occur between the first IMP intake date (included) and the last IMP intake date "+ 
30 days" (included), considering the definition of last study drug intake defined in 
Section 5.1.5 
or 
- Which occur before the first IMP intake date and which worsen (in terms of severity) or 
become serious according to the investigator opinion between the first IMP intake date 
(included) and the last IMP intake date "+ 30 days" (included), considering the definition of 
last study drug intake defined in Section 5.1.5. 
Note: Adverse events occurring or worsening or becoming serious on the day of the first study 
drug/associated agent intake (if any) is considered as emergent. 
Serious adverse events are defined from investigator assessment as all adverse events fulfilling 
at least one of the following seriousness criteria for immediate notification: death, 
hospitalisation or prolongation of hospitalisation, medically important, life-threatening, 
disability/incapacity or congenital anomaly. 
A fatal adverse event corresponds to an adverse event with “Fatal” as outcome. 
Adverse events related to Trifluridine/tipiracil correspond to adverse events associated with 
the answer "Related" to the "Is this event related to Trifluridine/tipiracil" question. 
Adverse events related to Futuximab/modotuximab correspond to adverse events associated 
with the answer "Related" to the "Is this event related to Futuximab/modotuximab" question. 
Adverse events related to the combination correspond to adverse events associated with the 
answer "Related" to the "Is this event related to Trifluridine/tipiracil " question and/or with the 
answer "Related" to the "Is this event related to Futuximab/modotuximab" question. 
Adverse events related to disease progression correspond to adverse events associated with 
the answer "Related" to the "Is this event related to disease progression" question. 
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The following information will be taken into account: 
- For the analyses where the severity of the adverse event is considered, the worst severity 
from the day of emergence and during the studied period (i.e. between the first study 
drug/associated agentintake date (included) and the last study drug/associated agent intake 
date (as defined in Section 5.1.5) “+ 30 days” (included) will be taken into account. 
- The number of patients by worst grade: for each patient, system organ class and preferred 
term, we analyze the worst grade of events. 
- The number of events by worst grade: for each patient, system organ class and preferred 
term, we analyse the worst grade of each event. The percentage will be calculated as the 
number of events of the PT concerned at grade X divided by the total number of events of 
the PT concerned. 
- For the analyses where the action taken regarding the study drug and the additional therapy 
requirement are considered, all the actions taken and additional therapy requirements 
recorded from the day of emergence and on the studied period will be taken into account. 
- However, in case of an episode of an emergent adverse event leading to studied treatment 
withdrawal reported after the last study drug/associated agent intake date (as defined in 
Section 5.1.5) “+ 30 days”, the adverse event will be considered as leading to studied 
treatment withdrawal during the studied period. 
- Seriousness is judged by event: if one episode is serious (whatever the time it occurs), the 
whole event will be considered as serious. 
- A severe adverse event corresponds to an adverse event with NCI CTCAE grade 3, 4 or 5. 
- Any grade corresponds to an adverse event with NCI CTCAE grade 1, 2, 3, 4 or 5. 
- All multicoded events will be taken into account in the analyses. 
- For the analysis of recovered emergent adverse event during / after treatment period, a TEAE 
is considered as recovered "during treatment period" ("after end of treatment period", 
respectively) if the associated outcome is recovered" or "recovered with sequelae" and 
occurs between the first study drug/associated agent intake date and the last study 
drug/associated agent intake date (as defined in Section 5.1.5) “+ 30 days” (included) 
(strictly after the last study drug/associated agent intake date (as defined in Section 5.1.5) “+ 
30 days”, respectively). 
The following rules are applied in case of missing severity: 
Table (7.1) 1 - Treatment-emergence of adverse events in case of missing severity/grade (if any) 
Severity/Grade 
Adverse event considered as 
Nearest before the first study 
drug/associated agent intake date 
During the study 
period 
Missing 
Missing 
→
Treatment-emergent
Missing 
Grade 1 
→
Non treatment-emergent
Missing 
Grade 2, 3, 4 or 5 
→
Treatment-emergent
Grade 1, 2, 3 
Missing 
→
Treatment-emergent
Grade 4 
Missing 
→
Non treatment-emergent
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In case of multiple samples: 
- For the description of the values at each planned post-baseline visit, only the first analysable 
one measured under treatment at the visit is taken into account. 
- Otherwise, each post-baseline value (test, re-test, planned, unplanned) measured under 
treatment is taken into account for analyses. 
Units 
All parameters will be analysed in international units (IU). 
Abnormal values 
Abnormal values are described according to: 
- Reference laboratory ranges for the non-gradable parameters. 
- CTCAE grade for gradable parameters. 
Table (7.3) 1 - Gradable and non-gradable laboratory parameters 
Laboratory 
parameters 
Parameter 
Highest 
Lowest 
Biochemistry 
Gradable 
Sodium 
Hypernatremia 
Hyponatremia 
Biochemistry 
Gradable 
Potassium 
Hyperkalemia 
Hypokalemia 
Biochemistry 
Gradable 
Total Calcium 
Hypercalcemia 
Hypocalcemia 
Biochemistry 
Gradable 
Magnesium 
Hypermagnesemia 
Hypomagnesemia 
Biochemistry 
Gradable 
Serum creatinine 
High creatinine* 
NA 
Biochemistry 
Gradable 
Albumin 
NA 
Low albumin 
Biochemistry 
Gradable 
Glucose 
Hyperglycemia 
Hypoglycemia 
Biochemistry 
Gradable 
GGT 
High GGT* 
NA 
Biochemistry 
Gradable 
AST 
High AST* 
NA 
Biochemistry 
Gradable 
ALT 
High ALT* 
NA 
Biochemistry 
Gradable 
Alkaline 
phosphatase 
High alkaline phosphatase* 
NA 
Biochemistry 
Gradable 
Total bilirubin 
High total bilirubin* 
NA 
Haematology 
Gradable 
Haemoglobin 
High haemoglobin* 
anemia 
Haematology 
Gradable 
White blood cells 
NA 
Low WBC 
Haematology 
Gradable 
Neutrophils 
NA 
Low neutrophils 
Haematology 
Gradable 
Lymphocytes 
High lymphocytes 
Low lymphocytes 
Haematology 
Gradable 
Platelets 
NA 
Low platelets 
Coagulation 
Non-gradable Prothrombin Time 
High Prothrombin Time 
NA 
Coagulation 
Gradable 
Activated Partial 
Thromboplastin 
Time (aPTT) 
High aPTT 
NA 
Biochemistry 
Non-gradable 
Creatinine 
clearance** 
NA 
Low creatinine clearance 
Biochemistry 
Non-gradable 
Chloride 
High chloride 
Low chloride 
Biochemistry 
Non-gradable 
Blood urea 
nitrogen 
High urea nitrogen 
NA 
Biochemistry 
Non-gradable 
LDH 
High LDH 
NA 
Biochemistry 
Non-gradable 
Phosphate 
NA 
Hypophosphatemia 
Haematology 
Non-gradable 
Red blood cells 
High RBC 
Low RBC 
*: Parameter with grade dependent on baseline value (grade cannot be computed if there is no value at baseline) 
**: Creatinine clearance is calculated in the ClinTrial database (by the data management department) if the data was not reported in the 
e-CRF. 
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Laboratory reference limits and CTCAE grades are reported in the database. Grades directly 
derived in the database (CTCAE v5.0) will be used for analyses. For the parameters which are 
gradable according to CTCAE v5.0 and for which the grade is not derived in the database, the 
grades will be derived using the local laboratory reference limits in analysis datasets. 
Table (7.3) 2 - Definition of CTCAE grade - Version 5.0 - 
Gradable parameters according to baseline value 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium (mmol/L) - 
Hypernatremia 
]ULN;150] 
]150;155] 
]155;160] 
>160 
Sodium (mmol/L) - 
Hyponatremia 
[130;LLN[ 
[120;130[ 
< 120 
Potassium (mmol/L) 
- 
Hyperkalemia 
]ULN;5.5] 
]5.5;6]  
]6;7] 
>7
Potassium (mmol/L) 
- 
Hypokalemia 
[3.0;LLN[ 
[2.5;3.0[ 
<2.5 
Total Calcium – 
Hypercalcemia 
]ULN ; 2.9] 
]2.9 ; 3.1] 
]3.1 ; 3.4] 
> 3.4 
Total Calcium - 
Hypocalcemia 
[2.0; LLN[ 
[1.75;2.0[ 
[1.5;1.75[ 
< 1.5 
Magnesium 
(mmol/L) - 
Hypermagnesemia 
]ULN;1.23] 
]1.23;3.30] 
> 3.30
Magnesium 
(mmol/L) - 
Hypomagnesemia 
[0.5;LLN[ 
[0.4;0.5[ 
[0.3;0.4[ 
<0.3 
Serum creatinine 
increased 
>ULN – 1.5 x ULN 
>1.5 x baseline – 3.0
x 
baseline 
(if 
baseline 
available) 
OR  
>1.5 x ULN – 3.0 x 
ULN
>3.0 x baseline (if 
baseline 
available)
OR 
>3.0 x ULN – 6.0 x 
ULN
>6.0 x ULN
Albumin (g/L) - 
Low 
[30; LLN[ 
[20; 30[ 
< 20 
Glucose (mmol/L) - 
Hypoglycemia 
[3.0;LLN[ 
[2.2;3.0[ 
[1.7;2.2[ 
< 1.7 
Glucose (mmol/L) - 
Hyperglycemia 
>
ULN and  >
baseline
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Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GGT increased 
> ULN – 2.5 x ULN 
if baseline is normal 
[≤ ULN]; 
2.0 x baseline – 2.5 x 
baseline if baseline is 
abnormal [> ULN] 
> 2.5 x ULN – 5.0 x 
ULN if baseline is
normal [≤ ULN];
> 2.5 x baseline – 5.0
x baseline if baseline
is abnormal [> ULN]
>5.0 x ULN – 20.0 x 
ULN if baseline is
normal [≤ULN];
> 5.0 x baseline – 
20.0 x baseline if
baseline is abnormal
[> ULN]
> 20.0 x ULN if
baseline is normal
[≤ ULN];
> 20.0 x baseline if
baseline is abnormal
[> ULN]
ASAT increased 
> ULN – 3.0 x ULN 
if baseline is normal 
[≤ ULN]; 
1.5 x baseline – 3.0 x 
baseline if baseline is 
abnormal [ > ULN] 
> 3.0 x ULN – 5.0 x 
ULN if baseline is
norma [≤ ULN]l;
> 3.0 x baseline – 5.0
x baseline if baseline
is abnormal [> ULN]
> 5.0 x ULN – 20.0 x 
ULN if baseline is
normal [≤ ULN];
> 5.0 x baseline – 
20.0 x baseline if
baseline is abnormal
[> ULN]
> 20.0 x ULN if
baseline is normal
[≤ ULN];
> 20.0 x baseline if
baseline is abnormal
[> ULN]
ALAT increased 
>ULN – 3.0 x ULN if 
baseline is normal 
[≤ULN];  
1.5 x baseline – 3.0 x 
baseline if baseline is 
abnormal [ > ULN] 
>3.0 x ULN – 5.0 x
ULN if baseline is
normal[≤ULN];
>3.0 x baseline – 5.0
x baseline if baseline
is abnormal [ > ULN]
>5.0 x ULN – 20.0 x 
ULN if baseline is
normal [≤ULN];
>5.0 x baseline –
20.0 x baseline if
baseline is abnormal
[ > ULN]
>20.0 x ULN x ULN
if baseline is normal
[≤ULN];
>20.0 x baseline if
baseline is abnormal
[ > ULN]
ALP increased 
> ULN – 2.5 x ULN
if baseline is normal
[≤ ULN]; 
2.0 
x 
baseline – 2.5 x 
baseline if baseline is
abnormal [> ULN]
> 2.5 x ULN – 5.0 x 
ULN if baseline is
normal [≤ ULN];
2.5 x baseline – 5.0 x
baseline if baseline is
abnormal [> ULN]
> 5.0 x ULN – 20.0 x 
ULN if baseline is
normal [≤ ULN];
> 5.0 x baseline – 
20.0 x baseline if
baseline is abnormal
[> ULN]
> 20.0 x ULN if
baseline is normal
[≤ ULN];
> 20.0 x baseline if
baseline is abnormal
[> ULN]
Total bilirubin 
increased 
> ULN – 1.5 x ULN
if baseline is normal
[≤ ULN];
1.0 x baseline – 1.5 x
baseline if baseline is
abnormal [> ULN]
>1.5 x ULN – 3.0 x
ULN if baseline is
normal [≤ ULN];
> 1.5 x baseline – 3.0
x baseline if baseline
is abnormal [> ULN]
> 3.0 x ULN – 10.0 x 
ULN if baseline is
normal [≤ ULN];
>
3.0 – 10.0 x 
baseline if baseline is
abnormal [> ULN]
> 10.0 x ULN if
baseline is normal
[≤ ULN];
> 10.0 x baseline if
baseline is abnormal
[> ULN]
Haemoglobin 
increased 
> ULN and increase
from baseline ]0 ;20]
(g/L)
> ULN and increase
from 
baseline
]20 ;40] (g/L)
> ULN and increase
from baseline > 40
(g/L)
Haemoglobin (g/L) - 
Anemia 
[100;LLN[ 
[80;100[ 
< 80 
White Blood Cells 
(G/L) - Low 
[3.0;LLN[ 
[2.0;3.0[ 
[1.0;2.0[ 
< 1.0 
Neutrophils (G/L) - 
Low 
[1.5;LLN[ 
[1.0;1.5[ 
[0.5;1.0[ 
<0.5 
Lymphocytes (G/L) 
- Low
[0.8;LLN[ 
[0.5;0.8[ 
[0.2;0.5[ 
<0.2 
Lymphocytes (G/L) 
- High
]4.0;20.0] 
>20 
Platelets (G/L) - 
Low 
[75;LLN[ 
[50;75[ 
[25;50[ 
<25 
Prothrombin Time 
increased 
APTT increased 
]ULN;1.5*ULN] 
]1.5*ULN;2.5*ULN] >2.5*ULN 
CREATCLR 
increased 
[60;LLN[ 
[30;60[ 
[15;30[ 
< 15 
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Any grade corresponds to a laboratory value with NCI CTCAE grade 0, 1, 2, 3 or 4. 
A grade 0 corresponds to a laboratory value within limit or reference range. 
The LOWEST value for a patient is defined as the lowest absolute laboratory value during the 
treatment period. A Lowest value for a cycle is defined as the lowest laboratory value in that 
cycle.  
The HIGHEST value for a patient is defined as the highest laboratory value during the 
treatment period. A highest value for a cycle is defined as the highest laboratory value in that 
cycle.  
Urinary results 
The category ‘Present’ corresponds to results ‘+’, ‘++’, ‘+++’ and ‘++++’. The category ‘More 
than one +’ corresponds to results ‘++’, ‘+++’ and ‘++++’. 
Worst value 
For the urinalysis parameters except specific gravity and pH, the worst class will correspond to 
‘Presence’ class, then ‘Trace’ and finally ‘Absence’ will be considered as normal class.  
For specific gravity and pH, the worst highest value as well as the worst lowest value will be 
derived. 
For creatinine clearance, the worst class will correspond to “severe” category, then “moderate”, 
then “mild” and finally “normal”. 
Baseline and post baseline worst grade for High and Low:  
- Low: If the result is below lower normal range limit, Low =grade (for gradable parameter), 
Else Low = 0. 
- High: If the result is above upper normal range limit, High =grade (for gradable parameter), 
Else High = 0. 
7.4. Vital signs and clinical examination  
Last value under treatment 
For ECOG, weight, BSA, respiratory rate, oxygen saturation, SBP, DBP and HR, the last value 
under treatment will be derived. 
Change from baseline 
For weight, BSA, respiratory rate, oxygen saturation, SBP, DBP and HR, the change from 
baseline to to last post-baseline value under treatment will be derived. 
Body Surface Area 
BSA is calculated in the ClinTrial database (by data management department) using the height 
at inclusion visit and the weight at a corresponding cycle. This derived BSA will be used for 
compliance/exposure calculations. 
The BSA will be calculated using the following Dubois formula (all BSA calculations are 
rounded to 2 decimal places) (Dubois, 1916). 
BSA (m²) = ([Body Weight (kg)] 0 425 x [Height (cm)] 0 725) x 0.007184 
ECOG performance status 
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8.
APPENDIX D: QUALITY OF LIFE
Not applicable. 
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9.
APPENDIX E: SOFTWARE AND PROGRAMMING CODES
Kaplan Meier survival analysis 
PROC LIFETEST data= work.data alpha=0.05 method=KM; 
time TIME *CENSOR (censoredval);  
strata ARM; 
id USUBJID; 
RUN; 
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10. APPENDIX F: EARLY FUTILITY (INTERIM 0)
Not applicable 
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11. REFERENCES
Guidelines
Guideline on Missing Data in Confirmatory Clinical Trials – Adopted by CHMP, June 2010, issued as 
EMA/CPMP/EWP/1776/99 Rev. 1. 
ICH E3 - Structure and Content of Clinical Study Reports – Adopted by CPMP, December 1995, issued as 
CPMP/ICH/137/95/step 5. 
ICH E3 Q&A - Structure and Content of Clinical Study Reports - Questions & Answers (R1) - July 2012, issued 
as EMA/CHMP/ICH/435606/2012. 
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
ICH E9(R1) – Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials - Adopted by CHMP, February 2020, issued as EMA/CHMP/ICH/436221/2017. 
ICH E14 – The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs – Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 
Bibliography 
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Cox DR. Regression Models and Life-Tables Journal of the Royal Statistical Society. Series B (Methodological), 
1972;Vol. 34, No. 2:187-220. 
Dubois D, Dubois EF. A formula to estimate the approximate surface area if height and weight be known. Arch 
Intern Med. 1916;17:863-871. 
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Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of the American Statistical 
Association 1958;53:457-481. 
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