A Phase III Randomized Study Evaluating Gemcitabine and Paclitaxel Versus Gemcitabine Alone After FOLFIRINOX Failure or Intolerance in Metastatic Pancreatic Ductal Adenocarcinoma
Phase: PHASE3
Conditions: Metastatic Pancreatic Adenocarcinoma
Sponsor: UNICANCER

 
 
 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
 
Protocol n°: UC-0110/1809_ version n°6 – 13 July 2023 
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UNICANCER Tumour Group: UCGI 
 
PRODIGE 65 – UCGI 36 
 
Protocol n°: UC-0110/1809 _ EudraCT n°: 2018-002886-21 
 
 
A Phase III randomized study evaluating gemcitabine and paclitaxel versus 
gemcitabine alone after FOLFIRINOX failure or intolerance in Metastatic 
Pancreatic Ductal Adenocarcinoma. 
 
Abbreviated title: GEMPAX 
 
Version n°6 – 13 july 2023 
 
PROTOCOL 
VERSION N° - DATE  
CPP approval 
ANSM 
authorisation 
INITIAL 
V 2 – 19 December 2018 
14Jan2019 
16Nov2018 
AMENDMENT 1 
V 3 – 03 September 2019 
14Jan2020 
19Dec2019 
AMENDMENT 3 
V 4 – 09 June 2020 
25Sep2020 
27Jul2020 
AMENDMENT 4 
V 5 – 28 September 2021 
24Jan2022 
17Dec2021 
AMENDMENT 5 
V 6 – 13 July 2023 
Pending 
Pending 
 
COORDINATING 
INVESTIGATOR 
(UNICANCER GI) 
Dr Christelle DE LA FOUCHARDIERE 
Institut Paoli Calmettes 
23 boulevard de Sainte-Marguerite 13009 MARSEILLE 
Phone: +33 (0) 4 91 22 33 33 
Email: DELAFOUCHARDIEREC@ipc.unicancer.fr 
CO-COORDINATING 
INVESTIGATOR 
(GERCOR) 
Pr Pascal HAMMEL 
Hôpital Beaujon 
100 Boulevard du Général Leclerc, 92110 CLICHY 
Phone : +33 (0)1 40 87 56 53 
Email: pascal.hammel@aphp.fr  
CO-COORDINATING 
INVESTIGATOR 
(FFCD) 
Pr Laetitia DAHAN 
Hôpital de La Timone – AP-HM 
264 rue Saint-Pierre 13365 MARSEILLE Cedex 05 
Phone: +33 (0)4 91 38 60 23 / Fax: + 33 (0)4 91 38 48 73 
Email: laetitia.dahan@ap-hm.fr 
 

 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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SPONSOR 
UNICANCER 
101, rue de Tolbiac 
75654 Paris Cedex 13 (France) 
Phone: + 33 (0)1 44 23 04 04 – Fax: + 33 (0)1 44 23 55 69 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol n°: UC-0110/1809_ version n°6 – 13 July 2023 
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CONTACT DETAILS  
PROTOCOL N°: UC-0110/1809 
 
 
Trial Title: A Phase III randomized study evaluating gemcitabine and paclitaxel 
versus gemcitabine alone after FOLFIRINOX failure or intolerance in 
Metastatic Pancreatic Ductal Adenocarcinoma 
 
 
WRITING COMMITTEE 
Dr Christelle DE LA FOUCHARDIERE, Dr Sylvie CHABAUD, Dr Pierre 
SAINTIGNY, M. Nicolas LACHAUX  
 
CONTACT DETAILS AND USEFUL INFORMATION 
Dr. Christelle DE LA 
FOUCHARDIERE 
Coordinating Investigator 
Institut Paoli Calmettes 
232 boulevard de Sainte-Marguerite 13009 Marseille - France 
Phone: +33 (0) 4 91 22 33 33 
Email: DELAFOUCHARDIEREC@ipc.unicancer.fr  
Dr. Sylvie CHABAUD 
Statistician 
Centre Léon Bérard 
28, rue Laennec 69373 Lyon cedex 08 - France 
Phone: +33 (0) 4 78 78 27 98 
Fax: +33 (0) 4 78 78 27 15 
Email: sylvie.chabaud@lyon.unicancer.fr 
Emilie BRUMENT 
Project Manager 
UNICANCER 
101 rue de Tolbiac – 75654 PARIS Cedex 13 
Phone: +33 (0) 1 71 93 61 64 
Fax: +33 (0) 1 44 23 55 69 
Email: e-brument@unicancer.fr  
Pharmacovigilance 
Notification 
UNICANCER Pharmacovigilance Unit 
Phone: + 33 (0)1 44 23 04 16 
Fax: + 33 (0)1 44 23 55 70 
Email: pv-rd@unicancer.fr 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol n°: UC-0110/1809_ version n°6 – 13 July 2023 
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APPROVAL AND SIGNATURE  
FOR PROTOCOL N°: UC-0110/1809 
 
Trial Title: A Phase III randomized study evaluating gemcitabine and paclitaxel 
versus gemcitabine alone after FOLFIRINOX failure or intolerance in 
Metastatic Pancreatic Ductal Adenocarcinoma 
 
Title 
Name 
Address 
Date 
(dd-Mmm-
yyyy) 
Signature 
Director of 
Clinical 
Operations 
Beata Juzyna 
UNICANCER 
101 rue de Tolbiac – 75654 PARIS Cedex 13 
Phone: + 33 (0)1 44 23 04 19 
Fax: + 33 (0)1 44 23 55 69 
Email: b-juzyna@unicancer.fr 
 
 
Project Manager Emilie BRUMENT 
UNICANCER 
101 rue de Tolbiac – 75654 PARIS Cedex 13 
Phone: +33 (0) 1 71 93 61 64 
Fax: +33 (0) 1 44 23 55 69 
Email: e-brument@unicancer.fr 
 
 
Coordinating 
Investigator 
Dr. Christelle  
DE LA 
FOUCHARDIERE 
Institut Paoli Calmettes 
232 boulevard de Sainte-Marguerite 13009 
Marseille - France  
Phone: +33 (0) 4 91 22 33 33 
Email:  
DELAFOUCHARDIEREC@ipc.unicancer.fr 
 
 
Biostatistician 
Dr. Sylvie 
CHABAUD 
Centre Léon Bérard 
28, rue Laennec 69373 Lyon cedex 08 - 
France 
Phone: +33 (0) 4 78 78 27 98 
Fax: +33 (0) 4 78 78 27 15 
Email: sylvie.chabaud@lyon.unicancer.fr 
 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol n°: UC-0110/1809_ version n°6 – 13 July 2023 
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TABLE OF CONTENT 
 
LIST of ABBREVIATIONS .................................................................................................................................. 8 
STATEMENT OF COMPLIANCE 
10 
Protocol Summary 
11 
Synopsis 
11 
1. 
Introduction 
19 
1.1 
Background information ......................................................................................................................... 19 
1.1.1 
Pathology epidemiology 
19 
1.1.2 
Prognosis 
19 
1.1.3 
Investigational medicinal products (IMP) 
19 
1.2 
Trial rationale .......................................................................................................................................... 20 
1.3 
Justification for the therapeutic regimens and treatment durations ....................................................... 21 
1.4 
Potential risks and benefits .................................................................................................................... 22 
1.4.1 
Known potential risks 
22 
1.4.2 
Known potential benefits 
23 
1.5 
Trial population ....................................................................................................................................... 24 
2. 
TRIAL OBJECTIVES 
24 
2.1 
Primary objective .................................................................................................................................... 24 
2.2 
Secondary objective(s) ........................................................................................................................... 24 
3. 
Trial DESIGN and endpoints 
24 
3.1 
Description of the trial Design ................................................................................................................ 24 
3.2 
Trial Endpoints ........................................................................................................................................ 24 
3.2.1 
Primary endpoint 
24 
3.2.2 
Secondary endpoint(s) 
25 
3.3 
Progression of the trial ........................................................................................................................... 25 
3.4 
Randomisation procedure ...................................................................................................................... 26 
3.5 
Premature Trial Terminations and Suspension ...................................................................................... 26 
3.6 
Patient’s trial withdrawal and discontinuation ......................................................................................... 26 
4. 
PATIENT SELECTION 
27 
4.1 
Diagnosis and inclusion criteria .............................................................................................................. 27 
4.2 
Non-inclusion criteria .............................................................................................................................. 27 
5. 
TRIAL treatments/interventions 
28 
5.1 
Description of trial treatments/interventions ........................................................................................... 28 
5.2 
Acquisition, reception, and storage ........................................................................................................ 29 
5.3 
Trial treatments accountability, return and destruction .......................................................................... 29 
5.4 
Formulation, appearance, packaging, and labelling ............................................................................... 30 
5.5 
Preparation ............................................................................................................................................. 30 
5.6 
Conditions for stopping the treatment .................................................................................................... 30 
5.7 
Patients’ discontinuations of treatment................................................................................................... 30 
5.7.1 
Delays cycles of chemotherapy- or rules for dose omissions and modified schedules 
30 
5.7.2 
Dose adaptation 
31 
5.7.3 
Doses modifications tables for hematologic toxicity 
31 
5.7.4 
Doses modifications tables for non- hematologic toxicity 
32 
5.8 
Concomitant medications and therapies ................................................................................................ 33 
5.8.1 
Authorised concomitant treatments 
33 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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5.8.2 
Prohibited concomitant treatments 
33 
5.8.3 
Rescue medications and therapies/Treatment at disease progression 
33 
5.8.4 
Contraception during the trial 
34 
6. 
EVALUATION OF TREATMENT EFFICACY AND SAFETY 
35 
6.1 
Efficacy evaluation.................................................................................................................................. 35 
6.2 
Safety evaluation .................................................................................................................................... 35 
6.3 
Centralised review .................................................................................................................................. 35 
7. 
DESCRIPTION OF VISITS AND INVESTIGATIONS 
35 
7.1 
Baseline visit ........................................................................................................................................... 35 
7.2 
Visits and assessment during treatment period ..................................................................................... 36 
7.3 
End-of-treatment visit ............................................................................................................................. 37 
7.4 
Follow-up ................................................................................................................................................ 37 
7.5 
Provisions in case of treatment or trial interruption ................................................................................ 38 
8. 
REPORTING OF ADVERSE EVENTS 
38 
8.1 
Adverse event: general definition ........................................................................................................... 38 
8.2 
Serious adverse event: general definition .............................................................................................. 38 
8.3 
Measures to be taken in case of a serious adverse event ..................................................................... 39 
9. 
ANCILLARY/translational STUDY(IES) 
41 
10. Description of STATISTICAL methods 
42 
10.1 Statistical hypothesis and sample size determination ............................................................................ 42 
10.2 Trial populations to be analysed ............................................................................................................. 42 
10.3 Planned statistical analysis .................................................................................................................... 42 
10.3.1 
General considerations 
42 
10.3.2 
Primary endpoint 
43 
10.3.3 
Secondary  endpoints 
43 
11. OVERSIGHT COMMITTEES 
44 
11.1 Independent data monitoring committee ................................................................................................ 44 
11.2 Steering Executive Committee ............................................................................................................... 45 
12. QUALITY ASSURANCE 
45 
12.1 Data collection ........................................................................................................................................ 45 
12.2 Access to data ........................................................................................................................................ 46 
12.3 Trial monitoring ....................................................................................................................................... 46 
12.4 Audits and inspections ........................................................................................................................... 47 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
48 
13.1 General requirements ............................................................................................................................. 48 
13.2 Patient identification ............................................................................................................................... 48 
13.3 Patient information and consent ............................................................................................................. 48 
13.4 Insurance compensation ........................................................................................................................ 49 
13.5 Investigator responsibilities .................................................................................................................... 49 
13.6 Federation of the Patient Committees for Clinical Research in Cancerology ........................................ 50 
13.7 Human biological samples collection ..................................................................................................... 50 
13.7.1 
Collecting additional biological samples for research purpose 
50 
14. DATA PROCESSING AND CONSERVATION OF DOCUMENTS AND DATA 
OF THE RESEARCH 
51 
14.1 Data processing ...................................................................................................................................... 51 
14.1.1 
Under the responsibility of the sponsor 
51 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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14.1.2 
In the investigational centre, when computerised medical records are used 
51 
14.2 Retention of documents by investigator sites ......................................................................................... 52 
15. DATA OWNERSHIP AND CONFIDENTIALITY 
52 
16. PUBLICATION RULES 
53 
17. REFERENCES 
54 
18. APPENDICES 
55 
Appendix 1. 
Performance status evaluation – WHO scale ......................................................................... 56 
APPENDIX 2. 
ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) ......................... 57 
Appendix 3. 
A brief summary of tumour classification RECIST v1.1 .......................................................... 58 
Appendix 4. 
Toxicity criteria (NCI-CTCAE) ................................................................................................. 61 
Appendix 5. 
Patient questionnaire(s) .......................................................................................................... 62 
Appendix 6. 
Summary of product characteristics (SmPC) .......................................................................... 63 
Appendix 7. 
Modified Glasgow Prognostic Score for Cancer Outcomes: Calculation method .................. 64 
 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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LIST of ABBREVIATIONS 
 
 
AE 
Adverse event 
ANSM 
Agence nationale de sécurité du médicament et des 
produits de santé 
ALAT, ALT (SGPT) 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
ASAT, AST (SGOT) 
Aspartate aminotransferase 
CBC 
Complete blood count 
CDA 
Cytidine deaminase 
CEA 
Carcinoembryonic antigen 
CPP 
Comité de protection des personnes 
CR 
Complete response 
CRF 
Case report form 
CRA 
Clinical research associate 
CSR 
Comité stratégique recherche 
CTCAE 
DCF 
DCR 
DNA 
Common terminology criteria for adverse events 
Data correction form 
Disease control rate 
Deoxyribonucleic acid 
EC 
Ethic committee 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
Ecrf 
EDTA 
Electronic case report form 
Ethylene diamine tetra acetic 
EMA 
European medicines agency 
EORTC 
 
European organisation for research and treatment of 
cancer 
ESDO 
ESMO 
European Society of digestive Oncology 
European Society for Medical Oncology 
G 
Gram 
GCP 
G-CSF 
Good clinical practice 
Granulocyte-Colony Stimulating Factor 
GGT 
HIV 
Gamma-glutamyl transferase 
Human Immunodeficiency virus 
HR 
Hazard ratio 
Hb 
Haemoglobin 
ICH 
International conference on harmonisation 
IDMC 
IEC 
Independent data monitoring committee 
Independent Ethic Committee 
IMF 
Investigator master file 
IMF-P 
Investigator master file-pharmacy 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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IMP 
Investigational medicinal products 
INN 
International non-proprietary name 
INR 
IRB 
International normalised ratio 
Institutional review board 
ITT 
Intent-to-treat 
IV 
Intravenous 
L 
Litre 
LDH 
MCID 
lactate dehydrogenase 
Minimal clinically important difference  
Mg 
milligram(s) 
Min 
minute(s) 
Ml 
millilitre(s) 
NCI 
NLR 
National cancer institute 
Neutrophil to Lymphocyte rate 
OS  
ORR 
PD 
PDAC 
Overall survival 
Objective response rate 
Progression disease 
Pancreatic ductal adenocarcinoma  
PR 
PS 
Partial response 
Performance status 
PFS 
Progression-free survival 
PTT 
Partial thromboplastin time 
QLQ 
Quality of life questionnaire 
QoL 
RBC 
Quality of life 
Red blood cell count 
RECIST 
Response evaluation criteria in solid tumours 
SAE 
Serious adverse event 
SAP 
SAR 
Statistical Analysis Plan 
Serious adverse reaction 
SD 
SUSAR 
Stable disease  
Suspected unexpected serious adverse reaction 
SmPC 
Summary of product characteristics 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
WBC 
WHO 
White blood cell 
World health organisation 
 
 
 
 
 
 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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STATEMENT OF COMPLIANCE 
 
 
UNICANCER, the trial sponsor, certifies that the trial GEMPAX will be conducted in compliance with the 
protocol described in this document, and in accordance with the French national regulatory requirements: 
 
 
Declaration of Helsinki, as modified in 2008, 
 
Loi n°2012-300 du 5 mars 2012 relative aux recherches impliquant la personne humaine, as modified 
in 2016 
 
Regulation (EU) 2016/679  on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data (General Data Protection Regulation) 
 
Loi Informatique et Libertés n°78-17 du 6 janvier 1978 modifiée, relative à la protection des personnes 
physiques à l'égard des traitements de données à caractère personnel, 
 
Loi n° 2004-800 du 6 août 2004 modifiée, relative à la bioéthique,  
 
Décision du 24 novembre 2006 fixant les règles de Bonnes Pratiques Cliniques pour les recherches 
biomédicales portant sur des médicaments à usage humain 
 
Arrêté du 24 mai 2006 relatif au contenu et aux modalités de présentation d’un protocole de recherche 
biomédicale portant sur un médicament à usage humain 
 
Good Manufacturing Practices, in particular, Annex 13 on investigational medicinal products. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the ethics committee (EC) for review and approval. Approval of both the protocol and the consent form will 
be obtained before any participant is included. Any amendment to the protocol will require review and approval 
by the EC before the changes are implemented in the study. In addition, all changes to the consent form will 
be EC-approved. Depending on the consent form modifications a decision will be made whether a new consent 
is required for patients who have already given consent. 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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PROTOCOL SUMMARY 
 
Synopsis 
 
A) TRIAL IDENTIFICATION 
Sponsor – protocol code number: PRODIGE 65 – UCGI 36 
Version (Number & date): V6  13 JULY 2023 
Trial title: A Phase III randomized study evaluating gemcitabine and paclitaxel versus gemcitabine 
alone after FOLFIRINOX failure or intolerance in metastatic pancreatic ductal adenocarcinoma. 
 
Abbreviated title: GEMPAX 
Coordinating investigator: Dr. Christelle de La Fouchardière 
Number of centres: 35 
Number of patients: 210 
 
B) SPONSOR IDENTIFICATION 
Name:  
UNICANCER 
101, rue de Tolbiac 
75654 Paris Cedex 13 
(France) 
Contact person: 
Mme Emilie BRUMENT 
Project Manager 
UNICANCER 
Tel: +33 (0)1 71 93 61 64 
Fax: + 33 (0)1 44 23 55 69 
email: e-brument@unicancer.fr 
 
C) TRIAL GENERAL INFORMATION 
Indication:  Metastatic Pancreatic Ductal Adenocarcinoma 
Trial description/design:  
A phase III, Randomized open label, comparative multicentric phase III trial comparing  gemcitabine + 
paclitaxel vs gemcitabine alone after FOLFIRINOX failure or intolerance 
Primary objective:   
The main objective of this study is to evaluate the superiority in terms Overall Survival (OS) of 
gemcitabine + solvent-based (sb)-paclitaxel over gemcitabine alone in metastatic pancreatic ductal 
adenocarcinoma after FOLFIRINOX failure or intolerance. 
Secondary objectives: 
The secondary objectives are the evaluation of: 
 The efficacy of the treatments in terms of: 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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 
Objective Response rate (according to RECIST 1.1) (ORR) 
 
Progression-Free Survival (PFS) 
 
Disease Control Rate at 4 months (4m-DCR) 
 Prognostic and predictive values of several biomarkers (Ca 19-9, CEA, neutrophil to 
lymphocyte ratio, albumin, modified Glasgow prognostic score) 
 Dose intensity of chemotherapy 
 Safety and tolerability of treatment (NCI-CTCAE version 5.0) 
 The effect of treatments on Quality of Life 
 The rate of subsequent chemotherapy (after progression) 
 Potential new biomarkers that may provide relevant information for clinicians as to whether the 
patients benefit from chemotherapy and to study the biomarkers dynamics across time and 
their association with primary and secondary endpoints of the trial.  
DIAGNOSIS AND INCLUSION CRITERIA:  
1. Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma 
(PDAC). 
2. Age ≥18 years old. 
3. At least one evaluable lesion according to RECIST 1.1 (Response Evaluation Criteria in Solid 
Tumors) outside any previously irradiated area. 
4. Failure of first line FOLFIRINOX therapy due to progressive disease during or within 3 months 
(+/- 15 days) after the end of therapy (including mFOLFIRINOX in adjuvant setting) or patient 
with FOLFIRINOX intolerance 
5. Performance Status (PS) ECOG 0 to 2. 
6. Life expectancy ≥12 weeks. 
7. Negative serology (HIV, hepatitis B and C) 
8. Adequate organs function: 
 Absolute neutrophils count ≥1.5x109/L 
 Platelets count ≥100x109/L 
 Haemoglobin ≥9 g/dl 
 Serum bilirubin levels <2 times upper limit of normal (ULN), up to 2.5 times ULN in case of 
hepatic metastasis (biliary drainage allowed) 
 Transaminases <5 times ULN. 
9. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female 
pre-menopausal patients. 
10. Woman of childbearing potential and male patients must agree to use adequate contraception 
for the duration of trial participation and up to 6 months after completing treatment/therapy 
11. Patients affiliated to the social security system 
12. Patient must have signed a written informed consent form prior to any trial specific procedures 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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NON-INCLUSION CRITERIA:  
1. Any other primary tumor or secondary malignancy except basal cell carcinoma of the skin or in 
situ carcinoma of the cervix uteri (patients adequately treated for other malignancies and 
without tumor during the last 5 years are eligible). 
2. Known cerebral metastasis. 
3. Uncontrolled severe infections. 
4. Patients with Kaposi’s sarcoma 
5. Peripheral neuropathy exceeding CTCAE (Common Terminology Criteria for Adverse Events) 
v5.0 grade 2. 
6. Previous treatment with taxane and/or gemcitabine. Patients treated with taxane and/or 
gemcitabine for another cancer are eligible.  
7. Patients with known allergy or severe hypersensitivity to any of the trial drugs or any of the trial 
drug excipients 
8. Patients with any other disease or illness which requires hospitalisation or is incompatible with 
the trial treatment.  
9. Patients unable to comply with trial obligations for geographic, social, or physical reasons, or 
who are unable to understand the purpose and procedures of the trial. 
10. Participation in another clinical trial within 14 days prior to randomization. 
11. Patients deprived of liberty or under legal protection measure(s) or patients whose willingness 
to participate in this clinical trial may be unduly influenced  
PRIMARY ENDPOINT: Overall survival (OS), defined as the time from date of randomization to the date of 
death from any cause. If a patient is alive at the database cut-off date, then the patient will be censored 
at the last date of follow-up 
SECONDARY ENDPOINT(S): 
 Efficacy objective: 
 
ORR (according to RECIST 1.1 criteria) defined as the percentage of patients with 
Complete Response (CR) or Partial Response (PR). Patients who discontinue 
treatment without a tumour assessment will be considered non-responders for the 
analysis 
 
PFS defined as the time from the date of randomisation to date of disease progression 
(radiological or clinical) or death from any cause, whichever occurs first. Patients 
without tumour progression or death at the time of analysis will be censored at the date 
of their last tumour assessment. 
 
4m-DCR is defined as proportion of patients with CR, PR, or a stable disease (SD), 4 
months after treatment initiation. 
 Value of biomarkers (Ca 19-9, CEA, Lymphocyte to Neutrophil ratio, albumin, modified 
Glasgow prognostic score) will be described by absolute or relative variation from baseline. To 
assess their prognostic or predictive values, baseline values of these biomarkers will be tested 
using Cox or logistic regression models.  
 Dose intensity of chemotherapy will be calculated from doses actually given instead of from 
targeted doses. Ratio between dose received compared to theoretical ones will be calculated 
by patient and presented as a percentage. 
 Safety and tolerability of treatment (NCI-CTCAE version 5.0) determined through the incidence 
of adverse events, treatment related adverse events, serious adverse Events (SAE), and 
death.  

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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D) INVESTIGATIONAL MEDICINAL PRODUCTS 
PRODUCT NAMES AND ADMINISTRATION:  
Drug name (INN) 
Registered name(1) 
Pharmaceutical 
form 
Administration route 
Posology 
 
Gemcitabine 
 
Powder for solution 
for IV injection 
 
intravenous  (IV) 
 
1000 mg/m2 
 
Drug name (INN) 
Registered name(1) 
Pharmaceutical 
form 
Administration 
Posology 
 
Paclitaxel 
 
 
Solution for 
injection 
 
intravenous  (IV) 
 
80 mg/m2 
(1) When any generic drug can be/is used indicate only the INN name. The choice of the registered 
name or brand name used in the trial is at the investigation centre discretion. 
THERAPEUTIC REGIMENS: 
 
Arm A : Experimental group 
GEMPAX (D1=D29) : 
Paclitaxel 80 mg/m² in IV infusion over 60 minutes at D1, D8 and D15 followed by 1 week of rest, every 
28 days. 
Gemcitabine 1000 mg/m² in IV infusion over 30-40 minutes at D1, D8, D15 followed by 1 week of rest, 
every 28 days.  
 
At each infusion day, paclitaxel will be administered before gemcitabine. 
 
 
Arm B : Control group 
GEM (D1=D29) : 
Gemcitabine 1000 mg/m² in IV infusion over 30-40 minutes at D1, D8, D15 followed by 1 week of rest, 
every 28 days. 
 
TREATMENT DURATION: 
The patient will be randomized in one of the two treatments arms and will receive their treatment 
every 28 days until disease progression, toxicity or patient’s decision. 
 
 
 
 Quality of life (EORTC QLQ-C30) during treatment. A deterioration of scores for five-targeted 
dimensions: pain, physical and emotional functioning, fatigue, and appetite will be compared 
between the two treatment arms, while other dimensions will be regarded as exploratory. 5-
point deterioration in HRQoL scores will be considered as the minimal clinically important 
difference (MCID). 
 Rate of subsequent chemotherapy (after progression). The type and the date of beginning of 
first-cycle of each line will be collected.  
 Translational research to identify biomarkers predictive of response in this clinical context 

 
 
 
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E) STATISTICAL ANALYSIS PLAN 
 
REQUIRED NUMBER OF PATIENTS TO BE SCREENED/INCLUDED: 210 
STATISTICAL ANALYSIS: 
 
The GEMPAX study was calibrated to detect a treatment effect hazard ratio (HR) of 0.625, translating 
in an improvement in median OS from 5 months (control arm: GEM) to 8 months (experimental arm: 
GEMPAX), with a 2:1 randomization.  
 
A total of 184 events in the study (deaths) would have 85% power to show statistically significant OS 
at a 2-sided 5% alpha (including one interim analysis of superiority according to OS spending function). 
Considering a recruitment duration of 24 months and a 12-months follow-up for the last included patient 
(total duration for the study: 36 months), 210 patients will be randomized in the study (70 patients in 
the control arm and 140 patients in the experimental arm). One interim analysis of efficacy after half of 
the planned events have occurred will be done. An independent data monitoring committee (IDMC) will 
review this analysis. In order to strongly control the type I error the Lan and DeMets approach that 
approximates the O’Brien and Fleming spending function will be used (Lan and DeMets 1983). The 2-
sided significance level at the interim analysis will be calculated based on the number of events 
occurred at the interim analysis.  
 
 
 
 
 
 
 
 
 
 

 
 
 
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F) SAMPLES COLLECTED FOR TRANSLATIONAL RESEARCH 
SAMPLE TYPES: Blood  Sample and archived tumour tissues 
 
SAMPLE QUANTITIES: 30 mL of blood (5 EDTA tubes of 6 mL) collected at day 1 and day 15 of cycle 1 
and at disease progression (total: 90 mL of blood collected per patient) 
 
ARCHIVED TUMOUR TISSUES: Archived tumor tissues available will be collected for analysis (frozen 
and/or FFPE tissues).  
 
 
 
 
G) TRIAL DURATIONS 
INCLUSION PERIOD: 24 MONTHS  
TRIAL TREATMENT PERIOD:  6 MONTHS (ESTIMATE) 
FOLLOW-UP:  6 MONTHS (ESTIMATE) 
DURATION UNTIL PRIMARY ENDPOINT EVALUATION: 20 MONTHS 
OVERALL TRIAL DURATION (INCLUDING FOLLOW-UP): 36 MONTHS 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
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EudraCT n°: 2018-002886-21 
 
 
 
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Section H: Trial flow chart 
 
 
Baseline 
Visits during study treatment 
End of Treatment 
(EOT) visit 
Follow-up 
 
Within 14 days prior to first 
study treatment. Imagery 
can be done within 28 days 
prior to first study treatment  
Cycle 1 
Cycles 2, 3, 4, etc. 
35 days (±5 days) 
after last study 
treatment injection 
Every 8 weeks after 
EOT. Every 12 weeks 
after progressive 
disease   
 
D1 
D8 
D15 
D1 
D8 
D15 
Consent signature 
x 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
 
 
Randomization 
x 
 
 
 
 
 
 
 
 
Diagnosis & prior anticancer therapies 
x 
 
 
 
 
 
 
 
 
Demographics, Medical history & signs and symptoms 
x 
 
 
 
 
 
 
 
 
Prior medication & concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
 
Clinical exam (physical exam, PS) + vital signs1  
x 
x 
 
 
x 
 
 
x 
x6 
Neurological exam (peripheral neuropathy evaluation)8 – only for Arm A 
 
x 
 
 
x 
 
 
x 
 
Modified Glasgow Prognostic Score evaluation7 
x 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
 
 
 
 
 
 
 
Serology (HIV, hepatitis B/C) 
x 
 
 
 
 
 
 
 
 
Pregnancy test (as applicable) 
x 
 
 
 
 
 
 
 
 
Complete Blood Count2  
x 
x 
x 
x 
x 
x 
x 
x 
 
Coagulation factors3 
x 
x 
 
 
x 
 
 
x 
 
Serum chemistries4 
x9 
x 
x5 
x5 
x 
x5 
x5 
x 
 
Tumor biomarkers CEA & CA19-9 (every 8 weeks from D1C3, till 
disease progression) 
x 
 
 
 
x 
 
 
x 
x 
CT-Scan (Thorax, Abdomen, Pelvis)  
(every 8 weeks from D1C3, till disease progression) 
x 
 
 
 
x 
 
 
x 
x 
QoL questionnaire (EORTC QLQ-C30) 
(every 8 weeks from D1C3 till disease progression) 
x 
 
 
 
x 
 
 
x 
x 
Optional procedures if patient consented to translational research 
Blood sample (5 EDTA tubes of 6 mL) 
 
x 
 
x 
x (at disease progression) 
Archived tumor material preparation and shipment 
x 
1) Vital signs : height, weight, blood pressure, pulse, body temperature. Height only at baseline.  

 
 
 
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2) CBC: hemoglobin, RBC counts, WBC and differential (neutrophils, eosinophils, basophils, monocytes, lymphocytes), platelets 
3) Coagulation factors: partial thromboplastin time (PTT), fibrin, prothrombin ratio, sedimentation rate   
4) Serum chemistries: Na, Ca, P, Mg, K, Cl, HCO3-, creatinine, urea, creatinine clearance, total protein, albumin, glucose, alkaline phosphatase, total bilirubin, conjugated bilirubin (as appropriate), AST, 
ALT, LDH, γGT 
5) Serum chemistries at days 8 and 15 of each cycle: only urea and creatinine 
6) During FUP visits: only physical examination and evaluation of PS (vital signs are not to be done) 
7) Modified Glasgow Prognostic Score calculation method: see Appendix 7 
8) Neurological exam for the evaluation of peripheral neuropathy related to paclitaxel is to be done only in Arm A (gemcitabine + paclitaxel) 
9) Serum  chemistries at baseline, in addition to the parameters reported at item 4), must also include the C-reactive protein to allow modified Glasgow prognostic score calculation. Regarding inclusion 
criteria n°8, total bilirubin only can be done to confirm eligibility. Nevertheless, if total bilirubin at baseline is abnormal but remains < x 2 ULN (or < x 2.5 ULN in case of liver metastases), conjugated bilirubin 
must be done and be < x 2 ULN (or < x 2.5 ULN in case of liver metastases) to confirm eligibility.

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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1. INTRODUCTION 
 
 
1.1 Background information 
 
1.1.1 Pathology epidemiology 
 
A recent study estimating cancer epidemiology in 2014 (within Europe) showed that pancreatic cancer was 
the fourth most common cause of cancer-related death in men after lung, colorectal, and prostate cancers, 
and in women after breast, colorectal and lung cancers. With a life expectancy of ~5% at 5 years, the prognosis 
of this cancer has not improved over the past 20 years, and incidence and mortality rates are very similar. 
Death due to pancreatic carcinoma is increasing in Europe with the number rising from 75 439 in 2009 to a 
projected 82 300 deaths in 2014 (+19%). Pancreatic adenocarcinoma is expected to be the second leading 
cause of cancer-related mortality in 2020. 
 
We designed this clinical trial in order to evaluate prospectively the efficacy and the tolerance of sb-paclitaxel 
in association with gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC). Indeed, few 
prospective data exist concerning the role of taxanes in PDAC. Nab-paclitaxel monotherapy has been 
prospectively and successfully evaluated in the first-line metastatic setting but it is not reimbursed in France. 
A recent small phase II study reported prolonged overall survival for the combination of oxaliplatin and 
docetaxel after gemcitabine failure. The use of taxanes was also suggested by the results of previous 
retrospective trials. With the hypothesis that paclitaxel is as efficient as nab-paclitaxel, our goal is to establish 
a standard treatment after FOLFIRINOX failure or intolerance, and to work around the reimbursement gap for 
nab-paclitaxel. 
 
1.1.2 Prognosis 
 
Prognosis of PDAC is dismal with a life expectancy below 5% after 5 years [22]. 
 
1.1.3 Investigational medicinal products (IMP) 
 
Gemcitabine (Gemzar®) (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an analogue of 
deoxycytidine. It was initially synthesized as a potential antiviral drug but selected for anticancer development 
because of its activity in in-vivo and in-vitro tumors. Gemcitabine is approved for the treatment of patients with 
pancreatic cancer and will be obtained commercially and relabeled as clinical supplies. Gemcitabine should 
be stored, reconstituted and administered according to the manufacturer’s recommendation. Gemzar is for 
intravenous use only. In pancreatic Cancer it is used at 1000 mg/m2 over 30 minutes once weekly for the first 
7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle. For further details, see the 
most recent version of the summary of product characteristics (SmPC) for gemcitabine. 
 
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and 
stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal 
dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular 
functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle 
and multiple asters of microtubules during mitosis.  TAXOL (paclitaxel) Injection is a clear, colourless to slightly 
yellow viscous solution. It is supplied as a non-aqueous solution intended for dilution with a suitable parenteral 
fluid prior to intravenous infusion. TAXOL is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) 
multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified 

 
 
 
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Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. For further details, 
see the most recent version of the SmPC for Paclitaxel.  
 
 
1.2 Trial rationale 
 
Chemotherapy is the mainstay of treatment for advanced PDAC. While gemcitabine remained the standard 
first-line agent for 15 years, Folfirinox has become, since 2011, the standard of care in the first-line metastatic 
setting for patients with normal bilirubin levels and a good performance status (ECOG-PS of 0 or 1). In the 
phase III PRODIGE4/ACCORD11 trial, patients receiving Folfirinox achieved a median overall survival of 11.1 
months vs 6.8 months in patients who received gemcitabine (hazard ratio (HR)=0.57; 95%CI [0.45–0.73]; 
P<0.001) [1]. Two years later, comparable results have been achieved (over gemcitabine monotherapy) by 
the combination of gemcitabine plus nab-paclitaxel (nanoparticle albumin-bound paclitaxel), with a median OS 
of 8.5 months in the gemcitabine-nab-paclitaxel group compared with 6.7 months in the gemcitabine group 
(HR=0.72; 95%CI [0.62-0.83]; p<0.001) [2]. In a comparative cost-analysis study, Goldstein et al showed that 
the most-costly regimen was the gemcitabine plus nab-paclitaxel combination when compared with Folfirinox 
or gemcitabine alone [3]. In France, Folfirinox is the preferred first-line regimen in metastatic, good general 
status PDAC patients. After its failure, about half of the patients receive a second-line chemotherapy, mainly 
gemcitabine-based, as recommended by the ESMO-ESDO current clinical practice guidelines [4].  
No prospective studies have evaluated second-line therapy for metastatic pancreatic cancer at progression 
after Folfirinox or gemcitabine plus nab-paclitaxel chemotherapy. The benefit of second-line treatment derives 
from a meta-analysis of clinical trials comparing second-line chemotherapy with best supportive care alone 
favoring chemotherapy, leading to a 6 months-median OS compared with 2.8 months with best supportive 
care [5]. The extrapolation of 3 randomized clinical trials in patients with metastatic pancreatic cancer that 
progressed on first-line gemcitabine represent also a basis from current recommendations [6]. Two of these 
studies used 5-fluorouracile (5FU) plus oxaliplatin and showed conflicting results about the benefits of adding 
oxaliplatin to 5FU in the second-line setting (CONKO-003 and PANCREOX) [7,8]. The NAPOLI-1 study 
recently demonstrated the interest of nanoliposomal irinotecan, in combination with fluorouracil plus folinic acid 
with a significant improvement of median OS (6.1 versus 4.2 months), PFS and ORR in the intent-to-treat 
population over fluorouracil/folinic acid alone [9]. Interestingly, nab-paclitaxel has been used in the second-line 
setting in small retrospective and prospective cohort studies, showing that gemcitabine-nab-paclitaxel was 
effective and well tolerated [10,11]. In the prospective cohort, median overall and progression free survivals 
were 8.8 (95%CI [6.2–9.7]) and 5.1 months (95%CI [3.2–6.2]) respectively and only few patients (7/57 = 
12.5%) had to stop nab-paclitaxel permanently because of peripheral neurotoxicity despite previous treatment 
with oxaliplatin. However, these results do not provide enough information regarding the management of tumor 
progression after first-line Folfirinox and prospective data are strongly needed [12]. 
Nab-paclitaxel is a solvent-free albumin-stabilized nanoparticle formulation of paclitaxel (solvent-based 
paclitaxel, sb-paclitaxel), developed to improve the solubility of paclitaxel and avoid infusion-related reactions 
associated with sb-paclitaxel. It shares the same mechanism of action of other taxanes family's members, 
mainly sb-paclitaxel and docetaxel, by targeting tubulin. Its superiority over sb-paclitaxel has never been 
demonstrated whether in breast or gastric cancers [11, 12]. Furthermore, no significant differences of grade 3 
to 4 hematological and non-hematological toxicities was showed in a meta-analysis in metastatic breast cancer 
recently published by Liu et al, except a more prominent sensory neuropathy for nab-paclitaxel-based 
chemotherapy (16.9% vs. 10.0%, OR = 1.89, 95% CI =1.36–2.61, P < 0.001; I2 = 42.5%) [13]. Identically, in 
the randomized, non-inferiority phase 3 trial in gastric cancer, weekly nab-paclitaxel was non-inferior to weekly 
sb-paclitaxel (hazard ratio 0.97, 97.5% CI 0.76–1.23; non-inferiority one-sided p=0.0085). However, as in 
breast cancer, the toxicity profile favored sb-paclitaxel with less grade 3 neutropenia and febrile neutropenia 
(g3 neutropenia: 29% vs 65%; febrile neutropenia: 1% vs 12%) and less neuropathy (2% vs 20%). As 

 
 
 
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expected, only the hypersensitivity reactions rate was superior in sb-paclitaxel arm, (5% vs 1%). A 
pharmacokinetic rationale exists to combine paclitaxel and gemcitabine as paclitaxel inhibits cytidine 
deaminase (CDA), the enzyme responsible for the liver inactivation of gemcitabine. Administration of paclitaxel 
combined with gemcitabine results in an increased intratumoral accumulation of gemcitabine [15–17]. In 2013, 
following the MPACT study's results, nab-paclitaxel became a new treatment option for patients with metastatic 
pancreatic cancer in the first-line setting. It also brought up to date the potential utility of taxanes in the 
treatment of PDAC. However, only few studies examined prospectively the efficacy of paclitaxel or docetaxel 
in metastatic PDAC and mainly after first-line gemcitabine's failure [18,19]. However, in contrast to breast and 
gastric cancer, no comparative data with sb-paclitaxel are available in PDAC. France and United Kingdom 
authorities consider that nab-paclitaxel provides a minor improvement of medical benefit in metastatic PDAC 
compared to the high cost supported by the society. Thereby, this drug has been registered but is not 
reimbursed by Social Security in France and has to be paid by the hospitals on their own resources. This 
decision has led to disparities in the management of patients, the vast majority of hospitals being unable to 
finance the treatment.  
 
Based on the lack of prospective second-line studies in metastatic PDAC, the similar mechanism of action 
between nab- and sb- paclitaxel (stabilization of microtubules), and a lower cost of sb-paclitaxel, we propose 
to set up a phase III trial, comparing gemcitabine versus gemcitabine + sb-paclitaxel in metastatic PDAC 
patients after Folfirinox failure or intolerance. 
 
 
 
1.3 Justification for the therapeutic regimens and treatment durations 
 
Previous studies have shown the efficacy and the tolerance of weekly paclitaxel and gemcitabine in particular 
in non-small cell lung and bladder cancers administrated 3 weeks/4 at 80 mg/m² for paclitaxel and 1,000 mg/m² 
for gemcitabine. 
 
During this trial, the drug will be administrated as indicated below: 
 
Experimental group 
GEMPAX (D1=D29): 
Gemcitabine 1000 mg/m² in IV infusion over 30-40 minutes at D1, D8, D15 followed by 1 week of rest, every 
28 days.  
 
Paclitaxel 80 mg/m² in IV infusion over 60 minutes at D1, D8 and D15 followed by 1 week of rest, every 28 
days. A premedication to prevent hypersensitivity reactions (e.g., dexamethasone, diphenhydramine, H2 
blockers) will be applied according to the Summary of Products Characteristics. Initial antiemetic prophylaxis 
is also recommended. 
 
Secondary prophylaxis of neutropenia (G-CSF) for weekly chemotherapy is not planned in EORTC 
recommendations. Center’s practices will be applied. Of note, the coordinator of the study is used to prescribe 
successfully pegylated G-CSF (pegfilgastrim=Neulasta®) on D1 and D15 of each cycle according to other 
published experience for weekly chemotherapy schedules [20]. 
 
At each infusion day, paclitaxel will be administered before gemcitabine. 
 
Control group 

 
 
 
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GEM (D1=D29): 
Gemcitabine 1000 mg/m2 in IV infusion over 30-40 minutes at D1, D8, D15 followed by 1 week of rest, every 
28 days.  
 
 
 
1.4 Potential risks and benefits 
 
 
1.4.1 
Known potential risks 
 
 
Know potential risks with gemcitabine 
 
The following adverse drug reactions are observed in patients treated with gemcitabine: 
 
 Very common (incidence ≥1/10 patients): leucopenia, thrombocytopenia, anaemia, dyspnea, nausea, 
vomiting, increases in transaminases (ASAT, ALAT, phosphatase alkaline), cutaneous eruption, 
alopecia, haematuria, proteinuria, flu-like syndrome, peripheral oedema   
 Common (≥1/100 but 1/10): febrile neutropenia, anorexia, headaches, insomnia, somnolence, cough, 
rhinitis, diarrhoea, stomatitis and mouth ulcers, constipation, bilirubin increase, sweating, pruritis, 
myalgia, dorsal pain, fever, asthenia, shivers 
 Uncommon (≥1/1000 but 1/100): interstitial pneumonia, bronchospasm. 
 Rare (≥1/10 000 but 1/1000): myocardial infarction, hypotension, GGT increase, ulceration, shedding, 
injection site reaction 
 Very rare (<1/10 000): thrombocytosis, anaphylactic reaction, severe cutaneous reaction 
 
The main dose-limiting toxicity is the haematological toxicity with leucopenia, thrombocytopenia and anaemia. 
The patients treated with gemcitabine must have complete blood counts before each injection. Dose adaptation 
must be considered when such toxicities occur.  
 
For further details, see the most recent version of the summary of product characteristics (SmPC) for 
gemcitabine. 
 
 
Know potential risks with paclitaxel 
 
The following adverse drug reactions are observed in patients treated with paclitaxel: 
 
 Very common (incidence ≥1/10 patients): infection, myelosuppression, bleeding, hypersensitivity 
reaction, neurotoxicity, hypotension, bradycardia, diarrhoea, nausea, vomiting, mucosal inflammation, 
alopecia, arthralgia, myalgia 
 Common (≥1/100 but 1/10): injection site reaction, slight and temporary changes of skin and nails, 
severe ASAT and phosphatase alkaline increase 
 Uncommon (≥1/1000 but 1/100): severe bilirubin increase, thrombosis, hypertension, tachycardia, 
cardiomyopathy, syncope with atrio ventricular block, myocardial infarction, heart failure, 
hypersensitivity reactions requiring treatment, septic shock 
 Rare (≥1/10 000 but 1/1000): pneumonia, peritonitis, sepsis, febrile neutropenia, anaphylactic 
reaction, motor neuropathy, pulmonary embolism, interstitial pneumonia, pleural effusion, dyspnea, 
respiratory failure, pulmonary fibrosis, pancreatitis, ischemic colitis, intestinal occlusion, intestinal 

 
 
 
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perforation, rash, pruritus, erythema, increased creatinaemia, pyrexia, dehydration, asthenia, oedema, 
fainting 
 Very rare (<1/10 000): acute myeloid leukaemia, myelodysplastic syndrome, anaphylactic shock, 
anorexia, mental confusion, autonomous neuropathy, tonic-clonic seizure, encephalopathy, ataxia, 
headaches, seizure, dizziness, visual troubles, ototoxicity, vertigo, tinnitus, hearing loss, 
supraventricular tachycardia, auricular fibrillation, vascular shock, cough, mesenteric thrombosis, 
ascites, constipation, oesophagitis, colitis, hepatic necrosis, hepatic encephalopathy, Stevens-
Johnson syndrome, onycholysis, urticarial, multiform erythema, epidermic necrolysis   
 
The main dose-limiting toxicity is the haematological toxicity (mainly neutropenia). The patients treated with 
paclitaxel must have complete blood counts before each injection. Dose adaptation must be considered when 
such toxicities occur. Neurotoxicity will also be carefully monitored. 
 
For further details, see the most recent version of the summary of product characteristics (SmPC) for paclitaxel. 
 
 
Know potential risks with gemcitabine combined with paclitaxel 
 
The gemcitabine is already combined with paclitaxel in inoperable, locally advanced or metastatic breast 
cancer after relapse to neoadjuvant/adjuvant chemotherapy. In this indication, the frequency of grade 3 and 4 
hematological toxicity (notably neutropenia) is significantly increased in the combination therapy. 
Nevertheless, this increased frequency is not associated to increased incidence of infections or haemorrhages. 
Fatigue and febrile neutropenia occur more frequently in the combination therapy. The fatigue usually 
recovered after the first cycle [21].  
The combination of gemcitabine and nab-paclitaxel is already approved in PDAC. The toxicity of nab-
paclitaxel-based chemotherapy was also compared to sb-paclitaxel-based chemotherapy or docetaxel-based 
chemotherapy in a meta-analysis in metastatic breast cancer. No significant differences of grade 3 to 4 
hematological and non-hematological toxicities was showed [13]. 
Identically, in the randomized, non-inferiority phase 3 trial in gastric cancer, weekly nab-paclitaxel was non-
inferior to weekly sb-paclitaxel. However, as in breast cancer, the toxicity profile favored sb-paclitaxel with less 
grade 3 and febrile neutropenia (g3 neutropenia: 29% vs 65%; febrile neutropenia: 1% vs 12%) and less 
neuropathy (2% vs 20%). The hypersensitivity reactions rate only, was superior in sb-paclitaxel arm, as 
expected (5% vs 1%). 
 
Thus, the combination of paclitaxel and gemcitabine is not expected to be more toxic than the nab-paclitaxel 
and gemcitabine combination, which is already approved in PDAC. In our trial, in patients receiving 
gemcitabine and paclitaxel we could expect a similar toxicity profile to that described above. 
 
 
 
1.4.2 
Known potential benefits 
 
The combination of gemcitabine and nab-paclitaxel is already approved in metastatic PDAC in first line, with a 
median OS of 8.5 months in the gemcitabine-nab-paclitaxel group compared with 6.7 months in the 
gemcitabine group (HR=0.72; 95%CI [0.62-0.83]; p<0.001) [2]. Due to the same mechanism of action of sb-
paclitaxel and the appropriate safety profile, we can expect similar potentials benefits. For patients treated in 
the gemcitabine arm, we could expect similar benefits as those observed in the routine clinical practice where 
around 50% of patients receive gemcitabine alone after failure to FOLFIRINOX [4]. 
  

 
 
 
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We can also expect that the combined treatment will have acceptable tolerance as was seen in others 
indications. 
 
1.5 Trial population 
 
The trial population is composed of men and women, aged ≥18 years old with confirmed metastatic pancreatic 
ductal adenocarcinoma. 
 
2. TRIAL OBJECTIVES 
 
2.1 Primary objective 
 
The primary objective of the trial is to evaluate the superiority in terms Overall Survival (OS) of gemcitabine + 
sb-paclitaxel over gemcitabine alone in metastatic pancreatic ductal adenocarcinoma after FOLFIRINOX 
failure or intolerance. 
 
2.2 Secondary objective(s) 
 
The secondary objectives are the evaluation of: 
 Objective Response rate (according to RECIST 1.1 criteria) (ORR)  
 Progression-Free Survival (PFS) 
 Disease Control Rate (4m-DCR) at 4 months 
 Evolution of several biomarkers (Ca 19-9, CEA, neutrophil to lymphocyte ratio, albumin, modified 
Glasgow prognostic score) to assess their prognostic value at baseline and their predictive value under 
treatment  
 Dose intensity of chemotherapy 
 Safety and tolerability of treatment (NCI-CTCAE version 5.0) 
 To evaluate the effect of treatments on Quality of Life 
 To evaluate the rate of subsequent chemotherapy (after progression) 
 To study and identify biomarkers that may provide relevant information for clinicians as to whether the 
patients benefit from chemotherapy and to study the biomarkers dynamics across time and their 
association with primary and secondary endpoints of the trial. 
 
 
3. TRIAL DESIGN AND ENDPOINTS 
 
3.1 Description of the trial Design 
 
This is a phase III, comparative, randomized open-label, multicentric trial comparing gemcitabine + paclitaxel 
over gemcitabine alone in metastatic pancreatic ductal adenocarcinoma after FOLFIRINOX failure or 
intolerance. 
 
3.2 Trial Endpoints 
 
 
3.2.1 
Primary endpoint 
 

 
 
 
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The primary end point is to evaluate the overall survival (OS), defined as the time from date of randomization 
to the date of death due to any cause. If a patient is alive at the database cut-off date, then the patient will be 
censored at the last date of follow-up. 
 
3.2.2 
Secondary endpoint(s) 
 
  
The secondary objectives are the evaluation of: 
 
 Translational research to identify biomarkers predictive of response in this clinical context 
 
3.3 Progression of the trial  
 
 
Patients participating in the trial will comply with the protocol for a total number of 12 months after 
randomization, including an estimate of 6 months of treatment and 6 months of follow-up. 
 
The investigation/examination schedule is defined by the trial schedule of activities in Section H of the protocol 
synopsis. 
 
 
 Efficacy endpoints: 
 
ORR (according to RECIST 1.1 criteria) defined as the percentage of patients with Complete 
Response (CR) or Partial Response (PR). Patients who discontinue treatment without a 
tumour assessment will be considered non-responders for the analysis 
 
PFS defined as the time from the date of randomisation to date of disease progression 
(radiological or clinical) or death from any cause, whichever occurs first. Patients without 
tumour progression or death at the time of analysis will be censored at the date of their last 
tumour assessment. 
 
4m-DCR is defined as proportion of patients with CR, PR, or a stable disease (SD), 4 months 
after treatment initiation. 
 Value of biomarkers (Ca 19-9, CEA, Lymphocyte to Neutrophil ratio, albumin, modified Glasgow 
prognostic score) will be described by absolute or relative variation from baseline. To assess their 
prognostic or predictive values, baseline values of these biomarkers will be tested using Cox or logistic 
regression models.  
 Dose intensity of chemotherapy will be calculated from doses actually given instead of from targeted 
doses. Ratio between dose received compared to theoretical ones will be calculated by patient and 
presented as a percentage. 
 Safety and tolerability of treatment (NCI-CTCAE version 5.0) determined through the incidence of 
adverse events, treatment related adverse events, serious adverse Events (SAE), and death.  
 Quality of life (QoL) (EORTC QLQ-C30) during treatment. A deterioration of scores for five-targeted 
dimensions: pain, physical and emotional functioning, fatigue, and appetite will be compared between 
the two treatment arms, while other dimensions will be regarded as exploratory. 5-point deterioration 
in Health-Related QoL (HRQoL) scores will be considered as the minimal clinically important difference 
(MCID). 
 Rate of subsequent chemotherapy (after progression). The type and the date of beginning of first-
cycle of each line will be collected.  

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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3.4  Randomisation procedure 
 
After the eligibility criteria have been fulfilled and the patient consent has been obtained, the patient will be 
randomised in the trial.  
 
According to randomization, patients will be assigned in a 2:1 ratio to receive Gemcitabine + Paclitaxel or 
Gemcitabine alone. 
 
Stratification factors at randomization which will be centralized and use minimization method will include: 
 ECOG-PS at baseline 0-1 or 2. 
 PFS duration at first-line therapy <6 months or ≥ 6 months 
 Ca 19-9 level at baseline <59× ULN or ≥59× ULN 
 Neutrophil Lymphocyte Ratio (NLR) at baseline ≤5 or >5 
 
The randomization will be performed using the module of the eCRF / Ennov Clinical® software. 
 
After the consent form has been signed and all inclusion/non-inclusion criteria checked, the investigator will 
proceed with the randomization through the Unicancer online e-CRF: https://ecrf.icm.unicancer.fr/CSOnline/ 
  
An automatic reply will be sent by e-mail to confirm the success of the randomization procedure to the:  
• 
Sponsor 
• 
Investigator 
• 
Data manager 
• 
Statistician 
  
The procedure of use of eCRF for randomization will be given to all investigators during the study opening of 
each of the centers. 
 
 
 
3.5 Premature Trial Terminations and Suspension 
 
 
The trial can be suspended or stopped by the sponsor after meeting with the coordinating investigator or 
following a request by the respective regulatory authority and/or the responsible Ethics Committee for the 
following reasons: 
 high frequency and/or unexpected severity of toxicity, 
 insufficient patient enrolment, 
 lack of efficacy (established at the planned interim analysis), 
 Insufficient quality of data collection. 
 
3.6 Patient’s trial withdrawal and discontinuation  
 
Patient withdrawal concerns patients who stop treatment and all other protocol-defined procedures. This can 
occur under the following circumstances: 
 
Patient withdraws consent and stipulates that no further data be collected (this should be noted in the 
patient’s medical file). 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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 
The principle investigator may terminate a patient’s participants from the study, if this is in the interest 
of the patient. 
 
Study patients may withdraw their consent at any time without justification, irrespective of the reason(s). In the 
case of study withdrawal the investigator should attempt to obtain as much information as possible. This 
information should be noted in the patient’s medical file. The patient’s withdrawal of consent does not impact 
the patient’s right to receive medical treatment. 
 
 
 
4. PATIENT SELECTION 
 
 
4.1 Diagnosis and inclusion criteria 
 
The following criteria must be verified during the baseline phase and before randomisation. 
In order to participate in the trial all patients must meet all of the following inclusion criteria: 
1. Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC). 
2. Age ≥18 years old. 
3. At least one evaluable lesion according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) 
outside any previously irradiated area. 
4. Failure of first line FOLFIRINOX therapy due to progressive disease during or within 3 months (+/- 15 
days) after end of therapy (including mFOLFIRINOX in adjuvant setting) or patient with FOLFIRINOX 
intolerance. 
5. Performance Status (PS) ECOG 0 to 2. 
6. Life expectancy ≥12 weeks. 
7. Negative serology (HIV, hepatitis B and C). 
8. Adequate organs function: 
 Absolute neutrophils count ≥1.5x109/L 
 Platelets count ≥100x109/L 
 Haemoglobin ≥9 g/dl 
 Serum bilirubin levels <2 times upper limit of normal (ULN), up to 2.5 times ULN in case of 
hepatic metastasis (biliary drainage allowed) 
 Transaminases <5 times ULN. 
9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-
menopausal patients. 
10. Woman of childbearing potential and male patients must agree to use adequate contraception for the 
duration of trial participation and up to 6 months after completing treatment/therapy 
11. Patients affiliated to the social security system 
12. Patient must have signed a written informed consent form prior to any trial specific procedures 
 
4.2 Non-inclusion criteria 
 
 
Patients are not eligible to participate in the trial if they comply with any of the following criteria: 
 

 
 
 
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1. Any other primary tumor or secondary malignancy except basal cell carcinoma of the skin or in situ 
carcinoma of the cervix uteri (patients adequately treated for other malignancies and without tumor 
during the last 5 years are eligible) 
2. Known cerebral metastasis. 
3. Uncontrolled severe infections 
4. Patients with Kaposi’s sarcoma 
5. Peripheral neuropathy exceeding CTCAE (Common Terminology Criteria for Adverse Events) v5.0 
grade 2 
6. Previous treatment with taxane and/or gemcitabine. Patients treated with taxane and/or gemcitabine 
for another cancer are eligible. 
7. Patients with known allergy or severe hypersensitivity to any of the trial drugs or any of the trial drug 
excipients 
8. Patients with any other disease or illness which requires hospitalisation or is incompatible with the trial 
treatment.  
9. Patients unable to comply with trial obligations for geographic, social, or physical reasons, or who are 
unable to understand the purpose and procedures of the trial 
10. Participation in another clinical trial within 14 days prior to randomization 
11. Patients deprived of liberty or under legal protection measure(s) or patients whose willingness to 
participate in this clinical trial may be unduly influenced 
 
 
 
 
5. TRIAL TREATMENTS/INTERVENTIONS 
 
 
5.1 Description of trial treatments/interventions 
 
Patients who have signed the informed consent form and who met all inclusion and non-inclusion criteria will 
be randomized and a treatment will be allocated. 
 
The investigational products will be prepared according to the chemotherapy safety standards. 
 
Treatment products will be supplied from the pharmacy stocks of each research hospital. 
 
For experimental group: 
Arm A : GEMPAX (D1=D29) : 
Paclitaxel 80 mg/m² in IV infusion over 60 minutes at D1, D8 and D15 followed by 1 week of rest, every 28 
days.  
Gemcitabine 1000 mg/m² in IV infusion over 30-40 minutes at D1, D8, D15 followed by 1 week of rest, every 
28 days.  
A premedication to prevent hypersensitivity reactions (e.g., dexamethasone, diphenhydramine, H2 blockers) 
will be applied according to the Summary of Products Characteristics. Initial antiemetic prophylaxis is also 
recommended.  
 
Secondary prophylaxis of neutropenia (G-CSF) for weekly chemotherapy is not planned in EORTC 
recommendations. Center’s practices will be applied. Of note, the coordinator of the study is used to prescribe 

 
 
 
UNICANCER Tumor Group: UCGI 
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EudraCT n°: 2018-002886-21 
 
 
 
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successfully pegylated G-CSF (pegfilgastrim=Neulasta®) on D1 and D15 of each cycle according to other 
published experience for weekly chemotherapy schedules [20]. 
 
At each infusion day, paclitaxel will be administered before gemcitabine. 
 
 
For control group: 
Arm B : GEM (D1=D29) : 
Gemcitabine 1000 mg/m² in IV infusion over 30-40 minutes at D1, D8, D15 followed by 1 week of rest, every 
28 days. 
 
 
5.2 
Acquisition, reception, and storage 
 
Gemcitabine and paclitaxel will be taken from the pharmacy stock at the investigator’s site.  
 
The pharmacist is responsible for a safe and proper handling and storage of the investigational medicinal 
products at the investigational centre. The investigational products must be stored in a locked facility with 
restricted access to the pharmacist and authorised personnel, and under environmental conditions consistent 
with the drug manufacturer recommendations (gemcitabine and paclitaxel SmPC). 
 
Gemcitabine must be stored at room temperature  
 
Paclitaxel must be stored at room temperature without exceeding +25°C, protected from light 
 
Up to date temperature logs must be maintained by the pharmacist/investigator to document adequate storage 
during the trial. These logs must be available at the site during monitoring visits, and in the event of an audits 
or inspection. 
 
If the storage conditions as indicated above are exceeded (e.g. temperature excursion) the 
pharmacist/investigator must place the corresponding treatments in quarantine and immediate notify the 
sponsor who will indicate the procedure to follow. Under no circumstances should these treatments be 
delivered to trial patients without prior authorisation by the sponsor. 
 
 
5.3 Trial treatments accountability, return and destruction 
 
The pharmacist or authorised staff must document the dispensation, and destruction of all investigational 
products used during this trial. Records on investigational products inventory at the centre, the delivery to each 
patient, and destruction by the site must be implemented and maintained by the pharmacist or another 
appropriately trained individual at the investigational centre. The following minimum information must be 
present: all relevant dates (dispensation and destruction), quantities, and expiry date and batch numbers. 
Accountability form will be provided by the sponsor to ensure trial treatment accountability.  
 
The pharmacist will implement an accounting of medicinal products dispensed, used and unused. The 
accountability of the used products will be systematically done by the pharmacist of the site.  
 
This process will be monitored by the UNICANCER CRA during the trial. The CRA will check that the 
accountability documentation has been filled in and signed by the pharmacist before the investigational 
products, used and unused, are destroyed. 

 
 
 
UNICANCER Tumor Group: UCGI 
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All remaining investigational products, used and unused, shall be collected and returned for destruction. The 
destruction will take place at the investigator centres under the responsibility of their pharmacist in accordance 
with national regulatory requirements, and with prior formal agreement from the sponsor. A certificate of 
destruction, identifying concerned products, will be given to the sponsor. 
 
5.4 Formulation, appearance, packaging, and labelling 
 
Gemcitabine is formulated as powder for solution for injection. Each type I glass bottle contains gemcitabine 
chlorhydrate corresponding to 200 mg or 1 000 mg of gemcitabine. After reconstitution, the solution contains 
38 mg/mL of gemcitabine (gemcitabine chlorhydrate). Each packaging of gemcitabine contains one or five 
bottles. 
 
Paclitaxel is formulated as a solution to dilute for injection. Each type I glass bottle to dilute contains 6 mg/mL 
of paclitaxel: 
A bottle of 5 mL contains 30 mg of paclitaxel 
A bottle of 16.7 mL contains 100 mg of paclitaxel 
A bottle of 25 mL contains 150 mg of paclitaxel 
A bottle of 50 mL contains 300 mg of paclitaxel 
A bottle of 100 mL contains 600 mg of paclitaxel 
Each packaging of paclitaxel contains one or five bottles.  
 
5.5 Preparation 
 
Please refers to the most recent version of the summary of product characteristics (SmPC) for gemcitabine 
and paclitaxel. 
 
 
5.6 
Conditions for stopping the treatment 
 
Toxicities will be graded according to NCI-CTCAE (version 5.0).  
If a dose reduction is necessary, the reduced posology (dosage) will be maintained until the end of treatment 
protocol. In case of recurrent grade 4 toxicity despite dose reduction, the clinical investigator and the patient 
may discuss the possibility of stopping treatment protocol. 
 
The decision to reduce the doses will be based on the maximum toxicity observed during the cycle. 
 
The dose adjustments should be based on the most significant toxicity grades. If a patient has several types 
of toxicity, the dose administered will be the one with the least risk to the patient. 
 
 
5.7 Patients’ discontinuations of treatment 
5.7.1 Delays cycles of chemotherapy- or rules for dose omissions and modified 
schedules 
 
 
Day 1 dose missed: 
 

 
 
 
UNICANCER Tumor Group: UCGI 
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If the dose held or missed was to be given at day 1, the cycle will not be considered to start until the day 1 
dose is actually administered to the patient. 
 
Day 8 dose is missed: 
 
If day 8 is not given, the treatment cycle continues per protocol, with one dose omitted.  
 
Day 15 dose missed: 
 
If day 15 is not given at a given cycle, the next cycle will start as planned per protocol, i.e. 4 weeks after day 1 
of previous cycle. 
 
A delay of 4 weeks maximum is allowed in this study. In case of delay >4 weeks, decision regarding end of 
study treatment will be discussed on a case-by-case basis between the investigator, the coordinating 
investigator and the sponsor. 
 
5.7.2 Dose adaptation 
 
Dose reductions may or may not be concomitant. A maximum of 2 dose level reductions are allowed.  
Patients experiencing study drug-related toxicities that require a delay in scheduled paclitaxel or gemcitabine 
dosing for more than 21 days will be discontinued from further treatment in this study (except for peripheral 
neuropathy). 
 
Dose Level 
Gemcitabine (mg/m2) 
Paclitaxel (mg/m2) 
Study dose 
1000 
80 
-1 
800 
60 
-2 
600 
40 
 
 
5.7.3 Doses modifications tables for hematologic toxicity 
 
Dose modifications due to hematologic toxicity within a treatment cycle should be adjusted.  
 
At Day 1 : 
 
Absolute Neutrophil Count 
(ANC) 
 
Platelets 
Timing 
≥ 1.5 x 109/L  
AND 
≥ 100 x 109/L  
Treat on time 
˂ 1.5 x 109/L  
OR 
˂ 100 x 109/L  
Delay by 1 week intervals until recovery  
 
At Day 8 : 
 
Absolute Neutrophil Count (ANC) 
 
Platelets (Plt) 
Timing 
≥ 1.0x109/L  
AND 
≥75x109/L  
Treat on time 
0.5 x109/L≤ANC˂1.0x109/L  
OR 
50x109/L≤Plt˂75x109/L  
Decrease dose by 1 level 
(treat on time) 
ANC˂ 0.5 x109/L 
OR 
Plt ˂ 50x109/L 
Hold and decrease next dose 
by 1 level 
 
At Day 15 : 
 
Absolute Neutrophil Count (ANC) 
 
Platelets (Plt) 
Timing 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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≥ 1.0x109/L  
AND 
≥75x109/L  
Treat on time 
0.5 x109/L≤ANC˂1.0x109/L  
OR 
50x109/L≤Plt˂75x109/L  
Same dose as D8 + GCSF a 
ANC˂ 0.5 x109/L 
OR 
Plt ˂ 50x109/L 
Hold + GCSF a 
 
a G-CSF is useless if descent only affects platelets. 
 
In case of febrile neutropenia (grade 3 or 4), hold upon recovery. Upon resuming dosing, either use GCSF for 
further cycles or decrease gemcitabine and paclitaxel to next lower dose levels.  
In case of recurrent febrile neutropenia (grade 3 or 4) occuring depsite G-CSF, hold upon recovery and 
decrease all drugs to next lower dose level. 
 
 
5.7.4 Doses modifications tables for non- hematologic toxicity 
 
 
 
Toxicity or dose held 
Gemcitabine / Gemcitabine-Paclitaxel 
Grade 0, 1 or 2 toxicity 
Same as Day 1 of previous cycle 
Grade 3 toxicity a, c 
Decrease gemcitabine +/- paclitaxel to next lower dose level 
Grade 4 toxicity a, b, c 
Off protocol treatment 
Dose 
held 
in 
2 
previous 
consecutive cycles 
Decrease gemcitabine +/- paclitaxel to next lower dose level and 
continue throughout the rest of treatment 
 
a If the toxicity only affects neuropathy, then only paclitaxel should be reduced. 
b Pulmonary embolism (Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt from this 
requirement.  
c except for nausea/vomiting and alopecia. 
 
 
Dose modifications may also be made for non-hematological toxicity within a cycle : 
 
Toxicity or dose held 
% of D1 Gemcitabine / Gemcitabine-Paclitaxel doses 
Grade 0 1 or 2 toxicity (and Grade 
3 nausea/vomiting and alopecia)  
100% 
Grade 3 toxicity a, c 
Hold either one or both drugs until resolution to ≤Grade 1. Then 
resume treatment at the next lower dose level. 
Grade 4 toxicity a, b, c 
Hold 
 
a If the toxicity only affects neuropathy, then only paclitaxel should be reduced. 
b Pulmonary embolism (Grade 4 toxicity in the CTCAE tables) if mild or a symptomatic, will be exempt from 
this 
requirement.  
c except for nausea/vomiting and alopecia. 
The decision as to which drug should be modified will depend upon the type of non-hematologic toxicity seen 
and which course is medically most sound in the judgment of the physician/investigator. 
 
Patients can discontinue the trial treatment/therapy for the following reasons: 
• 
Limiting toxicity. 
• 
Any delay in treatment administration of more than 4 weeks 
• 
Patients decline further treatment/therapy but accept to continue with protocol. 
• 
Investigator’s decision. 

 
 
 
UNICANCER Tumor Group: UCGI 
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After discontinuing all trial treatment, further treatment is left to the physician’s discretion. 
Patients who discontinue trial treatment will continue with the trial and the protocol-defined procedures, unless 
they specifically withdraw their consent and indicate that they do not want to perform any further trial-related 
visits or assessments (for patient withdrawals see Section 3.7.). 
 
5.8 Concomitant medications and therapies 
All medications (including herbal preparations) and therapies taken by the patients or administered to the 
patients from the onset of trial and given in addition to the investigational products during the trial are 
considered as concomitant medications. Any concomitant medication(s) trial will be recorded in the case report 
form (CRF). 
5.8.1 
Authorised concomitant treatments 
 
All symptomatic treatments/therapies required for the patients’ comfort (antiemetics, antidiarrhetics, antibiotics, 
sunscreen, and corticosteroids cream) are authorised. The posology and duration of administration are at the 
investigator’s discretion, as per standard of care. 
 
5.8.2 
Prohibited concomitant treatments 
 
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution 
should be exercised when paclitaxel is concomitantly administered with known substrates (eg, midazolam, 
buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. No specific drug interaction studies 
have been conducted with gemcitabine.  
The following treatments/therapies are prohibited during the trial: 
 
Other antitumor treatments (investigational or not), including chemotherapies, radiation therapies, 
hormonal therapies, biological response modifiers, and targeted therapies. Local treatment of isolated 
cancer lesions, excluded target lesions, for palliative intent, is acceptable (e.g., local surgery or 
radiotherapy) 
 
Systemic corticoids, except in case of an urgent indication or as antiemetics. Their use will require the 
highest precaution in patients with diabetes. 
 
It is advised not to use the association of warfarin (Coumadin®) with chemotherapy. It is preferable to 
use heparin and therapeutic anticoagulation with low-molecular weight heparin. If warfarin cannot be 
avoided, the rate of prothrombin must be checked more frequently and INR monitored. 
 
Pimozide (Orap®) and cisapride (Prepulsid®) are strictly contraindicated: they are associated with a 
major risk of ventricular rhythm disorder. 
 
Yellow fever vaccine. 
 
All concomitant medication must be recorded in the patient’s medical records and documented as appropriate 
in the CRF. The decision to withdraw a patient on the basis of concomitant medication should preferably be 
made jointly by the Sponsor and the Investigator. 
 
 
5.8.3 
Rescue medications and therapies/Treatment at disease progression 
 
At disease progression the treatment will be at the investigator’s discretion. 

 
 
 
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5.8.4 
Contraception during the trial 
 
Definitions 
Females of childbearing potential are those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral 
oophorectomy, or complete hysterectomy) or post-menopausal (for the definition of post-menopausal see 
below). 
 
Post-menopausal status is defined as: 
Women will be considered post-menopausal if they have been amenorrhea for 12 months without an 
alternative medical cause. The following age-specific requirements apply:  
 
Women <50 years of age would be considered post-menopausal if they have been amenorrhea for 12 
months or more following cessation of exogenous hormonal treatments and if they have luteinizing 
hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilisation (bilateral oophorectomy or hysterectomy).  
 
Women ≥50 years of age would be considered post-menopausal if they have been amenorrhea for 12 
months or more following cessation of all exogenous hormonal treatments, had radiation-induced 
menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses 
>1 year ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
Acceptable contraception during the trial 
 
Female patients of child-bearing potential 
Females of childbearing potential who are sexually active with a non-sterilised male partner must use one or 
more highly effective method of contraception (See Table 1 below) during the trial and for 6 months after the 
last trial treatment/therapy administration. Non-sterilised male partners of a female patient must use male 
condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed 
with a responsible physician. Female patients should also refrain from breastfeeding throughout this period. 
Table 1 - Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal methods 
Copper T intrauterine device 
Levonorgestrel-releasing intrauterine system 
(e.g., Mirena®)a 
 
Etonogestrel implants: e.g., Implanon or Norplan 
Intravaginal device: e.g., ethinylestradiol and 
etonogestrel 
Medroxyprogesterone injection: e.g., Depo-
Provera  
Normal and low dose combined oral 
contraceptive pill 
Norelgestromin/ethinylestradiol transdermal 
system 
Cerazette (desogestrel) 
aThis is also considered as a hormonal method. 
 
Male patients with a female partner of childbearing potential 

 
 
 
UNICANCER Tumor Group: UCGI 
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Non-sterilised males who are sexually active with a female partner of childbearing potential must use a male 
condom plus spermicide during the trial and for 6 months after the last trial treatment/therapy administration. 
Male patients should refrain from sperm donation throughout this period. 
 
6. EVALUATION OF TREATMENT EFFICACY AND SAFETY 
 
6.1 Efficacy evaluation 
 
 
Tumor assessment will be performed at baseline and every 8 weeks from day 1 of cycle 3. 
Treatment efficacy will be evaluated by measuring changes in tumour size in response to treatment; measured 
by Thoraco-Abdominal and Pelvic CT-Scan and assessed by RECIST v1.1 (see Appendix 3). 
 
6.2 Safety evaluation  
 
Treatment safety evaluation will be based on adverse event (AE) occurrence, the use of concomitant 
treatments, and changes occurring during treatment including those observed: during physical examinations, 
in vital signs (blood pressure, pulse, body temperature), in electrocardiogram (ECG), and with biological and 
clinical examinations (biochemistry, haematology). Safety criteria will be evaluated using the National Cancer 
Institute - common terminology criteria for adverse events (NCI-CTCAE) v5.0 (see Appendix 4).  
 
In case of emergency, the patient, a patient’s relative or the patient’s general practitioner will have to inform 
by phone the investigator about the occurrence of an AE. The possible treatment interruption or dose 
adaptation (decrease) for the investigational product will be considered as well as adequate concomitant 
treatment if necessary. 
 
6.3 Centralised review 
 
No centralised review. 
 
 
 
7. DESCRIPTION OF VISITS AND INVESTIGATIONS  
 
Patients will be monitored from the date of their consent’s signature until the date of death or study’s end.  
A summary of the visit schedule and follow-up examination is provided in Section H of protocol synopsis – 
Schedule of activities. 
 
 
7.1 Baseline visit 
 
Each candidate patient will be examined before starting the study to determine eligibility for participation. This 
must be done within 14 days prior to the first study treatment administration, except for radiologic assessment 
which can have been performed up to 4 weeks prior to study treatment start. The following investigations will 
be performed:  
 

 
 
 
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 
Informed consent: obtain written patient informed consent prior to any study specific procedure. 
Consent for the translational study (optional) will also be obtained during this visit. 
 
Verification of eligibility criteria 
 
Randomization 
 
Diagnosis and prior anticancer therapies 
 
Demographics, signs and symptoms, medical history, including non-cancer medical history, and 
concurrent illnesses  
 
Prior and concomitant medications 
 
Physical examination (weight, height, WHO Performance Status, vital signs (pulse, blood pressure, 
body temperature) 
 
Modified Glasgow prognostic score evaluation (see Appendix 7 for calculation method) 
 
Electrocardiogram (ECG) 
 
Serology (HIV, hepatitis B/C) 
 
Pregnancy test (all women of child bearing potential) 
 
Complete Blood Count (CBC) (refer to section H of synopsis for details) 
 
Coagulation factors (refer to section H of synopsis for details) 
 
Serum biochemistries, including C-reactive protein (refer to section H of synopsis for details) 
 
Tumor biological markers (CEA and CA19-9) 
 
Thoraco-Abdominal and Pelvic CT-Scan  
 
QLQ-C30 
 
Archived tumour material preparation and shipment organization (shipments can be pooled with 
several patients): can be done anytime during the patient’s study participation. 
 
 
 
7.2 Visits and assessment during treatment period 
 
During the treatment period, patients will come at hospital at day 1, day 8 and day 15 of each cycle (1 cycle = 
28 days. Delay ≤3 days is allowed).  
 
At day 1 of each cycle, patients will be assessed as follows prior to chemotherapy administration (refer to section 
H of synopsis for details): 
 
• 
Documentation of concomitant medication 
• 
Physical examination  
• 
Neurological examination for the evaluation of potential peripheral neuropathy due to paclitaxel. Only 
for patients randomized in Arm A (gemcitabine + paclitaxel) 
• 
Vital signs and WHO performance status 
• 
Recording of adverse events that occurred since last cycle 
• 
Complete Blood Count (CBC) (refer to section H of synopsis for details) 
• 
Coagulation factors (refer to section H of synopsis for details) 
• 
Serum biochemistries (refer to section H of synopsis for details) 
• 
Tumor biological markers (CEA and CA19-9), at day 1 cycle 3 then every 8 weeks till disease 
progression 
• 
CT-Scan (Thorax Abdomen Pelvis), at day 1 cycle 3 then every 8 weeks till disease progression 
• 
QLQ-C30, at day 1 cycle 3 then every 8 weeks till disease progression 
• 
Blood samples for translational research (optional, if patient consented) 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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At day 8 and day 15 of each cycle, patients will be assessed as follows (refer to section H of synopsis for details): 
 
• 
Documentation of concomitant medication 
• 
Recording of adverse events that occurred since last cycle 
• 
Complete Blood Count (CBC) (refer to section H of synopsis for details) 
• 
Limited serum biochemistries (refer to section H of synopsis for details) 
• 
Blood samples for translational research  only at day 15 of cycle 1 (optional, if patient consented) 
 
 
 
 
7.3 End-of-treatment visit 
 
Patients will perform an end-of-treatment visit 35 days (±5 days) following the last study drug administration: 
 
• 
Documentation of concomitant medication 
• 
Physical examination  
• 
Neurological examination for the evaluation of potential peripheral neuropathy due to paclitaxel. Only 
for patients randomized in Arm A (gemcitabine + paclitaxel) 
• 
Vital signs and WHO performance status 
• 
Recording of adverse events  
• 
Complete Blood Count (CBC) (refer to section H of synopsis for details) 
• 
Coagulation factors (refer to section H of synopsis for details) 
• 
Serum biochemistries (refer to section H of synopsis for details) 
• 
Tumor biological markers (CEA and CA19-9), every 8 weeks till disease progression 
• 
CT-Scan (Thorax Abdomen Pelvis), every 8 weeks till disease progression 
• 
QLQ-C30, every 8 weeks till disease progression 
 
 
7.4 Follow-up  
 
In absence of progression, patients will perform follow-up visits every 8 weeks (±2 weeks) until documented 
progressive’s disease, start of new anticancer therapy or end of study, whatever occurs first. 
  
The following assessments will be performed during the follow-up period (refer to section H of synopsis for details): 
• 
Physical examination  
• 
WHO Performance status 
• 
Information on safety data. 
• 
Tumor markers: CEA and CA 19-9 
• 
Thoraco-Abdominal and Pelvic CT-Scan 
• 
QLQ-C30 
• 
Information on further anticancer therapy 
 
After progression or starting of a new anticancer therapy (whatever occurs first), follow-up will only be 
performed every 12 weeks (±2 weeks) until patient’s death or end of study, whatever occurs first, and will 
consist in getting data about overall survival and safety data (if applicable). 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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7.5 Provisions in case of treatment or trial interruption 
 
If the trial treatment is discontinued for a patient, further treatment will be at the investigator’s discretion as per 
standard of care. 
 
 
8. REPORTING OF ADVERSE EVENTS 
 
8.1 Adverse event: general definition 
 
An adverse event (AE) is defined as any untoward medical occurrence, in a patient or clinical trial subject 
treated by a medicinal product and which does not necessarily have a causal relationship with this treatment. 
 
8.2 Serious adverse event: general definition  
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
 
results in death 
 
is life-threatening 
 
requires hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is medically relevant in the context of the pathology and the clinical trial 
 
These characteristics/consequences are to be considered at the time of the event. For example, regarding a 
life-threatening event, this refers to an event in which the subject 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 was more severe. 
 
The terms disability and incapacity correspond to any clinically relevant physical or psychological handicap, 
transient or permanent, which impacts the patient’s physical condition/activity and/or the quality of life. 
 
Medical and scientific judgment should be exercised in deciding whether other situations should be considered 
serious, such as important medical events that might not be immediately life-threatening or result in death or 
hospitalisation, but might jeopardise the patient or might require intervention to prevent one of the other 
outcomes listed in the definition above (for example: overdose, second cancer, etc.). 
 
The investigator will assess whether a reasonable causal relationship exists between the event and the 
treatment/therapy. If the sponsor disagrees with the investigator’s causality assessment, the opinion of both 
the investigator and the sponsor will be reported.  
 
The following events leading to a hospitalization or prolongation of hospitalization are not considered as 
Serious Adverse Events:  
- 
Hospitalisation already scheduled before the start of the trial, 
- 
Hospitalisation required as part of the protocol (biopsy, chemotherapy, etc.),  
 
The following events are considered as SAEs but should not be managed according to the section 8.3. These 
events do not require immediate reporting and should be reported only in the case report form:  

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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 
Hospitalization occurring in the context of tumor progression of disease under trial,  
 
Progression of disease under trial,  
 
Events related to progression of disease under trial.  
 
 
An Adverse reaction is a response to a medicinal product which is noxious an unintended 
 
A Serious adverse reaction (SAR) is an adverse reaction which results in death, is life-threatening, requires 
inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability 
or incapacity, is a congenital anomaly/birth defect, or is a medically relevant. 
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any serious adverse reaction, 
the nature, severity or outcome is not consistent with the applicable drug information (e.g. Investigator’s 
Brochure for an unapproved investigational product or package insert/summary of product characteristics for 
an approved product).  
 
The assessment of expected/unexpected character of the event is the responsibility of the sponsor. 
The reference document for assessment of expectedness in this study will be the SMPC of 
Gemcitabine and Paclitaxel. 
 
 
New event: is defined as any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the subjects.  
 
 Severity criterion: the severity criterion must not be confused with the seriousness criterion which is 
the guide for defining the reporting requirements. 
 
The intensity (severity) of events will be estimated using the extract of CTCAE v5.0 classification (see Appendix 
4). The intensity of adverse events not listed in this classification will be assessed according to the following 
qualifiers: 
 
Grade 1 (mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
 
Grade 2 (moderate): minimal local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3: severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting self-care ADL. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Grade 5: Death related to the event. 
 
8.3 Measures to be taken in case of a serious adverse event  
 
The investigator ensures that adequate medical care is provided to the patient. The investigator must 
immediately following knowledge of the event, notifies the UNICANCER pharmacovigilance unit of any SAE 
or any new event defined here above, whether or not related to the research, which occurs during the ‘trial 
reporting period’. This reporting period: 
 Starts at the date of the signature of the informed consent form,  
 covers the entire period during which the patient is receiving the investigational treatment or is subject 
to specific procedures related to the trial,  

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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 covers a period of 30 days after the last administration of the investigational product. 
 
Any later SAE, i.e. occurring after a period of 30 days, which is considered to be related to the experimental 
treatment(s) or to the research (other treatment used, diagnostic procedures and examinations carried out 
during the research) must be reported without any limitation in terms of deadline. 
 
Notification must be carried out immediately by fax to the UNICANCER pharmacovigilance unit by sending the 
form “notification of a SAE”, located in the Investigator Master File, completed as precisely as possible, dated 
and signed by the physician-investigator. 
 
Notification must be carried out immediately by fax to the UNICANCER pharmacovigilance unit: 
UNICANCER  
Pharmacovigilance unit, France 
Phone: +33 (0)1 44 23 04 16 – Fax: +33 (0)1 44 23 55 70 
Email: pv-rd@unicancer.fr 
 
Abnormal laboratory results should be reported as SAE if they possibly put at risk the patient or they 
require medical intervention to prevent an outcome corresponding to one of severity criteria. 
 
Second cancer, whether or not related to the research, must be reported to the UNICANCER 
pharmacovigilance unit without any limitation in terms of deadline.  
 
In the event of pregnancies: 
Pregnancy is not considered as an SAE but must be reported with the same modalities as an SAE, using a 
Pregnancy Notification Form. Pregnancy will be subject to a specific follow-up until the end of pregnancy. While 
pregnancy is not considered as a SAE, any anomaly detected in the foetus or child, any elective termination 
of a pregnancy for medical reasons, or spontaneous abortion will be reported as an SAE, using the same 
procedure as an SAE. 
 
Any pregnancy in a female partner of a male subject occurring during the treatment period or within 30 days 
after last trial treatment administration must be reported using the same procedure as an SAE. 
 
 
The investigator shall send additional information to the UNICANCER pharmacovigilance unit using a 
SAE declaration form (by ticking the Follow-up X box to specify that it is a follow-up and not an initial report) 
as soon as he is aware of the event. The investigator must also submit the last follow-up at the resolution or 
stabilisation of the SAE. 
 
The investigator is responsible for appropriate medical follow-up of patients until the resolution or stabilisation 
of the event or until the death of the patient. This can sometimes mean that the follow-up continues after the 
patient has left the trial. 
 
The investigator must keep the documents concerning the suspected SAE in order to supplement the 
information previously submitted if necessary. 
 
Requests for clarification and additional information may be sent to the investigator by the UNICANCER 
pharmacovigilance unit or CRA sponsor of the trial to document and treat the case.  

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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The physician-investigator should also attach to the form «notification of a SAE», whenever possible: 
 
a copy of the hospital report or extended hospitalisation report 
 
a copy of all results of additional investigations carried out, including also relevant negative results, 
and enclosing the normal laboratory values 
 
a copy of the autopsy report if necessary 
 
any other document deemed to be useful and pertinent 
 
All these documents must be anonymised. 
 
 
9. ANCILLARY/TRANSLATIONAL STUDY(IES) 
 
Ancillary studies (translational research and basic research lab) will address a clinically relevant issue in this 
disease, i.e. to identify biomarkers that may provide relevant information for clinicians as to whether the 
patients benefit from chemotherapy in this clinical context.  
 
It will include at least the analysis of constitutional DNA and circulating tumor DNA, performed before treatment 
to investigate constitutional (polymorphisms) or somatic (tumor-related molecular alterations) molecular factors 
with prognostic or predictive value. The correlation of tumor molecular biomarkers with clinical outcomes will 
also be analyzed.  
 
The following analyses will be performed for each treatment regimen: 
Descriptive statistics will be used to summarize biomarkers for responders versus non-responders. To assess 
relationship between response and biomarkers, a logistic regression analysis will be performed with effects for 
biomarker and treatment regimen in the model. To assess the relationship of overall survival (and PFS) with 
biomarkers, a Cox regression analysis will be used with effects for biomarker and treatment regimen in the 
model. In addition, for biomarkers with binary measures, survival will be summarized by median survival time 
for each biomarker category along with the hazard ratio. For each treatment regimen, the Kaplan-Meier curve 
for survival will be presented graphically for each biomarker category and differences in the curves will be 
tested using the log-rank test. 
 
We will study the biomarkers dynamics across time and their association with primary and secondary endpoints 
of the trial. These studies will be managed in the Cancer Research Centre of Lyon.  
 
Blood samples will be collected at day 1 (before treatment), day 15 of cycle 1 (before treatment) and at disease 
progression. Archived tumour tissues will be also collected (frozen and/or FFPE tissues). The biomarkers will 
be evaluated for their clinical relevance at different levels (circulating cell-free DNA, constitutive DNA, etc.). 
Analysis of mutations in a panel of genes (e.g. KRAS) will be done. 
All the samples will be transported and centralised at Centre des Ressources Biologiques d’UNICANCER, 
(CRB-CLB), under the responsibility of Ms. Séverine Tablone-Eglinger, located at the following address: 
 
Centre Léon Berard, 28 rue Laënnec – 69373 Lyon cedex 08, Bâtiment CHENEY B Rez de Chaussée – 
CRB échantillons biologiques) - France 
 
A separate laboratory manual is provided to detail the procedures for blood samples and archived tumour 
tissues preparation, storage and shipment. 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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10. DESCRIPTION OF STATISTICAL METHODS 
 
A comprehensive Statistical analysis plan (SAP) for the trial will be prepared before any statistical analysis. It 
will include detailed information on the analysis of primary and secondary outcome measures and the definition 
of major protocol deviations. Any revision of the SAP will be validated by the Steering Committee.  
The SAS software version 9.4 will be used for the analysis. 
 
 
10.1 Statistical hypothesis and sample size determination 
 
The study was calibrated to detect a treatment effect hazard ratio (HR) of 0.625, translating in an improvement 
in median OS from 5 months (control arm: GEM) to 8 months (experimental arm: GEMPAX), with a 2:1 
randomization.  
 
A total of 184 events in the study (deaths) would have 85% power to show statistically significant OS at a 2-
sided 5% alpha (including one interim analysis of superiority according to OS spending function). Considering 
a recruitment duration of 24 months and a 12-months follow-up for the last included patient (total duration for 
the study: 36 months), 210 patients will be randomized in the study (70 patients in the control arm and 140 
patients in the experimental arm). One interim analysis of efficacy after half of the planned events have 
occurred will be done. An independent data monitoring committee (IDMC) will review this analysis. In order to 
strongly control the type I error the Lan and DeMets approach that approximates the O’Brien and Fleming 
spending function will be used (Lan and DeMets 1983). The 2-sided significance level at the interim analysis 
will be calculated based on the number of events occurred at the interim analysis. As an example, if exactly 
50% of the final number of deaths have occurred at the interim analysis (92 deaths), then the significance level 
will be 0.3% at the interim and, accounting for the expected correlation between the proportion of events at the 
interim and at the final analysis, the 2-sided significance level at the final analysis will be approximately 4.9% 
 
 
 
10.2 Trial populations to be analysed 
 
All efficacy analyses will be performed on the ITT population including all randomized patients analysed 
according to the randomization scheme.  
 
A Per Protocol (PP) population defined as a subgroup of the ITT population containing all patients who do not 
have any major protocol violation and received study treatment at least once could be used as a sensitivity 
analysis for the primary endpoint. Major protocol violations will be defined in the Statistical Analysis Plan. 
 
The safety data will be analysed on the safety analysis set including all randomized patients having received 
at least one dose of study treatment and one safety follow-up, whether withdrawn prematurely or not. 
 
10.3 Planned statistical analysis 
 
10.3.1 
General considerations 
 
All statistical methods will be based on the International Conference on Harmonisation (ICH) E9 document 
“Statistical Principles for Clinical Trials”. 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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Qualitative variables will be described using frequency and percentage distributions. The number of missing 
data will be given, but will not be considered for the calculation of proportions. 
Quantitative data will be described using the number of observations, mean, standard deviation, median, 
minimum and maximum values.  
Patient characteristics and other baseline data (demographics, disease characteristics, clinical and biological 
data) will be summarized per treatment arm and in global, in order to characterize the study population and to 
ensure the initial comparability of the 2 study arms. For each parameter considered, baseline value will be the 
value before the 1st administration of study treatment. No formal statistical comparison between study arms is 
planned regarding baseline characteristics, except in case of obvious difference for a given item. The date of 
randomization will serve as a reference for calculation of durations unless otherwise indicated. 
 
 
10.3.2 
Primary endpoint 
 
Definitions 
OS will be defined as the time from the date of randomization to the date of death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last recorded date on 
which the patient was known to be alive and censored at the date of last contact for patients alive at this time. 
Analyses 
OS will be estimated using the Kaplan-Meir method and described in terms of median OS in each arm and 
hazard ratio between arms, along with the associated 2-sided 95% CIs for the estimates. OS distributions will 
be compared between the 2 arms using the Log-Rank test (stratified on Centre, PFS during first-line therapy 
<6 months or ≥ 6 months, and randomization.Ca 19-9 level at baseline <59× ULN or ≥59× ULN).  
 
 
10.3.3 
Secondary  endpoints 
 
Definitions 
Objective response rate (ORR) is defined as the proportion of patients with a complete or a partial response 
(CR or PR) as best overall response during the study.  
 
Progression Free Survival (PFS) is defined as the time from randomization until the date of event defined as 
the first documented progression, according to investigator assessment of RECIST version 1.1, or death (by 
any cause in the absence of progression). Patients who have not progressed or died at the time of analysis 
will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. 
 
Disease Control Rate at 4 months (4m-DCR) is defined as proportion of patients with a complete response 
(CR) of a partial response (PR) or a stable disease (SD), 4 months after treatment initiation. 
 
Dose intensity will be calculated from doses actually given instead of from targeted doses. Ratio between dose 
received compared to theoretical ones will be calculated by patient and presented as a percentage. 
 
Analysis 
ORR and 4m-DCR will be summarized by arm and in the whole population by a proportion together with its 
95% confidence interval and compared between the 2 study arms using a chi-square test if applicable, a Fisher 
exact test otherwise. 
 
PFS  will be analysed using survival method similar to those described for primary endpoint. 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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Dose Intensity will be summarized by arm and in the whole population. Correlation between dose intensity and 
efficacy parameters (PFS, OS) will be assessed using multivariate analysis. 
 
The safety will be determined through the incidence of adverse events, treatment related adverse events, 
serious adverse Events (SAE) and death. Tolerance will be assessed using the NCI-CTC AE v5.0 grading 
scale. Descriptive statistics will be provided for characterizing and assessing patients’ tolerance to treatment. 
 
The QoL will be assessed using the EORTC QLQ-C30 questionnaire. QLQ-C30 scores will be calculated at 
each time point according to the EORTC scoring manual. Descriptive statistics will be used to evaluate 
baseline scores and evolution of scores from baseline to each time point. A threshold of 5 points in score 
change from baseline will be considered as clinically relevant.  
 
Evolution of biomarkers (Ca 19-9, CEA, neutrophil to lymphocyte ratio, albumin, modified Glasgow prognostic 
score) will be described by absolute or relative variation from baseline. To assess their prognostic or predictive 
values, baseline values of these biomarkers will be tested using Cox or logistic regression models. 
 
 
 
11. OVERSIGHT COMMITTEES 
 
 
11.1 Independent data monitoring committee 
 
 
The Independent Data Monitoring Committee (IDMC), with expertise and experience in the pathology, and 
without direct involvement in the conduct of the trial, will be set up specifically to guarantee effective protection 
of patients, insure the ethical conduct of the trial, benefit/risk ratio of the trial, and to ensure the independent 
review of the scientific results during the trial and at the end of the trial. 
An IDMC charter must be available upon initial submission of the trial protocol to the Competent authority. 
 
The IDMC will be composed of at least: 
• 
Two oncologists 
• 
A statistician 
 
The IDMC will meet at a first meeting 6 months after the first patient’s randomization to evaluate that the 
Benefit/Risk ratio is always in favour of the continuation of the study. A particular attention will be paid in 
observed haematological toxicities. It will also review one interim analysis of efficacy after half of the planned 
events have occurred. The IDMC will decide during this first meeting the further frequency of IDMC meetings 
(at least annually). 
 
Data presented to IDMC are strictly confidential. Interim analyses will be presented to the IDMC 
 
The IDMC may recommend the early termination of the trial if one of the following conditions is met: 
• 
The results of the interim analysis clearly show that the experimental treatment is superior to the 
reference treatment; 
• 
An unacceptable toxicity  
• 
Data available from the trial or any other source of information are sufficiently convincing to influence 
the therapeutic practice of the majority of clinicians. 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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The IDMC has only a consultative role; it will inform the sponsor who will decide whether the IDMC 
recommendation will be followed. 
 
11.2 Steering Executive Committee 
 
The Unicancer Project leader will coordinate the day-to-day study activities according to the planned calendar. 
The study progress and any relevant information or issues will be communicated to the coordinating 
Investigators, and discussed with the collaborative UCGI group.   
 
A dedicated steering committee, including at least the Study Coordinators, the Project Leader, and 
representatives from the investigational sites will meet regularly to supervise the trial. The steering committee 
will be responsible for the review of clinical issues arising during the study, the quality of the trial, verification 
of study-related collaborations, the interpretation of results, and the development of a communication strategy 
for the study. SAEs and SUSARs reported, study accrual, as well as, difficulties encountered by investigators 
will be discussed during steering committee meetings. The committee may decide to amend the study during 
these meetings, if required. The Steering Committee will meet as frequently as needed to discuss potential 
critical points but no less than twice annually. The UCGI steering committee will also monitor the trial and 
ensure the good execution and progress of the trial. 
 
The Steering executive committee will assist UNICANCER in resolving issues and/or questions encountered 
during the trial and will consider with UNICANCER changes to the protocol as necessary. 
 
 
 
12. QUALITY ASSURANCE 
 
12.1 Data collection 
All data necessary for the research must be entered into the trial case report forms (CRFs) in a timely manner. 
CRFs will be completed by the principle investigator and other staff members duly designated. The data 
entered must be accurate and complete. 
 
 
In order to guarantee the authenticity and credibility of the data in accordance with the Good Clinical Practices, 
the sponsor will set up an assurance quality program that includes: 
• 
specific procedures for the protocol 
• 
management of the trial according to trial specific procedures provided by UNICANCER.  
• 
control of the quality of the data provided by the investigation site is performed by the 
study monitor the role of which is to match and check the consistency of the data reported 
in the observation handbook with respect to the source-documents, 
• 
possible audit of investigational sites,  
• 
conducting a centralized review covering certain aspects of the protocol (to be specified). 
 
The trial database will be hosted by: 
 
Institut du Cancer Montpellier (ICM) – Val d’Aurelle 
Unité de Biométrie – CTD INCa 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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208 rue des Apothicaires - Parc Euromédecine 
34298 Montpellier Cedex 5 – France 
 
 
Database management will be provided by an electronic Case Report Form (eCRF) developed using the 
CSOnline module of Ennov Clinical® software. In case of technical problem with the eCRF, the investigator 
may refer to the specific operating procedure of the eCRF or directly contact:  
 
ICM – Unité de Biométrie – CTD INCa 
Data centre UNICANCER 
from Monday to Friday 9 am-5 pm 
email: support.ecrf@icm.unicancer.fr 
Fax: +33 (0)4 67 61 37 18 
Tel: +33 (0)4 67 61 45 48/24 52 
 
The access code (login) and passwords to access the eCRF will be sent directly to each users personal email 
account. The logins and personal passwords to connect to the eCRF, via the website - 
https://ecrf.icm.unicancer.fr/ CSOnline, will automatically be generated by CSOnline. 
 
A password non-disclosure certificate will be signed by the principal investigator of each centre engaging 
his/her responsibility regarding the confidentiality of the access codes for all users of the eCRF at their centre.  
 
Trial data will be entered directly by the principle investigator or by designated staff members of each centre, 
via the eCRF, and will be controlled and validated according to the standard procedures (included those in the 
software and the sponsor’s quality assurance procedures). When using the eCRF, traceability of access and 
changes made to the eCRF are traced by the software (audit trail). At the end of the trial and once all the eCRF 
data are validated, the investigator will login to the eCRF to sign all the pages to validate the data entered for 
each patient. 
The sponsor will create and send an electronic copy (PDF file) of each patient’s CRF to the corresponding 
investigator. This pdf file must be printed and signed by the investigator, and then archived at the investigator’s 
site. 
 
The CRF will be considered as the source document for the data indicated above. 
 
 
 
12.2 Access to data 
 
 
The sponsor has direct access to all investigator sites, original records, source data/document and reports to 
allow quality control and auditing by the sponsor or on behalf of the sponsor. 
 
Investigators will make available to the authorised persons the documents and the patients’ individual data 
that are essential to monitor the trial on an ongoing basis, to perform quality control and audit of this research 
in accordance with national regulatory requirements. 
 
12.3 Trial monitoring 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
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 The management and the monitoring of the trial according to UNICANCER procedures. The 
monitoring strategy is built according to a systematic, prioritised, risk-based approach, and is 
documented in the monitoring plan. 
 The quality control of data at the investigational centres by the monitor(s), which involves: 
 verifying that the protocol, as well as the current guidelines ICH-GCP, the national regulatory 
requirements, are adhered to 
 verifying the informed consent and the eligibility of each patient participating in the trial 
 verifying that the CRF data is consistent and in agreement with the source documents 
 verifying the notification of each SAE 
 verifying the drug traceability (dispatching, storage, and accountability) 
 verifying (if applicable) that patients are not already participating in another clinical study 
making them ineligible for this protocol.  
 
The quality control of data by a centralised monitoring process. Centralised monitoring is a remote 
evaluation of data, performed in a timely manner, supported by appropriately qualified and trained 
persons (e.g., data managers, biostatisticians). Review, that may include statistical analyses, of 
accumulating data from centralised monitoring can be used to: 
 Identify missing data, inconsistent data, data outliers, unexpected lack of variability, and 
protocol deviations. 
 Examine data trends such as the range, consistency, and variability of data within and across 
sites. 
 Evaluate for systematic or significant errors in data collection and reporting at a site or across 
sites; or potential data manipulation or data integrity problems. 
 Analyse site characteristics and performance metrics. 
 Select sites and/or processes for targeted on-site monitoring. 
 
The audit of participating investigational centres when deemed necessary 
 
The monitors/CRAs in charge of trial monitoring will be mandated by the sponsor. They must have direct 
access to all patient data required to perform their duty in accordance with the national regulatory 
requirements. The monitors/CRAs are bound by professional secrecy under the national regulatory 
requirements. Written reports must be issued to ensure the traceability of monitoring visits. 
 
To ensure optimal research quality control the investigator will ensure that the monitor/CRA has direct access 
to all trial patient files.  
 
12.4 Audits and inspections 
 
 
As part of UNICANCER’s audit program, the sponsor may audit some investigational centres. The centre and 
the investigator agree that audits be carried out by Sponsor or any person duly authorised during the trial and 
for at least 15 years after the trial.  
 
The investigational centre and the investigator agree to devote the time necessary for the audit procedures, 
allow the control of the trial documentation, and provide additional information requested by the sponsor. 
 

 
 
 
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A Competent Authority may also request a trial inspection (during the trial or after its completion). If a 
Competent Authority requests an inspection, the investigator must inform the sponsor immediately of this 
request. The investigator must allow the inspectors direct access to the trial documents and source documents. 
The investigational centre and the investigator agrees to devote the time necessary for inspections procedures, 
allow the control of the trial documentation, and provide additional information requested by the inspectors of 
the concerned Competent Authority. 
 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1 General requirements 
 
Prior to the start of the trial, the sponsor or the investigator will submit the trial protocol, patient information 
sheet(s), informed consent form(s), and other trial-related documents as required by local regulations, to the 
respective regulatory authorities for their authorizations and the responsible Independent Ethic Committee 
(IEC)/Institutional Review Board (IRB) for their written approval. 
 
The sponsor or the investigator will inform the IEC/IRB and regulatory authorities, according to local 
regulatory requirements, about protocol amendments including any new information that require an 
ethical/regulatory reconsideration of the trial protocol. 
The collection of biological samples implemented within the framework of the trial was declared to ANSM in 
the same time that the request of Clinical Trial Authorization. After the trial, and in case of storage, the 
storage of the collection of biological samples will be notified to the Minister of Research (and submitted to 
the CPP to notice if change of purpose of Research). 
 
The trial must be conducted in accordance with the French national regulatory requirements: 
• 
The principles of ethics as stated in the last version of the Declaration of Helsinki. 
• 
Loi n°2012-300 du 5 mars 2012 relative aux recherches impliquant la personne humaine as modified 
in 2016 
• 
Regulation (EU) 2016/679  on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data (General Data Protection Regulation). 
• 
Amended Loi Informatique et Libertés n° 78-17 du 6 janvier 1978, relative à la protection des 
personnes physiques à l'égard des traitements de données à caractère personnel, 
• 
Amended Loi n° 2004-800 du 6 août 2004, relative à la bioéthique,  
• 
Décision du 24 novembre 2006 fixant les règles de bonnes pratiques cliniques pour les recherches 
biomédicales portant sur des médicaments à usage humain 
• 
Good Manufacturing Practices, in particular, Annex 13 on investigational medicinal products. 
 
13.2 Patient identification 
 
Patient will be identified by a code, the first letter of the last name/surname, the first letter of the first name, 
and the month and year of the date of birth.  
 
All patients will receive a unique patient identification number when signing the informed consent form by the 
patient and before any trial procedure is performed. This number will be used to identify the patient throughout 
the trial and must be used on all trial documentation related to this patient. The patient identification number 
must remain constant throughout the trial. 
 
13.3 Patient information and consent 
 

 
 
 
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Patient information and informed consent from the patient must be handled in accordance with the “French 
regulation, especially article L.1122-1 and subsequent articles. 
Prior to the participation of a patient in the trial, this patient will be informed both verbally and in writing about 
the objectives of the trial, its methods, anticipated benefits and potential risks and the discomfort to which they 
may be exposed. All items must be explained by the investigator in a language and in terms that are easy to 
understand by the patient. The patients must be given enough time to consider their participation and decide 
whether they wish to participate or not in the trial. Patients will also be informed that their participation is 
voluntary and that they have the right to withdraw from the trial at any time without giving the reasons and 
without this impacting their subsequent medical care. 
The patient information sheet and the informed consent form must be associated within the same document 
to ensure that all information regarding the trial is provided to the patient. Patients will confirm their consent in 
writing prior to starting the trial and before undergoing any trial-related procedure. Two original informed 
consent forms must be personally dated and signed by the patient and investigator. An original copy will be 
filed in the Trial Master File (TMF). The other original patient information sheet and the signed informed consent 
form will be given to the patient. 
If the patient decides to withdraw from the trial, the patient is not obliged to give reason(s) for withdrawing. 
However, the investigator should make a reasonable effort to obtain the reason(s) while fully respecting the 
patient’s rights. 
In conformance with the data protection regulation, the patient may use their right to access to, rectify or 
oppose the use of their personal data in the research. In these situations, the investigator shall inform the 
sponsor without delay in order to take the appropriate steps. 
 
If any changes in the written patient information or informed consent form occur during the trial, the investigator 
will ensures that all patients impacted by the changes and still participating in the trial receive the updated 
patient information in a timely manner and are asked for written consent for the changes made. 
 
 
13.4 Insurance compensation 
 
UNICANCER, the sponsor of the trial certifies that it has taken out a civil liability insurance policy covering its 
civil liability for this clinical trial under its sponsorship. This insurance policy is in accordance with local laws 
and requirements. The insurance of the sponsor does not exempt the investigator and its team from 
maintaining their own liability insurance policy.  
 
13.5 Investigator responsibilities 
 
The principal investigator of each investigator site participating in the trial commits to conduct the trial as 
specified in this protocol and in accordance with the “Décision portant sur les Bonnes Pratiques Cliniques, 24 
November 2006”. 
 
It is the responsibility of the principal investigator to: 
• 
Provide to the sponsor with their curriculum vitae (CV) and those of their collaborators, and evidence 
that the centre will be able to conduct the trial. The CV must be current (no older than 1 year), dated 
and signed; 
• 
Identify the members of their team who participate in the trial and define each team members role and 
responsibilities; 
• 
Start recruiting patients only after receiving approval from the sponsor; 

 
 
 
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• 
Be available for monitoring visits, audits, and investigator meetings (if applicable). 
 
It is the responsibility of each principal investigator and each investigator team member to: 
• 
Ensure the confidentiality of all data recorded during the trial; 
• 
Collect the informed consent, written, dated, and signed personally by each individual research 
participant before any specific selection procedure for the trial; 
• 
Regularly complete the case report form (CRF) for each patients included in the trial and allow clinical 
research associate(s) (CRA), mandated by the sponsor, direct access to the source documents in 
order to validated the data collected in the CRF; 
• 
Declare to the sponsor as soon as being aware of, any serious adverse event occurring during the 
trial according to provisions of this protocol; 
• 
Accept regular visits by the CRA(s) and possibly those of auditors mandated by the sponsor or the 
inspectors of the respective regulatory authorities; 
• 
Date, correct, and sign the corrections made in the CRF and the requests of the data correction forms 
(DCF) for each patient included in the trial. 
 
13.6 Federation of the Patient Committees for Clinical Research in Cancerology 
 
This committee reviews trial documents provided to patients in oncology clinical studies, and makes 
suggestions for improving these, in terms of the quality of information given to patients. 
The French patient committees’ federation is coordinated by the “Ligue Nationale Contre le Cancer” and the 
French NCI (INCa).  
 
13.7 Human biological samples collection 
 
Biological studies are necessary to increase the knowledge of diseases, which may allow the development of 
new and more effective treatments. These studies use human biological samples (blood samples) that are 
collected from patients either while they receive medical care (examination, surgery) or specifically for the 
research purpose. 
 
These biological samples will be prepared, stored, shipped, and used for the purpose of research. 
 
These biological samples are subject to written consent from the patient. This consent is revocable at any time 
during the trial. Similarly, at any time during the research, the patient has the possibility to request the 
destruction of their samples. 
 
Furthermore, it must be noted that the results of biological studies may be published only if all data relative to 
the patients are made anonymous. 
 
Concerning genetic research patients must consent to participation in these studies after being informed of 
the proposed research, irrespective of the type of sample collected (already existing or specifically collected). 
 
Furthermore, it must be noted that the results of biological studies may be published only if all data relative to 
the patients are made anonymous. 
 
 
13.7.1 
Collecting additional biological samples for research purpose 
 

 
 
 
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The study includes a translational research aiming to study and identify relevant biomarkers that may provide 
relevant information for clinicians as to whether the patients benefit from chemotherapy in this clinical context.  
 
It will include at least the analysis of constitutional DNA and circulating tumor DNA, performed before treatment 
to investigate constitutional (polymorphisms) or somatic (tumor-related molecular alterations) molecular factors 
with prognostic or predictive value. The correlation of tumor molecular biomarkers with clinical outcomes will 
also be analyzed.  
 
Blood samples will be done at day 1 (before treatment), day 15 of cycle 1 and at disease progression. These 
biological samples will be prepared, stored and used for the purpose of the research. These additional samples 
are optional and subject to a specific additional written consent from the patient. This specific consent for the 
translational research is revocable at any time. In addition, the patient has the right to request the destruction 
of their samples at any moment. The patient can participate to the main study if he refuses to participate to the 
translational study. 
 
14. DATA PROCESSING AND CONSERVATION OF DOCUMENTS AND DATA 
OF THE RESEARCH 
 
14.1 Data processing 
 
14.1.1 
Under the responsibility of the sponsor 
 
The statistical data will be transferred to the trial statistician for analysis. The trial data remain the property of 
UNICANCER, the research sponsor. 
 
The software Clinsight® will be used for data entry, management, and archiving of data. The statistical analysis 
will be performed using Stata software version 13.0. 
 
 
14.1.2 
In the investigational centre, when computerised medical records are used 
 
If computerised patient records are used in a participating centre to process or store trial data, the centre must: 
• 
Verify and document that the computer system used to process the data conforms with the 
requirements concerning data completeness, accuracy, and reliability with respect to expected 
performances (quality validation) 
• 
Define and follow the standardised procedures related to these systems 
• 
Ensure that these systems allow modifications of collected data, that each modification is automatically 
authentified, and that the data cannot be removed (i.e. any change or modification of the data must 
be traceable) 
• 
Set up and maintain a security control to prevent unauthorised access to the data 
• 
Establish and regularly update the list of persons authorised to have access and modify the data 
• 
Carry out appropriate backups of the data 
• 
Ensure confidentiality, whenever it is applicable (e.g. during data input) 
Ensure that the individual computerised patient data are processed in accordance with the “Loi 
Informatique et Libertés n° 78-17, 6 January 1978 modified” 
 
If data are transformed while being processed, it should always be possible to compare them with the original 
observations/records. 

 
 
 
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The computerised system used to identify trial patients must not be ambiguous must allow the identification of 
all data collected for each patient while maintaining confidentiality in accordance with the “Loi Informatique et 
Libertés n° 78-17, 6 January 1978 modified”. 
 
14.2 
Retention of documents by investigator sites  
 
The investigator must maintain source documents for each trial patient. 
 
All information in case report forms must be traceable and consistent with source documents, which are 
generally maintained in the patient’s file. The source documents should contain all demographic and medical 
information, laboratory data, radiology, electrocardiograms, etc., including the original copy of the signed 
patient information sheet and informed consent form. 
 
The investigator must retain essential documents as described below. The investigator agrees to adhere to 
the document retention procedures by signing the protocol. Essential documents include: 
 
• 
Approvals from the CPP for the trial protocol and all relevant amendments 
• 
Authorisations from the ANSM for the trial protocol and all relevant amendments 
• 
All source documents and laboratory records; 
• 
CRF copies; 
• 
Patients’ informed consent forms; 
• 
Investigator master file (IMF) and Investigator master file-pharmacy (IMF-P); 
• 
Any other pertinent trial document. 
 
All trial documents must be kept in a locked and secured place and be considered as confidential. 
 
Data will be archived under the responsibility of the principal investigator of each participating centre according 
to the “Décision portant sur les Bonnes Pratiques Cliniques, 24 November 2006”. The trial documents, 
including a list of patient’s identifications for a minimum period of 15 years after the end of the trial. 
UNICANCER will inform the investigational centres when the trial-related records are no longer required.  
The investigational centre may destroy the data only after written authorisation from the sponsor. 
 
 
 
15. DATA OWNERSHIP AND CONFIDENTIALITY 
 
By signing the protocol, the investigator agrees to keep all information provided by UNICANCER strictly 
confidential and to ensure similar confidentiality from their staff. This obligation does not cover information 
provided to the patients and information already publically available. 
 
Trial documents provided by UNICANCER (protocols, investigators’ brochures, CRFs, and other material) will 
be stored appropriately to ensure their confidentiality. The information provided by UNICANCER to the 
physician-investigator may not be disclosed to others without direct written authorisation from UNICANCER.  
 
The physician-investigator commits to not publish, spread or use in any manner, directly or indirectly, the 
scientific and technical information and results related to the trial. 
 

 
 
 
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16. PUBLICATION RULES 
 
 
All information resulting from this trial is considered to be confidential, at least until appropriate analysis and 
checking has been completed by the sponsor, the principal investigator and the statistician of the trial. 
 
Any publication, abstract or oral presentations including results of the trial must be submitted to the sponsor 
(UNICANCER) for approval. 
 
Additionally, all communications, manuscripts or oral presentations must include a section mentioning 
UNICANCER as well as any institution, physician-investigators, collaborative research group, scientific society 
that has contributed to the trial, including organisations that have provided financial support. 
 
The first author and writer of the main publication will be the principal investigator. The principal investigator 
may however designate another person to (co-) write the publication.  
 
As for the main publication authors are listed in the following order: 
 
the trial coordinator (first or last author) 
 
the other investigators will appear in the list of co-authors in decreasing order, according to the number 
of recruited patients regardless of their affiliation to a cooperative group 
 
a person representing each cooperating group, if a representative is not listed in the sites with the 
highest recruitment rates 
 
the statistician (The statistician’s position is among the first three authors or the last author of the 
publication) 
 
a UNICANCER representative 
 
Similarly, publication of the sub-studies (e.g. biological/ancillary studies) will include persons who have carried 
out the sub-studies as well as the names of all individuals who have contributed to these sub-studies and a 
sponsor representative. 
 
It is desirable to include the contributors from weakly recruiting centres who have not been mentioned in the 
first article in the later publications. 
 
Any conflict regarding publication authorship will initially be submitted to the trial IDMC and then to the CSR 
(Comité Stratégique Recherche [Strategic Research Committee]) for resolution in case of major disagreement. 
 
UNICANCER will arbitrate and rule any dispute that may arise. 
 
 

 
 
 
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17. REFERENCES 
 
[1] 
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus 
gemcitabine 
for 
metastatic 
pancreatic 
cancer. 
NEnglJMed 
2011;364:1817–25. 
doi:10.1056/NEJMoa1011923. 
[2] 
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic 
cancer 
with 
nab-paclitaxel 
plus 
gemcitabine. 
NEnglJMed 
2013;369:1691–703. 
doi:10.1056/NEJMoa1304369. 
[3] 
Goldstein DA, Krishna K, Flowers CR, El-Rayes BF, Bekaii-Saab T, Noonan AM. Cost description of 
chemotherapy regimens for the treatment of metastatic pancreas cancer. Med Oncol Northwood Lond 
Engl 2016;33:48. doi:10.1007/s12032-016-0762-8. 
[4] 
Seufferlein T, Bachet JB, Van Cutsem E, Rougier P. Pancreatic adenocarcinoma: ESMO–ESDO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 2012;23:vii33-vii40. 
doi:10.1093/annonc/mds224. 
[5] 
Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in advanced pancreatic 
cancer: a comprehensive analysis of published clinical trials. Ann Oncol Off J Eur Soc Med Oncol 
2013;24:1972–9. doi:10.1093/annonc/mdt166. 
[6] 
Sohal DPS, Mangu PB, Khorana AA, Shah MA, Philip PA, O’Reilly EM, et al. Metastatic Pancreatic Cancer: 
American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34:2784–96. 
doi:10.1200/JCO.2016.67.1412. 
[7] 
Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al. Second-Line Oxaliplatin, Folinic Acid, 
and Fluorouracil Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: 
Outcomes From the CONKO-003 Trial. J Clin Oncol 2014;32:2423–9. doi:10.1200/JCO.2013.53.6995. 
[8] 
Gill S, Ko Y-J, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al. PANCREOX: A Randomized Phase 
III Study of 5-Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic 
Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol Off J Am Soc Clin 
Oncol 2016. doi:10.1200/JCO.2016.68.5776. 
[9] 
Wang-Gillam A, Li C-P, Bodoky G, Dean A, Shan Y-S, Jameson G, et al. Nanoliposomal irinotecan with 
fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy 
(NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet Lond Engl 2016;387:545–57. 
doi:10.1016/S0140-6736(15)00986-1. 
[10] Portal A, Pernot S, Tougeron D, Arbaud C, Bidault AT, de la Fouchardière C, et al. Nab-paclitaxel plus 
gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective 
multicentre cohort. Br J Cancer 2015;113:989–95. doi:10.1038/bjc.2015.328. 
[11] Zhang Y, Hochster H, Stein S, Lacy J. Gemcitabine plus nab-paclitaxel for advanced pancreatic cancer 
after first-line FOLFIRINOX: single institution retrospective review of efficacy and toxicity. Exp Hematol 
Oncol 2015;4:29. doi:10.1186/s40164-015-0025-y. 
[12] Strobel O, Büchler MW. Pancreatic cancer: Clinical practice guidelines - what is the evidence? Nat Rev 
Clin Oncol 2016;13:593–4. doi:10.1038/nrclinonc.2016.127. 
[13] Liu Y, Ye G, Yan D, Zhang L, Fan F, Feng J. Role of nab-paclitaxel in metastatic breast cancer: a meta-
analysis of randomized clinical trials. Oncotarget 2017. doi:10.18632/oncotarget.18900. 
[14] Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, et al. Nab-paclitaxel versus solvent-
based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, 
randomised, 
non-inferiority, 
phase 
3 
trial. 
Lancet 
Gastroenterol 
Hepatol 
2017;2:277–87. 
doi:10.1016/S2468-1253(16)30219-9. 
[15] Shord SS, Faucette SR, Gillenwater HH, Pescatore SL, Hawke RL, Socinski MA, et al. Gemcitabine 
pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer. 
Cancer Chemother Pharmacol 2003;51:328–36. doi:10.1007/s00280-002-0560-1. 
[16] Kroep JR, Giaccone G, Voorn DA, Smit EF, Beijnen JH, Rosing H, et al. Gemcitabine and paclitaxel: 
pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer. J Clin 
Oncol Off J Am Soc Clin Oncol 1999;17:2190–7. doi:10.1200/JCO.1999.17.7.2190. 

 
 
 
UNICANCER Tumor Group: UCGI 
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[17] Ciccolini J, Serdjebi C, Peters GJ, Giovannetti E. Pharmacokinetics and pharmacogenetics of Gemcitabine 
as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother 
Pharmacol 2016;78:1–12. doi:10.1007/s00280-016-3003-0. 
[18] Maeda S, Motoi F, Onogawa T, Morikawa T, Shigeru O, Sakata N, et al. Paclitaxel as second-line 
chemotherapy in patients with gemcitabine-refractory pancreatic cancer: a retrospective study. Int J Clin 
Oncol 2011;16:539–45. doi:10.1007/s10147-011-0220-8. 
[19] De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, et al. A multicenter analysis 
of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. 
Cancer Chemother Pharmacol 2012;69:415–24. doi:10.1007/s00280-011-1704-y. 
[20] Jake Lokich (2005) Same-Day Pegfilgrastim and Chemotherapy, Cancer Investigation, 23:7, 573-576, 
DOI: 10.1080/07357900500276899 
[21] Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, et al. Gemcitabine plus 
Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior 
anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. doi: 10.1200/JCO.2007.11.9362. 
[22] De Angelis et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a 
population-based study. Lancet Oncol. 2014 Jan;15(1):23-34. doi: 10.1016/S1470-2045(13)70546-1. 
Epub 2013 Dec 5. 
 
  
 
 
 
18. APPENDICES 
 
 
1. Performance status evaluation – WHO scale 
2. ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) 
3. A brief summary of tumour classification RECIST v1.1 
4. Toxicity criteria (NCI-CTCAE) version 5.0 
5. Patient questionnaire(s) – QLQ-C30 
6. Gemcitabine and paclitaxel SmPC 
7. Modified Glasgow Prognostic Score for Cancer Outcomes: calculation method  
 
 

 
 
 
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Appendix 1. 
Performance status evaluation – WHO scale  
 
Performance status 
ECOG-ZUBROD/ OMS 
value 
 
 
Fully active, able to carry on all pre-disease performance without Restriction. 
 
0 
 
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. 
 
1 
 
 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
 
2 
 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
3 
 
 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
 
4 
 
 

 
 
 
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Appendix 2. 
ICH Harmonised Tripartite Guideline for Good Clinical Practice 
(ICH-GCP) 
 
The current ICH-GCP can be found on the European Medicine Agency web page via 
the link provided below: 
 
http://www.ema.europa.eu/ 
 

 
 
 
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Appendix 3. 
A brief summary of tumour classification RECIST v1.1 
(Eur. J. Cancer, 45(2009), 228-247 [47]) 
Full article available at: http://ctep.cancer.gov/ 
 “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)” E.A. Eisenhauer, 
P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, 
L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. 
 
Summary:  
 
Measurability of tumour at baseline: 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable as follows: 
 
Measurable 
Tumour lesions: Must be accurately measured in a 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 calliper measurement by clinical exam; 
 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 exam that is 
not measurable by reproducible imaging techniques. 
 
Remark: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require special considerations 
regarding lesion measurability (see below): 
 
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. 
 
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. 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. 
 
The baseline sum diameters will be used as reference to further characterise any objective tumour regression 
in the measurable dimension of the disease. 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
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 R3_DOC_45_Protocol (EN)- v2 
 
 
 
 
Non-target lesions 
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’ during the trial. 
 
 
Response criteria: 
 
 
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 
 
Warning: 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 trial. This means that when lymph nodes are included as target lesions, the ‘sum’ of lesions 
may not be zero even if complete response criteria are met, since a normal lymph node is deﬁned as having 
a short axis of <10 mm. In order to qualify for CR, each node must achieve a short axis <10 mm.  
 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progression). 
 
Warning: when a progression is recorded with respect to the Nadir but there is a response with respect to 
baseline, progression must be considered. 
 
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for PR nor sufﬁcient increase to qualify for PD, 
taking as reference the smallest sum diameters while on trial. 
 
 
Non-target lesions 
 
 
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. 
. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
Page 60 / 64 
 R3_DOC_45_Protocol (EN)- v2 
 
 
Overall response: 
 
Target lesions 
Non-target lesions 
New lesions 
 
Overall response 
CR 
CR 
No 
= 
CR 
CR 
Non CR/Non PD 
No 
= 
PR 
CR 
PR 
Not evaluated 
Non PD or not all evaluated 
No 
No 
= 
= 
PR 
PR 
SD 
Non PD or not all evaluated 
No 
= 
SD 
Not all evaluated 
PD 
Non PD 
No change 
No 
Yes or No 
= 
= 
Not-evaluable 
PD 
No change 
PD 
Yes or No 
= 
PD 
No change 
No change 
Yes 
= 
PD 
 
 
Special considerations regarding baseline lesion measurability 
 
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. 
  
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. 
 
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. Trial protocols should detail the conditions under which such lesions would be considered 
measurable. 
 
 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
Page 61 / 64 
 R3_DOC_45_Protocol (EN)- v2 
 
 
Appendix 4. 
Toxicity criteria (NCI-CTCAE) 
 
In the present trial, adverse events will be recorded according to the 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE), (Publish Date 
November 27, 2017) 
 
Toxicity evaluation scale provided separately in attached documents or download it 
from the NCI website  
 
 
 
 
 
 
http://ctep.cancer.gov/ 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
Page 62 / 64 
 R3_DOC_45_Protocol (EN)- v2 
 
 
 
 
 
 
Appendix 5. 
Patient questionnaire(s) 
 
 
 
 
 
http://groups.eortc.be/qol/sites/default/files/img/slider/specimen_qlq-c30_english.pdf 
 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
Page 63 / 64 
 R3_DOC_45_Protocol (EN)- v2 
 
 
 
 
Appendix 6. Summary of product characteristics (SmPC) 
 
Please refer to the following websites for gemcitabine and paclitaxel SmPC : 
 
Gemcitabine SmPC: http://agence-
prd.ansm.sante.fr/php/ecodex/extrait.php?specid=67728176 
 
Paclitaxel SmPC : http://agence-
prd.ansm.sante.fr/php/ecodex/extrait.php?specid=61174122 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
UNICANCER Tumor Group: UCGI 
Protocol n°: UC-0110/1809 
EudraCT n°: 2018-002886-21 
 
 
 
Protocol GEMPAX n°: UC-0110/1809_version n°6  – 13 July 2023 
Page 64 / 64 
 R3_DOC_45_Protocol (EN)- v2 
 
 
 
Appendix 7. 
Modified Glasgow Prognostic Score for Cancer Outcomes: 
Calculation method 
 
 
 
 
C-reactive protein 
level (mg/L) 
Albumin level 
(g/dL) 
Modified Glasgow Prognostic 
Score (mGPS) 
Interpretation 
≤ 10 
≥ 3.5 
0 
Good prognosis 
≤ 3.5 
> 10 
≥ 3.5 
1 
Intermediate prognosis 
> 10 
≤ 3.5 
2 
Poor prognosis 
 
 
Website link for calculation: https://www.mdcalc.com/modified-glasgow-prognostic-score-
mgps-cancer-outcomes