Clinical trial NCT01655693
Conditions: Carcinoma, Hepatocellular
Keywords: Intermediate/advanced hepatocellular carcinoma After failure or intolerance to Sorafenib.
Sponsor: Valerio Therapeutics
Start date: 2012-06-01; Completion date: 2019-05-01
Enrollment: 397 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this phase III study is to determine whether Doxorubicin Transdrug (DT) is effective in the treatment of patients suffering from advanced Hepatocellular Carcinoma (HCC) after failure or intolerance to Sorafenib. Patients with HCC with or without cirrhosis and with good liver functions are eligible. Only those who can not benefit from treatment for which efficacy is demonstrated are eligible.

These patients are usually proposed either best standard of care (BSC) or participation to clinical trials. Patients eligible for the RELIVE study will receive either DT at 20 mg/m2 or DT at 30 mg/m2 or the BSC.

Detailed description:
Doxorubicin-Transdrug™ (DT) is a nanoparticle formulation of doxorubicin.In in vitro and in vivo models, DT was shown to overcome the multidrug resistance (MDR) and to be more effective than doxorubicin on both sensitive and resistant tumour models and in particular in the X/myc bi-transgenic MDR murine model of HCC.

Arms: arm 1: DT will be infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity arm 2: DT will be infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity arm 3: Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or unacceptable toxicity
Interventions: intervention 1: Doxorubicin 20 mg/m2 intervention 2: Doxorubicin 30 mg/m2 intervention 3: Best Standard of Care
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
Doxorubicin Transdrug™ 
Protocol BA2011/03/04 
Version 7.0, July 27th, 2017 
Confidential 
Page 1 / 123 
CLINICAL TRIAL PROTOCOL 
The particulars contained in this protocol are reserved for the Investigator and the Investigator’s staff, the Ethics 
Committee/Institutional Review Board and relevant authorities. They may not be disclosed to any third parties without the 
written authorization of ONXEO (formerly known as BioAlliance Pharma), with the exception of patients or volunteers in 
the context of informed consent. 
 
Compound Name: 
Doxorubicin Transdrug™
EudraCT Number: 
IND: 
Protocol Number: 
BA2011/03/04 
Phase: 
Phase III 
Version and Date: 
Sponsor: 
Version 7.0, July 27th, 2017 
Replaces 6.0, April 29th, 2016 
ONXEO (formerly known as BioAlliance 
Pharma) 
 NCT Number: 01655693
MULTICENTRE, RANDOMISED, CONTROLLED, OPEN-LABEL, STUDY 
COMPARING THE EFFICACY AND SAFETY OF SLOW REPEATED 
INTRAVENOUS INFUSIONS OF 2 DOSES OF DOXORUBICIN 
TRANSDRUG™ (DT) (20 MG/M2 OR 30 MG/M2) TO THOSE OF BEST 
STANDARD OF CARE (BSC) IN PATIENTS WITH ADVANCED 
HEPATOCELLULAR CARCINOMA (HCC)  
AFTER FAILURE OR INTOLERANCE TO SORAFENIB.  
ReLive study 




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RESEARCH FACILITIES 
 
Monitoring Europe and Turkey 
Company 
CHILTERN INTERNATIONAL SARL 
Address 
 
 
 
Monitoring US 
Company 
CHILTERN INTERNATIONAL SARL 
Address 
  
  
 
Monitoring MENA (Middle East and North Africa ) 
Company 
MCT 
Address 
 
 
 
 
 
 
Drug packaging  
Company 
AMATSI 
Address  
  
 
 
Pharmacokinetics Analyses 
Company 
Bertin Pharma at CEA/LEMM  
Address 
 
 
 
Data Management 
Company 
LINCOLN  
Address 
 
 
 
 
Biostatistics (Safety data for DSMB meetings) 
Company 
Effi-Stat 
Address 

  
 
Biostatistics (Final analysis) 
Company 
CHILTERN INTERNATIONAL SARL 
Address 
 
 
 
 


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ACCEPTANCE OF THE PROTOCOL BY THE SPONSOR 
AND THE INVESTIGATOR 
 
TITLE OF THE PROTOCOL:  
Multicentre, randomised, controlled, open-label study comparing the efficacy and 
safety of slow repeated IV infusions of 2 doses of Doxorubicin-Transdrug™ (DT) 
(20mg/m2 or 30mg/m2) to those of Best Standard of Care (BSC) in patients with 
advanced Hepatocellular Carcinoma (HCC) after failure or intolerance to 
Sorafenib. 
ReLive study 
 
 
Name 
Position 
Date 
Signature 
The Sponsor: 
 
 
Clinical Development 
Director 
 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
The signature constitutes the approval of this protocol and the attachments, and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and according to local and regulatory requirements and applicable US federal regulations, 
European regulations, other local regulations and ICH E6 Guidance for Good Clinical Practice. 


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SYNOPSIS 
NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
Study Title: Multicentre, randomised, controlled, open-label study comparing the efficacy and safety of slow 
repeated IV infusions of 2 doses of Doxorubicin Transdrug™ (DT) (20mg/m2 or 30mg/m2) to those of  Best 
Standard of Care (BSC) in patients  with advanced Hepatocellular Carcinoma (HCC) after failure or intolerance to 
Sorafenib. The ReLive Study 
Study Code Number: BA2011/03/04 
Objectives: 
Primary objective :  
− 
To compare the overall survival (OS) of repeated slow IV infusions of 20 mg/m² or 30 mg/m² DT to the 
Best Standard of Care (BSC) in patients with advanced HCC after failure or intolerance to Sorafenib. 
Secondary objectives :  
− 
To compare additional efficacy parameters as progression free-survival (PFS) and objective response rate; 
− 
To determine the optimal dose of DT infusions; 
− 
To evaluate the safety of DT; 
− 
To assess PK parameters of DT at the doses of 20 and 30 mg/m2; 
− 
To evaluate pharmacodynamics parameters and predictive factors of safety and efficacy: relationship 
between efficacy and safety (clinical, biological…) parameters, concentrations of doxorubicin and blood 
biomarkers. 
− 
To measure QoL using a generic health-related questionnaire 
Methodology/Study Design: 
Multicentre, open label, randomised, with 3 parallel groups study comparing DT 20 mg/m2, DT 30 mg/m2 to BSC 
Phase: III 
Number of Subjects: 130 patients per group for a total of 390 patients  
Number of centres:  around 100 centres 
Diagnosis and Main Criteria for Inclusion: 
Inclusion criteria: 
1. Male or non-pregnant, non-breast feeding female;  
2. Aged  18 years; 
3. Patients with 
− advanced HCC (BCLC-C according to BCLC staging classification) having progressed under Sorafenib 
therapy or intolerant to Sorafenib, or 
− intermediate HCC (BCLC-B) non eligible or non responders to transarterial chemoembolization (TACE), 
and having progressed under or intolerant to Sorafenib therapy;  
4. Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic vein thrombosis without 
extension in inferior/superior vena cava, are eligible; 
5. HCC diagnosed according to the AASLD and/or EASL criteria: 


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NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
− Radiological Criteria applicable in cirrhotic liver: 
− 
Nodule  10 mm: one imaging technique among MRI and CT-scan showing typical appearances for 
HCC defined as arterial enhancement and rapid washout in portal venous or delayed phase; 
− 
If appearance not typical for HCC on initial imaging: second contrast enhanced study (CT or MRI) 
showing typical appearances for HCC defined as arterial enhancement and rapid wash-out in portal 
venous or delayed phase; 
− And/Or cyto-histology criteria (e.g. in case of atypical lesions for HCC at imaging, absence of cirrhosis); 
6. Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included); 
7. ECOG Performance Status 0 or 1; 
8. Adequate laboratory tests, in particular with: 
− 
Platelets  50,000 /mm3 
− 
Neutrophil count   1000 /mm3 
− 
Hemoglobin  10g/dL 
− 
Serum transaminases < 5 ULN (NCI/CTC grades 0, 1, or 2) 
− 
Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2) 
− 
Serum bilirubin < 35 µM/L (or 2.0 mg/dL); 
9. Signed and dated written informed consent form. 
 
Exclusion criteria: Patients with any of the following criteria must not be included 
1. Cirrhosis with a Child-Pugh score B8-C15; 
2. Untreated chronic hepatitis B (in case of chronic hepatitis B, an efficacious antiviral treatment should have been 
started before randomisation to be included in the study); 
3. Patients eligible for curative treatments (transplantation, surgical resection, percutaneous treatment); 
4. Patients eligible for palliative treatments with demonstrated efficacy: TACE, sorafenib; Patients who failed to 
sorafenib treatment or intolerant to sorafenib are eligible and can be included if sorafenib has been stopped at 
least 2 weeks before randomisation;  
5. Other prior malignancy without complete remission in the last five years, with the exception of adequately 
treated basal cell carcinoma or in situ cervical cancer; in case of other prior malignancy, the diagnosis of HCC 
has to be histologically proven; 
6. HCC developed on transplanted liver; 
7. Known HIV infection; 
8. Risk of variceal bleeding  - i.e. patients with stage 2-3 varices with fragility signs (patients at risk for variceal 
bleeding may be included after a preventive treatment (oesophageal varices ligation, beta blockers) has been 
administered); DT will not be administered in case of digestive bleeding in the 4 previous weeks; 
9. SaO2 < 95%; 
10. Presence of a significant acute or chronic respiratory disease defined as NCI /CTCAE > grade 2; 
11. Presence of recent (< 6 months) or current cardiac failure (class II, III or IV NYHA classification), baseline 
LVEF < LLN by either cardiac ultrasound or cardiac scintigraphy; recent (< 6 months) acute coronary 
syndrome, clinically significant ECG abnormalities or recent (less than 6 months) acute vascular diseases 
(stroke, MI…);  
12. Prior cumulative dose of 300 mg/m² of doxorubicin or equivalent; 
13. Patients currently treated with immunosuppressive agents that cannot be stopped; 
14. Patients whose medical or surgical conditions are unstable and may not allow the study completion or 
compliance, and especially patients with uncontrolled diabetes; 
15. Uncontrolled systemic infection;   
16. Patients with a life expectancy of less than 2 months; 


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NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
17. Patients who have received an experimental drug in another clinical trial in the last 30 days prior to 
randomisation in the present clinical trial; 
18. Women of child-bearing age who are unwilling or unable to use an effective contraception method (oral 
contraception or intra-uterine device for woman) during the study treatment period and for 6 months after the 
last administration of study drug, and their male partner(s) refusing to use a condom (if applicable),  
Men who are unwilling or unable to use a condom during the study treatment period and for 6 months after the 
last administration of study drug, and  their female partner(s) refusing to use one of the appropriate effective 
contraception methods (if applicable); 
19. Patients unwilling or unable to comply with protocol requirements and scheduled visits. 
 
Randomisation : Randomisation will be performed using IWRS with stratification per region 
Drug Being Tested, Dose, Method of Administration : 
Product name:
Doxorubicin Transdrug™ 10 mg (DT)
Unit dose:
Two dose levels: 20 mg/m2 and 30 mg/m2
Regimen:
Once every 4 weeks
Mode/route:
Slow IV Infusion over 6 hours 
Study treatment period: 
1. The patients randomised in Doxorubicin Transdrug™ groups will be hospitalized or will have an 
outpatient visit on D0 to check eligibility criteria for continuing treatment and to ensure that the 
premedication will be taken. Patient will receive DT infusion on D1 and will be hospitalized until D2. 
Patient could be discharged on D2 or on D3 in the absence of toxicity. Study treatment will be repetead 
every 4 weeks until unequivocal progression (assessed by the investigator) or unacceptable toxicity. Study 
visits will be performed at the beginning of each cycle, at day 14 of each cycle and one month after the 
last study drug administration (end of study visit). 
2. The patients randomised in control group will receive the Best Standard of Care per local practice. Study 
visits in the control group will be performed at the same schedule than in the DT arms on each cycle 
initiation, day 14 and one month after the last study drug administration (end of study visit).  
Duration of Treatment:  
In all groups, until disease progression or unacceptable toxicity. For patient randomised in Doxorubicin 
Transdrug™ group, the total dose of Doxorubicin or equivalent will not exceed 550 mg/m2 (this takes into account 
prior anthracyclins cumulative dose and DT cumulative dose).  
 
Follow-up period: 
Follow-up survival status of all patients (including patients who prematurely withdraw) will be maintained every 3 
months until death. The follow-up period is defined as “until 2 years after the Last Patient In”.  
 
Criteria for Evaluation: 
Primary endpoint: Overall survival (OS)
Secondary efficacy endpoints:  
− 
Progression-free survival (PFS) by the Independent Radiological Review according to RECIST 1.1; 


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NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
− Objective Response Rate (ORR) by the Independent Radiological Review according to RECIST 1.1 
Exploratory efficacy endpoints*:  
− 
Progression-free survival by the investigator’s evaluation according to RECIST 1.1; 
− 
Objective Response Rate by the investigator’s evaluation according to RECIST 1.1; 
− 
Time To Progression (TTP), Best Overall Response and Disease Control Rate;  
− 
Time to Objective Response and Duration of Response; 
− 
Evolution in serum α-fœtoprotein levels (AFP). 
*PFS and ORR will be analyzed by the investigator evaluation according to RECIST 1.1 and according to 
modified RECIST for HCC (if possible), and by the Independent Radiological Review according to the modified 
RECIST for HCC (if possible). TTP, Best Overall Response, Disease Control Rate, time to objective response and 
duration of response will be analyzed by the Investigator Evaluation and by the Independent Radiological 
Review, according to RECIST 1.1 and according to modified RECIST for HCC (if possible). 
Safety endpoints:  
Respiratory: 
− 
Incidence and duration of reduction of SaO2 during DT infusion (in DT arms); 
− Incidence and severity of respiratory events; 
Cardiac  
− Incidence and severity of cardiovascular events (including BP and HR); 
− ECG and LVEF change; 
Overall 
− Incidence and severity of all TEAEs and SAEs according to NCI-CTCAE v4.0 scale; 
− Biological (haematology and biochemistry analyses, and particularly AST/ALT, WBC). 
Pharmacokinetic endpoints (in selected sites for PK): 
− 
Pharmacokinetic profile of Doxorubicin and its metabolites; 
− Relationship between efficacy and safety (e.g., clinical, biological) parameters, concentrations of total 
and free doxorubicin and doxorubicinol and blood biomarkers  
Quality of Life: 
− 
EuroQoL EQ-5D questionnaire to be completed by patients during the study treatment period: at 
baseline, then every 2 cycles and finally, at progression or at the latest, if treatment is stopped for other-
than-progression reasons (e.g., end of study visit)  
 
Statistical methods: Sample size calculation and main efficacy analyses 
The study primarily aims at demonstrating the efficacy of a 6-hour slow DT infusion in patients with advanced 
HCC after failure or intolerance to Sorafenib.  
Sample Size Calculation: 
Overall population: 


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NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
Under the assumptions of a median survival of the control group of 8 months and a hazard ratio of 0.69, the required 
total sample size to achieve a 85% power to compare the experimental group (pooled DT 20mg/m2 and DT 30mg/m2 
groups) versus BSC with a significance level of 2.5% one sided is 348 patients in the ITT population (116 patients 
in the BSC group and 232 patients in DT groups). It is expected that 10% of patients will be lost to follow-up; this 
leads to a calculated total sample size of 390 randomised patients. 
Child Pugh A population (85% of the patient population): 
Under the assumptions of a median survival of the control group of 9 months and a hazard ratio of 0.68, the required 
total sample size to achieve a 80% power to compare experimental group (pooled DT 20mg/m2 and DT 30mg/m2 
groups) versus BSC with a significance level of 2.5% one sided is 291 patients in the ITT Child Pugh A population 
(97 patients in the BSC group and 194 patients in DT groups). It is expected that 10% of patients will be lost to 
follow-up; this requires for a calculated total sample size of 324 ITT Child Pugh A randomised patients. 
Main efficacy analyses: 
Results will be presented by treatment group and with all treatment groups pooled. 
The primary endpoint is overall survival in the ITT population (all randomized patients). The 95% confidence 
intervals for hazard ratios and median times will be constructed and the Kaplan-Meier method will be used and 
plotted as curves by treatment group (pooled DT 20mg/m2 and DT 30mg/m2 groups) versus BSC group. The  
comparison between experimental group and BSC group will be made using the unstratified LogRank test. The 
analysis will be performed when 285 events have been observed.  
The hierarchical sequential closed test procedure will be used to control the overall type I error rate of 5% to evaluate 
first the OS primary endpoint in the ITT overall population, then if statistically significant, the OS primary endpoint 
in ITT Child Pugh A population and then if statistically significant, the two main secondary endpoints (PFS and 
OOR) in the ITT Child Pugh A population. 
To determine the optimal dose of DT between 20mg/m2 or 30 mg/m2, all statistical analyses (efficacy and safety) 
will be repeated as exploratory in the DT 20mg/m2 group alone versus BSC and DT 30mg/m2 group alone versus 
BSC. The dose of DT which presents the best benefit/risk ratio will be selected.  
For secondary and exploratory endpoints, all time to event endpoints will be estimated using the Kaplan-Meier 
method and plotted as curves by treatment groups. The comparisons between DT groups and BSC will be made 
using LogRank tests. Proportion of subjects with objective response, disease control… will be compared between 
DT groups and BSC by the chi-square test. Estimates and 95% confidence intervals for the difference in proportions 
between DT groups and BSC will be provided. Estimate and confidence intervals for the odds-ratio will also be 
provided. 
 
Data and Safety Monitoring Board (DSMB): 
An independent DSMB will be organized to regularly evaluate the safety of DT during the study. The DSMB will 
be regularly provided with safety data. Safety data will be provided  by patient and by treatment group with 
relevant information every 75 patients (around 25 patients/group) or at least twice a year. The DSMB will remain 
blinded for its evaluation but may ask for unblinding if required. The DSMB will receive every serious adverse 


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NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
events within 24 hours and will recommend to continue or halt the recruitment in case of serious and related 
adverse events in the respective cohort.  
Following their risk evaluation, the DSMB reserves the possibility of alerting the Sponsor in the event of 
observation of highly unexpected events. The DSMB may request a futility analysis on the primary criterion of 
overall survival. This futility analysis serves one objective: to recommend the potential discontinuation when it is 
unlikely, based on the interim results, to achieve statistically significant results at the end of the study. This futility 
analysis will be realized under the responsibility of the DSMB statistician. The results of this futility analysis will 
be disclosed only to DSMB members. No one in the Sponsor representatives has access to such information. No 
information about these results will be communicated to investigators and the International Coordinating 
Investigator. 
Study Timelines: 
Study Duration (FPI to final primary endpoint analysis) : 5 years 
Start date (FPI): Quarter 2 2012  
End of recruitment date (LPI): anticipated End 2016/Q1 2017 
Final primary endpoint analysis): anticipated 2017 
End of Study: End of overall survival follow-up period defined as 2 years after LPI; anticipated Q1 2019 
 
Safety measures:  
For patients randomised in the DT groups: 
Premedication will be administered during three consecutive days starting one day before DT administration. It 
will consist of methylprednisolone 32 mg (or equivalent) + cetirizine 20 mg (or equivalent ) per day.  
SaO2 will be monitored during 24 hours as follows: 
o During the 6-hour DT infusion  
- 
Continuous monitoring of SaO2: 
 
If SaO2 < 93%  reduction of DT infusion rate by half. No changes in dose; 
 
If SaO2  90% 	
	

 
- 
Monitoring of respiratory symptoms: 
 
In case of a respiratory symptom (dyspnoea, increase in respiratory rate by 5 beats/min and RR > 
20/min)  reduction of DT infusion rate by half. No changes in dose; 
 
In case of persistence of symptoms within 1 hour  immediate and definitive infusion stop. 
o After the end of DT infusion.  
- 
In case of marked decrease in SaO2 or occurrence of respiratory symptoms,  the patient should be 
transferred to intensive care unit for monitoring and treatment up to recovery. 
In case of SaO2 decrease ( 90%) during or after DT infusion, SaO2 will be closely monitored and collected every 
hour until resolution to SaO2  93%.  
Patients with a respiratory adverse event during a previous DT infusion who remain eligible to continue DT 
treatment will have reinforced respiratory safety measures for each additional DT infusions and SaO2 collected 
every hour during infusion and within the 6 hours after the end of infusion. 
The recommended treatment of drug-induced pneumonitis is based on systemic corticosteroids with 
methylprednisolone 1 g/day for 3 days in patients with respiratory failure or lower doses of corticosteroids (i.e 


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NAME OF COMPANY: 
Onxeo (formerly known as 
BioAlliance Pharma) 
NAME OF FINISHED 
PRODUCT: Doxorubicin 
Transdrug™ 10 mg 
NAME OF ACTIVE 
INGREDIENT: Doxorubicin 
methylprednisolone 60 mg every 6 hours) in less severe cases. Before initiating corticosteroid therapy, an 
infectious etiology must be excluded. Supportive care, bronchodilators, IV fluid, vasopressors, and mechanical 
ventilation could be indicated in patients with severe hypersensitivity reactions and circulatory collapse. 
 
In case of ARDS and/or any related life-threatening respiratory serious adverse event, DT study therapy will 
be definitively stopped (i.e. patient will not receive any additional DT infusion).  
Before each additional DT infusions, the following criteria must be met: 
- 
Adequate liver function :  
 Child-Pugh score from A5 to B7 included (if cirrhosis)  
 Serum bilirubin < 35 µM/L (or 2.0 mg/dL) 
- 
Adequate respiratory function defined as SaO2  95%; 
- 
Absence of ongoing infection 
- 
Adequate haematologic tests : 
 Neutrophil count  1000 /mm3 
 Platelets count  50,000 /mm3  
 Haemoglobin  10 g/dL 
- 
No clinical evidence of upper gastrointestinal bleeding 
- 
No other limiting toxicity > grade 2 
In case of grade 3-4 AE, infusion should be delayed  up to 4 weeks until resolution or recovery to CTC grade  2. 
 
For patients randomised in the BSC group 
For patients enrolled in the BSC group, safety measure will be done according to the specificity of the Standard 
of Care and the local practice. 
 








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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AASLD 
American Association for Study of Liver Diseases 
AE 
Adverse Event  
AFP  
Alpha foetoprotein 
ALD 
ALP  
Alcoholic Liver Diseases 
Alkaline Phosphatase  
ALT 
AML 
ARDS 
SGPT or GPT, Alanine Transaminase 
Acute Myeloide Leukemia 
Acute Respiratory Distress Syndrom 
AST 
SGOT or GOT, Aspartate Transaminase 
AUC 
Area Under the Curve 
BCLC 
Barcelona Clinic Liver Cancer 
BP 
BSA 
BSC 
Blood Pressure 
Body Surface Area 
Best Standard of Care 
BW 
Body Weight 
°C 
Celsius degree 
CBC 
CHF 
CI 
Cl 
Complete Blood Counts 
Congestive Heart Failure 
Confidence Interval 
Clearance 
CLD 
Chronic Liver Disease 
CLIP 
Cancer of the Liver Italian Program 
CK 
Creatinin Protein Kinase 
CR 
Complete Response 
CRA 
Clinical Research Assistant 
e-CRF 
Electronic Case Report Form 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CT scan 
Computed tomography Scanner 
CV 
D 
Coefficient of Variation 
Day 
DCR 
DLCO 
DLT 
DSMB 
Disease Control Rate 
Carbon Monoxide Diffusing Capacity 
Dose Limiting Toxicity 
Data and Safety Monitoring Board 


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DT 
Doxorubicin-Transdrug™ 10mg 
EASL 
European Association for the Study of the Liver 
EC 
Ethic Committee 
ECG 
Electrocardiogram 
ECOG 
EDTA 
FEV1 
Eastern Cooperative Oncology Group  
Ethylenediaminetetraacetic acid 
Forced Expiratory Volume in one second 
GCP 
Good Clinical practice 
GGT 
Gamma Glutamyl Transferase 
H 
Hours 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
β-HCG 
Hct 
Human Chorionic Gonadotropin 
Hematocrit 
HCV 
HIA 
HIV 
HR 
Hepatite C virus 
Hepatic intra-Arterial 
Human immunodeficiency virus 
Heart Rate 
IA 
Intra Arterial 
ICF 
Informed Consent Form 
ICH 
IC50 
International Conference on Harmonization 
Half maximal Inhibitory Concentration 
IEC 
Independent Ethic Committee 
IMP 
INR 
ITT 
IV 
IWRS 
Investigational Medicinal Product 
International Normalized Ratio 
Intent To Treat 
Intra-venous 
Interactive Web Response System 
LDH 
Lactate Deshydrogenase  
LVEF 
Left Ventricular Ejection Fraction 
MDR  
Multidrug Resistance 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MELD 
MI 
Model for End-stage Liver Disease 
Myocardial infarction 
µg 
Microgram 
MRI 
Magnetic Resonance Imaging 
MRP 
MTD 
Multidrug Resistance associated Protein 
Maximale Tolerate Dose 


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NASH 
Non Alcoholic Steato-Hepatitis 
NCI/CTC 
NE 
NYHA 
ORR 
OS 
PCT 
National Cancer Institute/Common Toxicity Criteria 
Not Evaluable 
New York Heart Association 
Objective Response Rate 
Overall Survival 
Percutaneous Treatment 
PD 
PFS 
Progressive Disease 
Progression Free Survival 
Pgp 
P-glycoprotein 
 
 
PK 
p.o. 
Pharmacokinetics 
Per Os 
PP 
Per Protocol 
PR 
PS 
Partial Response 
Performance Status 
RECIST 
RF 
Response Evaluation Criteria In Solid Tumour 
RadioFrequency 
RFA 
Radio Frequency Ablation 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SaO2 
SAP 
Oxygen saturation 
Statistic Analysis Plan 
SD 
Stable Disease 
SmPC 
TACE 
Summary of Product Characteristics 
Trans Arterial ChemoEmbolisation 
TEAE 
TNM staging system 
TTP 
Treatment Emergent Adverse Event 
Tumor lymph Node Metastasis staging system 
Time To Progression 
ULN 
VS 
WBC 
Upper Limit Normal 
Versus 
White Blood Cells 
WHO 
World Health Organization 
 
 


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Table of Contents 
1INTRODUCTION ................................................................................................................. 21 
1.1Background ...................................................................................................................... 21 
1.2Rationale .......................................................................................................................... 25 
2TRIAL OBJECTIVES ........................................................................................................... 36 
2.1Primary objective ............................................................................................................. 36 
2.2Secondary objectives ....................................................................................................... 36 
3TRIAL DESIGN ................................................................................................................... 37 
4SUBJECT SELECTION ....................................................................................................... 38 
4.1Inclusion Criteria ............................................................................................................. 38 
4.2Exclusion Criteria ............................................................................................................ 39 
4.3Patient Registration .......................................................................................................... 40 
4.4 Subject Premature Withdrawal ....................................................................................... 40 
5ENDPOINTS AND ASSESSMENTS .................................................................................. 42 
5.1Primary endpoint .............................................................................................................. 42 
5.2Secondary efficacy endpoints .......................................................................................... 42 
5.3Exploratory efficacy endpoints ........................................................................................ 42 
5.4Safety endpoints ............................................................................................................... 43 
Respiratory: ........................................................................................................................... 43 
Cardiac: ................................................................................................................................. 43 
Overall: ................................................................................................................................. 43 
5.5Pharmacokinetic endpoints .............................................................................................. 43 
5.6Quality of life ................................................................................................................... 44 
6TRIAL TREATMENTS ........................................................................................................ 45 
6.1Allocation to Treatment ................................................................................................... 45 
6.2Drug Supplies................................................................................................................... 45 
6.3DT Administration ........................................................................................................... 45 
6.4Best Standard of Care administration .............................................................................. 46 
6.5 Compliance ..................................................................................................................... 46 
6.6 Dose adjustment, dose delay and infusion duration........................................................ 47 
6.6.1  Dose Adjustment: DT Arms ..................................................................................... 47 
6.6.2 Dose Delay: DT arms ................................................................................................ 49 
6.6.3 DT Infusion duration ................................................................................................. 49 
6.6.4 Best Standard of Care Arm ........................................................................................ 49 
6.7Drug Storage and Drug Accountability ........................................................................... 50 
6.8Concomitant Medication(s) ............................................................................................. 50 
6.9Prohibited Medications during the study therapy ............................................................ 50 
6.10 Post study therapy ......................................................................................................... 51 
7TRIAL PROCEDURES ........................................................................................................ 52 
 
7.1 ......................................................................................... SCREENING (DAY-28 TO DAY-
1) ................................................................................................................................... 52 


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7.2Trial Period ...................................................................................................................... 53 
7.2.1. Design of each Cycle of treatment during treatment period ..................................... 53 
7.2.1.1  On Day 0 (24h before study treatment)............................................................... 54 
7.2.1.2 On Day 1 – Treatment visit .................................................................................. 56 
7.2.1.3 On Day 2 and Day 3 (optional) after study treatment .......................................... 57 
7.2.1.4 On Day 14 after study treament ........................................................................... 58 
7.2.2Additional Cycles. ...................................................................................................... 59 
7.2.3End of treatment Notification ..................................................................................... 59 
7.2.4End of Study treatment visit: 1 month after last infusion ........................................... 59 
7.2.5Follow-up period ........................................................................................................ 60 
7.3Biobank and biological material taken during the study ................................................. 60 
7.3.1. Pharmacokinetic study .............................................................................................. 61 
7.3.2. Pharmacogenetic study ............................................................................................. 62 
7.4 Supporting board: Independent Data and Safety Monitoring Board .............................. 63 
7.5Possible risks or discomforts ........................................................................................... 64 
7.6Safety measures ............................................................................................................... 64 
7.6.1 Pulmonary toxicity .................................................................................................... 64 
7.6.2 Haematological toxicity ............................................................................................. 66 
7.6.3 Liver toxicity ............................................................................................................. 66 
7.6.4 Cardiac toxicity ......................................................................................................... 66 
7.6.5 Any other adverse events ........................................................................................... 67 
8SAFETY CRITERIA ............................................................................................................ 68 
8.1Adverse Events ................................................................................................................ 68 
8.2Unexpected Adverse Event Definition ............................................................................ 69 
8.3Serious Adverse Events ................................................................................................... 69 
8.4Severity Assessment ........................................................................................................ 70 
8.5Causality Assessment....................................................................................................... 70 
8.6Withdrawal Due to Adverse Events ................................................................................. 71 
8.7Reporting Requirements .................................................................................................. 71 
8.7.1Non-Serious Adverse Event Reporting Requirements ............................................... 71 
8.7.2Serious Adverse Event Reporting Requirements ....................................................... 72 
8.7.3Progression of underlying malignancy ....................................................................... 73 
9DATA ANALYSIS/STATISTICAL METHODS ................................................................ 74 
9.1Statistical considerations .................................................................................................. 74 
9.1.1Statistical Analysis Plan (SAP) .................................................................................. 74 
9.1.2Sample Size Determination ........................................................................................ 74 
9.1.3General conventions ................................................................................................... 76 
9.1.4Disposition of patients ................................................................................................ 76 
9.1.5Protocol deviations ..................................................................................................... 76 
9.2Population to be analyzed ................................................................................................ 77 
9.3Subjects characteristics .................................................................................................... 77 


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9.4 Efficacy endpoints .......................................................................................................... 77 
9.4.1 Primary endpoint ....................................................................................................... 77 
9.4.2 Secondary endpoints .................................................................................................. 78 
9.4.3 Exploratory endpoints ............................................................................................... 79 
9.5Safety endpoints ............................................................................................................... 81 
Respiratory: ........................................................................................................................... 81 
Cardiac: ................................................................................................................................. 81 
Overall: ................................................................................................................................. 81 
9.6 Determination of the optimal dose of DT ....................................................................... 82 
9.7Interim Efficacy Analysis ................................................................................................ 83 
9.8Risk estimation of any event according to drug exposure ............................................... 83 
10DATA QUALITY ASSURANCE ...................................................................................... 85 
10.1 Data Collection ............................................................................................................. 85 
10.2Study Monitoring ........................................................................................................... 85 
10.3Data Management .......................................................................................................... 85 
11QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 87 
11.1Training of Investigators ................................................................................................ 87 
11.2Training of Monitors – Clinical Research Associates (CRA) ....................................... 87 
11.3Standard Operating Procedures...................................................................................... 87 
11.4Monitoring ..................................................................................................................... 87 
11.5Auditing the Trial by the Sponsor .................................................................................. 87 
11.6Auditing the Trial by Regulatory Authorities ................................................................ 87 
12DATA HANDLING AND RECORD KEEPING ............................................................... 88 
12.1Case report form and Source Data ................................................................................. 88 
12.2Monitoring Plan (visits) ................................................................................................. 88 
12.3Archiving Clinical Trial Files ........................................................................................ 88 
13ETHICS, REGULATORY & LEGAL CONSIDERATION .............................................. 90 
13.1Ethical aspects ................................................................................................................ 90 
13.2Independent Ethics Committees (IEC) .......................................................................... 90 
13.3Ethical Conduct of the Study ......................................................................................... 90 
13.4Regulatory Authority Approvals/Authorizations ........................................................... 91 
13.5Subject Information and Consent................................................................................... 91 
13.6Amendment to the protocol ........................................................................................... 92 
14CONFIDENTIALITY ......................................................................................................... 92 
15DOCUMENTATION AND SOURCE DOCUMENTS ..................................................... 92 
16PUBLICATION OF TRIAL RESULTS ............................................................................. 94 
17FINANCIAL CONDITIONS .............................................................................................. 94 
18REFERENCES .................................................................................................................... 95 
19LIST OF APPENDICES ................................................................................................... 100 


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1 
INTRODUCTION 
1.1 
Background 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 1.2 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
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2 
TRIAL OBJECTIVES 
2.1 
Primary objective 
To compare the efficacy of repeated slow IV infusions of DT at doses of 20 mg/m² or 30 mg/m² 
to Best Standard of Care (BSC) in patients with advanced HCC after failure or intolerance to 
Sorafenib on overall survival (OS). 
2.2 
Secondary objectives 
− To compare DT and BSC in additional efficacy parameters as progression free-survival 
(PFS) and objective  response rate, 
− To determine the optimal dose of DT infusions; 
− To evaluate the safety of DT; 
− To assess PK parameters of DT at the doses of 20 and 30 mg/m2; 
− To evaluate pharmacodynamics parameters and predictive factors of safety and efficacy. 
− To measure QoL using a generic health-related questionnaire 
 
 


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3 
TRIAL DESIGN 
This is a multicentre, open-label, randomised, comparative, 3 arms (DT 20 mg/m², DT 30 
mg/m², Best Standard of Care) study in patients suffering from hepatocellular carcinoma.  
The study will be carried out at multiple hepatology or oncology centres that manage patients 
with HCC with or without cirrhosis. Approximately 100 centres will be involved in the trial. 
Based on the survival data obtained in the phase II clinical trial, it has been calculated that 390 
patients have to be included to adequately compare the efficacy of DT 20 mg/m² and DT 30 
mg/m² to that of BSC.  
A safety evaluation will be carried out on a regular basis at least twice a year by the Data Safety 
Monitoring Board (DSMB) and every 75 patients (around 25 patients/group) whichever comes 
first.  
Patients who meet the inclusion/exclusion criteria will be randomised according to a 1:1:1 ratio 
to receive either DT 20 mg/m², DT 30 mg/m², or BSC. Only those patients whose survival 
expectations is longer than 2 months and could receive more than 1 DT infusion will be 
enrolled. 
The study duration for each patient includes a screening period of 28 +/- 2 days maximum 
before baseline visit (D0 Cycle 1). The patient will then be randomised to receive either DT 20 
mg/m² or DT 30 mg/m² as protracted IV infusion over 6 hours once every 4 weeks or BSC.  
Patients will receive study therapy until unequivocal tumour progression (assessed by the 
investigator) or occurrence of unacceptable toxicity.  
All patients will be evaluated by CT scan or MRI every 2 months for tumour assessements.  
After study therapy discontinuation, an end of study visit will be performed 1  month +/- 7 days 
after the last DT infusion or last BSC treatment.  
Then, a follow up of all patients (including those who withdrew prematurely from the study) 
will be maintained every 3 months until death. The following information will be recorded: 
• 
Survival (patient alive or deceased) 
• 
Date of progression (in the case of withdrawal for other reason than progression during 
the study treatment period) 
• 
Administration of any other anti-cancer treatment. 
The follow-up period is defined as “until 2 years after Last Patient In”.  
 
 


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4 
SUBJECT SELECTION 
The study will be carried out in patients suffering from advanced hepatocellular carcinoma 
(HCC), who meet all the inclusion and exclusion criteria presented in sections 4.1 and 4.2. 
4.1 
Inclusion Criteria 
All patients included in the study will have to meet the following criteria for inclusion in the 
study: 
1. Male or non-pregnant, non-breast feeding female;  
2. Aged  18 years; 
3. Patients with: 
− advanced HCC (BCLC-C according to BCLC staging classification) having progressed 
under Sorafenib therapy or intolerant to Sorafenib, or; 
− intermediate HCC (BCLC-B) non eligible or non responders to transarterial 
chemoembolization (TACE), and having progressed under or intolerant to Sorafenib 
therapy;  
4. Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic 
vein thrombosis without extension in inferior/superior vena cava, are eligible; 
5. HCC diagnosed according to the AASLD and/or EASL criteria: 
- 
Radiological Criteria applicable in cirrhotic liver: 
− Nodule  10 mm: one imaging technique among MRI and CT scan showing typical 
appearances for HCC defined as arterial enhancement and rapid washout in portal 
venous or delayed phase; 
− If appearance not typical for HCC on initial imaging: second contrast enhanced study 
(CT or MRI) showing typical appearances for HCC defined as arterial enhancement 
and rapid wash-out in portal venous or delayed phase; 
−  And/Or cyto-histology criteria (e.g. in case of atypical lesions for HCC at imaging, 
absence of cirrhosis); 
6. Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 
included (appendix II)); 
7. ECOG Performance Status 0 or 1 (appendix IV); 
8. Adequate laboratory tests, in particular with: 
• Platelets  50,000/mm3  
• Neutrophil count  1000/mm3  
• Haemoglobin  10g/dL 
• Serum transaminases < 5 ULN (NCI/CTC grades 0, 1, or 2) 
• Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2) 
• Serum bilirubin < 35 µM/L (or 2.0 mg/dL) 
9. Having given a written informed consent. 
 
 


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4.2 
Exclusion Criteria 
Exclusion criteria are as follows:  
1. Cirrhosis with a Child Pugh score B8-C15; 
2. Untreated chronic hepatitis B (in case of chronic hepatitis B, an efficacious antiviral 
treatment should be prescribed before randomisation to be included in the study); 
3. Patients eligible for curative treatments (transplantation, surgical resection, percutaneous 
treatment); 
4. Patients eligible for other efficacious treatments: TACE, Sorafenib. Patients who failed to 
Sorafenib treatment or intolerant to Sorafenib are eligible and can be included if Sorafenib 
has been stopped at least 2 weeks before randomisation;  
5. Other prior malignancy without complete remission in the last five years with the exception 
of adequately treated basal cell carcinoma or in situ cervical cancer. In case of other prior 
malignancy, the diagnosis of HCC has to be histologically proven; 
6. HCC developed on transplanted liver; 
7. Known HIV infection; 
8. Risk of variceal bleeding - i.e. patients with stage 2-3 varices with fragility signs (patients 
at risk for variceal bleeding) may be included after a preventive treatment (oesophageal 
varices ligation, beta blockers) has been administered; DT will not be administered in case 
of digestive bleeding in the 4 previous weeks; 
9. SaO2 < 95%; 
10. Presence of a significant acute or chronic respiratory disease defined as NCI /CTCAE > 
grade 2; 
11. Presence of recent (< 6 months) or current cardiac failure (class II, III or IV NYHA 
classification), baseline LVEF < LLN by either cardiac ultrasound or cardiac scintigraphy, 
recent (< 6 months) acute coronary syndrome, clinically significant ECG abnormalities or 
recent (less than 6 months) acute vascular diseases (stroke, MI…); 
12. Previous cumulative dose of > 300 mg/m² of doxorubicin (or equivalent);  
13. Patients currently treated with immunosuppressive agents that cannot be stopped; 
14. Patient whose medical or surgical conditions are unstable and may not allow the study 
completion or compliance, and specially patients with uncontrolled diabetes; 
15. Uncontrolled systemic infection; 
16. Patient with a life expectancy of less than 2 months; 
17. Patients who have received an experimental drug in another clinical trial in the last 30 days 
prior to randomisation in the present clinical trial; 
18. (a) Women of child-bearing age who are unwilling or unable to use an effective 
contraception method (oral contraception or intra-uterine device for woman) during the 
study treatment period and for 6 months after the last administration of study drug, and 
their male partner(s) refusing to use a condom (if applicable),  
(b)  Men who are unwilling or unable to  use a condom during the study treatment period and 
for 6 months after the last administration of study drug, and their female partner(s) refusing 
to use one of the appropriate effective contraception method (if applicable);  
19. Patients unwilling or unable to comply with protocol requirements and scheduled visits. 


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4.3 
Patient Registration 
Enrollment will occur after informed consent has been obtained and all screening assessments 
have been performed. 
The assignment of number and code for patient’s identification will ensure patient’s anonymity. 
Patients will be assigned a sequential patient number in each center and will be identified by: 
− The identification center number (a 3-digit number) 
− The patient number (a 4-digit number); these four numbers being allocated 
according to the sequence of presentation for trial participation in each centre. 
As soon as a potential patient is screened by an investigational centre, the investigator will have 
to complete the eCRF. If needed, he may contact Onxeo (formerly known as BioAlliance 
Pharma) or its representative in order to review the inclusion criteria. 
ONXEO  
(formerly known as BioAlliance Pharma) 
  
If eligibility criteria are met, patients will be included, randomised in one of the three groups : 
- 
Doxorubicin Transdrug™ at 20mg/ m²  
- 
Or Doxorubicin Transdrug™ at 30 mg/m².  
- 
or Best Standard of Care.  
Randomisation will be performed using IWRS with stratification on region (Europe versus 
United States versus other countries (Turkey, Egypt, Lebanon, Saudi Arabia)).  
 
  
4.4  
Subject Premature Withdrawal  
In accordance with the Declaration of Helsinki as amended from time to time, subjects are free 
to withdraw from the study at any time if they wish so, for any reason specified or unspecified. 
The criteria for enrollment must be followed explicitly. If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be discontinued from the study 
and Onxeo (formerly known as BioAlliance Pharma) or its designee must be contacted. An 
exception may be granted in rare circumstances where there is a compelling ethical reason to 
allow the patient to continue taking study drug. In these rare cases, the investigator must obtain 
documented approval from the Onxeo (formerly known as BioAlliance Pharma) medical 
monitor to allow the patient to continue in the study. 
In addition, a patient’s participation may also be discontinued at any time at the discretion of 
the investigator or Sponsor. The following are some of the potential reasons that could lead the 
investigator or sponsor to remove a patient from the study drug or the study, or both: 


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− The investigator believes that a change of therapy would be in the best interest of 
the patient (e.g. the patient needs to be treated, for any reason, with another anti 
cancer therapy);  
− The patient experiences an intolerable AE. An intolerable AE is an event that, even 
with optimal treatment, causes such discomfort or disability that the patient is unable 
or unwilling to continue further study participation 
− The patient is non compliant with study requirements 
− The patient becomes pregnant during the study or fails to use adequate birth control 
(for those patients who are able to conceive) 
− The patient requires a medication prohibited by the study protocol 
− The Sponsor decides to terminate the trial  
The reason for withdrawal will have to be recorded in the e-CRF for all withdrawn subjects. 
The e-CRF has to be completed until the time of drop out. All drop outs after the first intake of 
investigational product should be given a post-study assessment as appropriate.The premature 
termination form in the e-CRF must be completed for all drop outs. The survival status of all 
patients (including patients prematurely withdrawn) will be collected every 3 months until death 
with the follow-up contact 
 
 


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5 
ENDPOINTS and ASSESSMENTS 
5.1 
Primary endpoint 
 
 
 
 
 
5.2 
Secondary efficacy endpoints 
 
 
 
 
 
 
 
 
  
 
 
 
 
5.3 
Exploratory efficacy endpoints 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.4 
Safety endpoints 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
  
 
5.5 
Pharmacokinetic endpoints 
 
 
 
 
 


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5.6 
Quality of life  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 


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6 
TRIAL TREATMENTS 
6.1 
Allocation to Treatment 
Patients will be assigned identification numbers as described in section 4.3. 
6.2 
Drug Supplies 
Doxorubicin Trandrug (DT) will be supplied by the Sponsor as an investigational medicinal 
product (IMP). The IMP will be packaged, labeled and released according to current good 
manufacturing practice (GMP) guidelines, GCP guidelines and national legal requirements (as 
applicable).  
In the control group, patients will receive the usual standard of care as decided by the 
investigator. The standard of care treatment will be handled, used and stored according to 
local’s practice. 
 
DT Formulation and Packaging 
s
 for suspension for injection that is to be reconstituted 
with 25 mL of glucose 2,5% for injection and filtered. See Appendix VII for details on study 
drug preparation procedures: 
 
DT Dispensing 
The investigational products will be sent from 
 to the 
pharmacy of each investigational centre, which will ensure storage, dispensation and the 
reconstitution for each Cycle.  
 
6.3 
DT Administration 
In DT groups, based on DSMB recommendation after their careful review of the safety profile 
reported in the first 75 patients, a shorter period of hospitalization could be recommended since 
Name 
Doxorubicin Transdrug™ 10 mg 
INN 
Doxorubicin 
Excipients 
 
 
 
Pharmaceutical Form 
powder for suspension for injection  
Route of Administration 
Intravenous 
Method of Administration 
Slow IV infusion of 6 hours 
Dosage Strength and Form 
10 mg/vial 
Name of Manufacturing 
Laboratory 
 
Packaging  
 
Distribution 
 
 
Storage 
5°C ± 3°C 


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version 5.0, June 10th, 2014 as compared to the previous protocol version. The premedication 
will be unchanged as compared to the previous protocol version and administered to the patient 
according to each centre’s usual practice. On D0, one day before each DT administration, 
patient will be hospitalized or will have an outpatient visit to check eligibility criteria for 
continuing treatment and to ensure that the premedication is taken. Patient will receive DT 
infusion on D1 and will be hospitalized until D2. Patient could be discharged on D2 or on D3 
in the absence of toxicity. Hospitalization until D3 is optional.  
Hospitalization or outpatient visit on D0 and prolonged hospitalization until D3 will be adapted 
according to hospital practice and/or patient preference.  
Day 0 defined as one day before the treatment with DT 
- 
Premedication with methylprednisolone 32 mg p.o. (or equivalent) and cetirizine 20 mg 
p.o.(or equivalent); 
Day 1 : Day of therapy with DT 
- 
H-1: premedication with methylprednisolone 32 mg p.o. (or equivalent) and cetirizine 
20 mg p.o.(or equivalent); 
- 
Fasting is not needed; 
- 
H0: 20 mg/m² or 30 mg/m² of DT will be prepared and infused over 6 hours through 
intravenous route (Appendix VII). 
- 
Patient will have a continuous SaO2 monitoring during infusion and the 24 hours after 
the infusion start. 
Any modification in the infusion rate must be recorded in the e-CRF (see section 7.6: safety 
measures). 
Day 2 : The day after the DT therapy: 
- 
Premedication with methylprednisolone 32 mg p.o. (or equivalent) and cetirizine 20 mg 
p.o.(or equivalent); 
D0 = D28 
Each Cycle will be repeated every 28 days up to progression or toxicity. 
 
6.4 
Best Standard of Care administration 
The patient in BSC group will be treated and monitored according to the centre’s usual practice. 
Patients will receive BSC as judged by their treating physician. Those therapies considered 
acceptable include, but are not limited to, anticancer therapy and/or supportive care (e.g. 
antibiotics, analgesics, antiemetics, ascitis drainage, blood transfusions, and/or nutritional 
support (enteral or parenteral)). If it is unclear whether a therapy would be regarded as BSC, 
Onxeo (formerly known as BioAlliance Pharma) should be consulted. 
 
6.5  
Compliance 
Patients in the DT arm need to be hospitalised at the investigational site to receive the study 
therapy. Patients in the control arm may not be hospitalized if the local pratice doesn’t  require 
hospitalisation for the study therapy administration. However, per protocol, they should comply 
with the planned  visits on days 1 and 14 of each cycle. 


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For the DT groups : the  drug accountability will be assessed by recording the dispensation of 
treatment. The investigator and/or the hospital pharmacist must keep an up-to-date drug 
dispensing log containing the following information:  
− Identification of the patient to whom the medication was dispensed 
− Dates of the study drug administered to the patient 
− The total dose administered to the patient  
The investigator or the hospital pharmacist must only use DT for patients participating in the 
study. 
For BSC group: The patient will be treated according to the centre’s usual practice and no drug 
accountability is required. Any treatment administered to the patient (usual supportive care 
and/or anticancer treatment) will be recorded in the e-CRF.  
 
6.6  
Dose adjustment, dose delay and infusion duration  
6.6.1  Dose Adjustment: DT Arms 
Dose adjustement will be based upon haematologic and non haematologic toxicities observed 
after the previous dose administration.  
All dose reductions for patients randomised to receive either treatment A (DT 20 mg/m2) or B 
(DT 30 mg/m2) will be calculated based upon the following dose level reduction guidelines.  
 
Dose level reduction guidelines: 
 
Arm A (DT 20 mg/m2) 
Initial Dose Level 
20 mg/m2 
Dose Level -1 
15 mg/m2 
 
                                 Arm B (DT 30 mg/m2) 
Initial Dose Level 
30 mg/m2 
Dose Level -1 
20 mg/m2 
Dose Level -2 
15 mg/m2 
 
Haematologic criteria for dose modifications: 
• In case of grade 3 (500 – 1000/mm3) or grade 4 (< 500/mm3) neutropenia whatever the 
duration of neutropenia and/or in case of grade 3 (25 000 – 50 000/mm3) or grade 4 (< 
25 000/mm3) thrombocytopenia, DT will be interrupted until resolution to a grade  2. 




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Any patient who requires a dose reduction will be treated with a reduced dose for any 
subsequent doses. 
Arm A patients requiring dose reductions below dose level -1 must discontinue. Arm B patients 
requiring dose reduction below dose level -2 must discontinue. 
6.6.2 Dose Delay: DT arms 
To initiate a new DT infusion, the patient needs to meet the following continuing treatment 
criteria: 
• Adequate liver function:  
 Child-Pugh score from A5 to B7 included (if cirrhosis)  
 Serum bilirubin < 35 µM/L (or 2.0 mg/dL) 
• Adequate respiratory function defined as SaO2  95%; 
• Absence of ongoing infection 
• Adequate haematologic tests : 
 Neutrophil count  1000 /mm3 
 Platelets count  50,000 /mm3  
 Haemoglobin  10 g/dL 
• No clinical evidence of upper gastrointestinal bleeding 
• 
No other limiting toxicity  > grade 2  
 
If one of these  criteria is not met, the next infusion should be delayed for a maximum of four 
weeks. In case one of these criteria is not met after the 4 weeks delay, the patient will be 
withdrawn from the study treatment period and the end of therapy notification form will be 
completed. 
  
6.6.3 DT Infusion duration 
 
DT will be administered as a protracted i.v infusion during 6 consecutive hours. That infusion 
duration will be prolonged up to 12 consecutive hours if any of the condition described in 
section 7.6 occurs. In case of accidental infusion acceleration, i.e accidental infusion duration 
 2 hours, urgent safety precautions should be rapidly available at the patient bedside. Those 
measures include, but are not limited to, mechanical respirator and supplemental oxygen, i.v 
corticosteroids, i.v antibiotics if infection is suspected. 
The maximum allowed cumulative dose of doxorubicin (or equivalent) is < or equal to 550 
mg/m2 (this takes into account prior anthracyclins cumulative dose and DT cumulative 
dose).  
 
6.6.4 Best Standard of Care Arm  
Throughout the study, dose adjustement or delay in the BSC arm will be based upon the specific 
standard of care and according to local pratice. 
 


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6.7 
Drug Storage and Drug Accountability  
The investigational product (DT) will be stored in a secure limited access area at 5°C± 3°C. 
The pharmacist at the trial centre will be responsible for the correct storage, handling of the 
study products and for all the documentation on drug supplies. 
A drug movement form of all investigationals products dispensed during the study will be 
maintained. 
All investigational materials (medication and packaging) unused in the study will be returned 
to 
 (or its designee) before, or at the termination of the study, together with an 
accountability form.  
All DT administered units will be destroyed on site, according to routine hospital practice and 
current national guidelines/regulations. 
 
6.8 
Concomitant Medication(s) 
As doxorubicin is metabolized by the liver and is a subtrate of CYP3A4, CYP2D6 and P-gp, 
the concurrent use of inhibitors or inducers of CYP3A4, CYP2D6 and P-gp should be used with 
caution and based on the benefit/risk for the patient. A list of the most commun CYP3A4, 
CYP2D6, P-gp inhibitors or inducers is provided in appendix XII. All treatments administered 
and date of administration must be recorded in the e-CRF. Use of any concomitant medication 
will be recorded in the e-CRF with the following information: 
− reason for treatment; 
− name of the drug, type of formulation, and unit strength; 
− dose administered; 
− duration of treatment. 
 
6.9 
Prohibited Medications during the study therapy 
The following treatments are not allowed at inclusion and during treatment period : 
- 
For all patients : 
• Other investigational drugs; 
• Sorafenib; 
 
- 
Only for patients randomised in the Doxorobucin TransdrugTM groups: 
• TACE; 
• Loco-regional treatment (Percutaneous ethanol...); 
• Cytotoxic drugs; 
• Interferon; 
• Recently introduced statins (less than 1 month); 
• Hormone therapy. 
 
 


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6.10 
 Post study therapy 
 
No cross over to DT is allowed for the patients enrolled in the control arm. After disease 
progression, patients in both arms will be allowed to receive any anti cancer therapy as deemed 
appropriate by the investigator including Sorafenib. Post anticancer therapy will be recorded in 
the eCRF. 
 
 




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• Left ventricular ejection fraction (LVEF) evaluation using cardiac ultrasound or cardiac 
scintigraphy; the same technique for the same patient is recommended throughout the 
study; 
• Respiratory Function Tests: vital capacity (VC), total lung capacity, carbon monoxide 
diffusing capacity (DLCO), Forced Expiratory Volume in one second (FEV1); 
• Clinical laboratory tests: 
o Haematology: complete blood counts (CBC), platelets count; 
o Biochemistry: AST, ALT, GGT, ALP, total bilirubin, albumin, protein 
electrophoresis, ferritin, CRP, LDH, CPK; 
o Na+, Cl-, K+, HCO3-, urea and creatinine; 
o Coagulation: INR/Prothrombin, Factor V; 
o Calcium and phosphorus; 
o Metabolism : Total cholesterol, triglycerides, glycaemia; 
o -foetoprotein (AFP); 
o Serum -HCG for women of childbearing potential. 
Factor V and protein electrophoresis ( at screnning, baseline and throughout the study) 
are not mandatory if sites cannot perform these tests at their routine local lab. For 
Egyptian sites, a central lab may be used. 
• Imaging: 
o Chest X-ray; 
o Abdominal and pelvic including hepatic spiral CT scan or MRI; 
o Thoracic CT scan. 
If one of these imaging have been realized as part as routine pratice before screnning 
(i.e. before ICF signed), these radiologic exams can be considered as sufficient for the 
screnning period if realized within 28 days before baseline. 
 
7.2 
Trial Period 
7.2.1. Design of each Cycle of treatment during treatment period 
 
 
 
 
 
 
 
 
 
 
 
  






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7.3.1. Pharmacokinetic study 
The pharmacokinetic study of DT will be performed only in selected centers that can meet the 
requirements of blood sampling.  
The primary aim of pharmacokinetic evaluation will be to determine the population 
pharmacokinetic 
parameters. 
The 
secondary 
objective 
will 
be 
to 
analyse 
the 
pharmacokinetic/pharmacodynamic correlation with DT efficacy and toxicity, and to evaluate 
inter-cycles AUC stability. For this purpose, blood sampling will be performed at the first and 
third treatment cycles. For patients still on treatment after Cycle 3, an optional and limited 
sampling at cycle 4, cycle 6 and beyond (e.g. every 2 cycles until the end of study treatment) 
will also be performed. 
The bioanalytic method will be described in separate bioanalytical study plans and analysis of 
the study samples will be centrally performed at 
 Blood 
samples collected and stored in the biobank are aimed at measuring total doxorubicin, free 
doxorubicin and doxorubicinol plasma concentrations. Each sequence of analysis will be 
performed according to current quality standards, especially in term of quality control samples, 
calibration curve and acceptance criteria.  
Pharmacokinetic data analysis will be performed under the responsibility of the Sponsor. A 
formal Statistical Analysis Plan (SAP) for PK analysis will provide further details of the 
statistical analyses and will be finalized before database lock. The section below is an overview 
of the PK statistical analyses planned for this study.  
Total doxorubicin, free doxorubicin and doxorubicinol concentration data will be analysed 
using a 3 compartment model. This will allow for determination of both the steady-state and 
the elimination pharmacokinetic parameters of free doxorubicin, total doxorubicin and its major 
metabolite doxorubicinol.  
The following pharmacokinetic parameters will be derived for total doxorubicin, free 
doxorubicin and doxorubicinol: 
Cmax, Tmax, AUC (last, and inf), Half-life, Clearance  
The study protocol is planned to present pharmacokinetic parameters as mean, standard 
deviation (SD), coefficient of variation (CV%), median, minimum and maximum values (and 
geometric mean when appropriate).  
The influence of covariates such as demographics and liver impairment will be investigated.  
 
Amount of blood samples taken for the pharmacokinetic study (see appendix VIII) 
A maximum of thirty-six (36) blood samples will be taken for PK during the study within the 
first 3 months. The amount of blood taken each time will be less than 10 ml each: fourteen (14) 
times during treatment period Day 0 to Day 3, during the 1st and the 3rd Cycle of treatment to 
measure the study drug concentration in the blood and, if possible, one additional blood sample 
at Day 4, Day 8, Day 14 and Day 28 of the 1st and the 3rd Cycle. 
In patients still on study treatment after Cycle 3, an optional and limited blood sampling will 
be drawn on each Day 1 (4 times: at T0, 4h, 6h, 8h), Day 14 (once) and Day 28 (once) of Cycle 
4, Cycle 6, and beyond (e.g. every 2 cycles until the end of study treatment).  


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Thus, total amount of blood to be drawn during the study period will not exceed 360 ml 
throughout the first 3 months (a blood donor usually donates about 500 ml at once). The amount 
of each additional and optional limited sampling after 3 months for the ongoing patients will 
not exceed 60 ml every 2 months. 
7.3.2. Pharmacogenetic study 
The pharmacogenetic study will be realized in all patients who have accepted and signed an 
appropriate genetic informed consent form.  
A blood sample bank will be constituted to evaluate any other potential biomarkers which will 
be identified as possibly relevant predictive / prognostic factors. 
One additional blood sample will be taken for the pharmacogenetic study. The amount of blood 
is around 10 ml. Measurement of plasma concentrations of biomarkers will be realized before 
treatment (at baseline).  
Analysis will be centrally performed under the responsibility of sponsor (see Annex VIII).


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7.4 Supporting board: Independent Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be organized to regularly 
evaluate the safety of DT during the study. The complete role and responsibilities of DSMB is 
described in the DSMB charter. The DSMB will be provided with blinded safety data by patient 
and treatment group every 75 patients (around 25 patients/group) and will review the data at 
least twice a year. The DSMB will remain blinded for its evaluation, but may ask for unblinding 
if required.  
At the end of each meeting, the DSMB will have to make recommendations to the Sponsor as 
follows: 
- 
To continue the trial without modification; 
- 
To continue the trial and amend the protocol, as specified; 
- 
To suspend the trial pending further information or evaluations;  
- 
To terminate the trial prematurely. 
The DSMB will receive every SAE within 24 hours of the knowledge of the occurrence or at 
the latest, on the following working day.  
In case of suspected pulmonary SAEs, DSMB will recommend whether to continue, suspend 
or definitively stop the recruitment and infusions in the respective cohort and make 
recommendations to the sponsor.  
If deemed necessary, the DSMB may elect to postpone the recommendation, pending external 
consultation(s) with required specialists and/or receipt of additional data and a subsequent 
closed DSMB meeting session. 
The DSMB members will be appointed by the Sponsor. DSMB is an independent expert group 
consisting of specialists in hepatology, liver oncology disease, lung diseases and statistics, well 
experienced in the management of patients with HCC and adverse lung reactions. DSMB will 
elect the chairman. Appropriate Onxeo (formerly known as BioAlliance Pharma) employees 
(including Pharmacovigilance and Clinical Departments) will participate to the DSMB 
meetings but will not have any voting rights.  
DSMB will have the responsibility for providing the following: 
• Assurance of patient safety, 
• Trial integrity, 
• Discussion with the Sponsor and required specialists, 
• Recommendations and commitment in the study. 
 
Following their risk evaluation, the DSMB reserves the possibility of alerting the Sponsor in 
the event of observation of highly unexpected events. The DSMB may request a futility analysis 
on the primary criterion of overall survival. This futility analysis serves one objective: to 
recommend the potential discontinuation when it is unlikely, based on the interim results, to 
achieve statistically significant results at the end of the study. This futility analysis will be 
realized under the responsibility of the DSMB statistician. The results of this futility analysis 
will be disclosed only to DSMB members. No one in the Sponsor representatives has access to 


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such information. No information about these results will be communicated to investigators and 
the International Coordinating Investigator. 
Copies of correspondence between the sponsor and DSMB members will be distributed to all 
DSMB members. 
National Authorities as applicable and all investigational centres will be informed of the DSMB 
recommendations. 
 
7.5 
Possible risks or discomforts 
Like with any other medicines in cancer treatment, side-effects may occur during the treatment 
period.  
The following side-effects were reported in previous studies: leukopenia, neutropenia, 
lymphopenia, abdominal pain, thrombopenia, elevated liver enzymes, nausea, anaemia, 
headache, moderate fever, asthenia, hypotension, cough, diarrhoea, O2 desaturation, 
tachycardia, pain, minor dyspnoea, alopecia, vomiting, moderate dorsal, lumbar or chest pains.  
The progression of all of these side-effects was favourable more or less rapidly, either 
spontaneously or after symptomatic treatment. The complete list of TEAE is given in the 
Investigator’s Brochure. 
Some serious respiratory disorders have also occurred consisting mainly of decrease in SaO2, 
pleural effusion and for the worst cases pulmonary oedema, acute respiratory distress syndrome 
(ARDS), and death.  
Pulmonary adverse events  will be collected on a specific adverse event form in the e-CRF. 
 
7.6 
Safety measures 
In case of unexpected life-threatening AE that may or may not be related to the investigational 
product, all clinical measures considered as mandatory should be taken and symptomatic 
treatments administered. 
Dose adjustement and dose delay are described in section 6.6. Dose adjustement will be based 
upon haematologic and non haematologic toxicities observed after the previous dose 
administration. Any patient who requires a dose reduction will be treated with a reduced dose 
for any subsequent doses. Arm A patients requiring dose reductions below dose level -1  must 
discontinue and arm B patients requiring dose reductions below dose level -2 must discontinue. 
7.6.1 Pulmonary toxicity 
In previous studies where DT was injected through the hepatic intra arterial route in 15-30 
minutes, 5 cases of ARDS were reported in 5 patients, resulting in death in two of them. 
Preclinical experiments showed that respiratory events were prevented by reduction of the DT 
infusion rate. A careful review of human safety data confirmed that dose and infusion rates 
were parameters driving the DT toxicity and led to recommend to infuse DT through the IV 
route over 6 hours. In order to prevent the occurrence of ARDS, respiratory safety measures 
have been implemented, including premedication with methylprednisolone 32 mg p.o (or 
equivalent) + non sedating antihistamine H1 at double dose (e.g. cetirizine 20 mg p.o or 
equivalent) administered the day and 1 hour before infusion, then the day after infusion, and 
close monitoring following each infusion:  


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SaO2 monitoring during the 6-hour infusion: 
- 
Continuous monitoring of SaO2: 
− In case of SaO2 decrease to < 93%, the DT infusion rate will be reduced by 
half (12-hour infusion). The total dose will not be changed; 
− In case of SaO2 decrease to ≤ 90%, DT infusion will be immediately and 
definitively stopped; 
- 
Monitoring of respiratory symptoms: 
− In case of a respiratory symptom (dyspnoea, increase in respiratory rate by 
5 beats/min and RR > 20/min), the DT infusion rate will be reduced by half 
(12-hour infusion); the total dose will not be changed; 
− In case of persistence of symptoms in the following hour, DT infusion will 
be immediately and definitively stopped. 
 
SaO2 monitoring after the end of DT infusion :  
A SaO2 monitoring during 24 hours after infusion start is mandatory.  
In case of a marked decrease in SaO2  or occurrence of respiratory symptoms, the patient will 
be transferred to intensive care unit for monitoring and treatment until recovery.  
In case of SaO2 decrease ( 90%) during or after DT infusion, SaO2 will be closely monitored 
and collected every hour until resolution to SaO2  93%.  
Patient with a respiratory adverse event during a DT infusion who remain eligible to continue 
DT treatment will have reinforced respiratory safety measures for each additional DT infusions 
and SaO2 collected every hour during infusion and within the 6 hours after the end of infusion. 
The recommended treatment of drug-induced pneumonitis is based on systemic corticosteroids 
with methylprednisolone 1 g/day for 3 days in patients with respiratory failure or lower doses 
of corticosteroids (i.e methylprednisolone 60 mg every  6 hours) in less severe cases. Before 
initiating corticosteroid therapy, an infectious etiology must be excluded. Supportive care, 
bronchodilators, IV fluid, vasopressors, and mechanical ventilation could be indicated in 
patients with severe hypersensitivity reactions and circulatory collapse (Vahid B., 2008[49]). 
In case of ARDS and/or any related life-threatening respiratory serious adverse event, DT 
will be definitively stopped and the patient will not receive any additional DT infusion.  
In case of grade 3 or grade 4 AE, infusion should be delayed up to 4 weeks, when AE decreases 
to grade  2. Further DT infusions should be performed only if adequate respiratory function 
defined as SaO2  95% is obtained (see section 6.6). 
A decrease of SaO2 below 90%, regardless of any respiratory symptoms or signs, will be 
considered as SAE and reported to Onxeo (formerly known as BioAlliance Pharma) 
within 24 hours. 
In any case, the total DT dose administered will be carefully recorded in the source document 
and e-CRF. 


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7.6.2 Haematological toxicity 
Asymptomatic neutropenia and thrombopenia are frequent in patients with cirrhosis and related 
to hypersplenism and portal hypertension. The risk of neutropenia, anemia and thrombopenia 
will be carefully monitored before each study treatment administration, then every day for 3 
days, at day 14 and day 28 during each cycle.  
- 
In case of febrile neutropenia or any suspicion of infection, the patient should be 
hospitalized without delay for monitoring and treatment up to recovery; 
- 
In case of neutropenia or anemia, patient will be treated according to the centre’s usual 
practices; haematopoietic growth factors (G-CSF) and/or erythropoietin (EPO) could be 
administered according their respective SmPC in patients with documented anemia or 
cytopenia; 
In case of febrile neutropenia, any grade 3 or grade 4 thrombopenia or neutropenia, DT will be 
interrupted and infusion should be delayed up to 4 weeks until resolution to a grade  2.  
Further DT infusions should be performed only if haematologic tests fulfil the following 
criteria: neutrophil count  1000 / mm3 (grade  2) , platelets count  50,000 /mm3 (grade  2) 
and haemoglobin  10 g/dL (grade < 2). 
Dose reduction is authorized in case of grade 4 related heamatological adverse events as 
described in section 6.6.1. The dose to be administered will be reduced ( minus 1 dose level) in 
case of febrile neutropenia of any duration, grade 4 neutropenia lasting > 7 days and grade 4 
thrombocytopenia.  
 
7.6.3 Liver toxicity 
Cirrhosis may decompensate and liver function may deteriorate in cirrhotic patients. Clinical 
signs and symptoms and liver function tests will be closely monitored thoughout the study, 
before each study treatment administration, then every day for 3 days, at days 14 and 28 during 
each cycle.  
In case of aggravation of liver function tests, the investigator may prolong the hospitalisation, 
take all appropriate measures and administer symptomatic treatments as required. If 
hospitalisation is prolonged (> Day 3), investigator should inform Onxeo (formerly known 
as BioAlliance Pharma), fill in and fax a SAE form. 
Further DT infusions should be performed only if liver function tests returned to baseline values 
with a Child-Pugh score from A5 to B7 included (if cirrhosis) and serum bilirubin < 35 µM/L 
(or 2.0 mg/dL) (see section 6.6).  
Infusion could be delayed by up to 4 weeks. Dose reduction is authorized as described in section 
6.6.1.  
7.6.4 Cardiac toxicity 
Cardiac toxicity has been reported with doxorubicin. Congestive heart failure (CHF) is among 
the most serious toxicities of doxorubicin, increases with the cumulative dose of doxorubicin, 
and is estimated to be 5 % at a cumulative dose of 400 mg/m2, 16 % at 500 mg/m2 and 26 % at 
550 mg/m2. To date, no cardiac events have been reported in patients suffering from HCC and 
treated with DT.  


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According to the potential cardiac risk, LVEF will be monitored every other month and ECG 
every month before each infusion.  
In case of ECG modifications or any symptoms associated to a decreased LVEF and/or LVEF 
below the lower limit of normal values, additional DT infusions will not be authorized until a 
cardiologist is consulted for aetiologic work-up. The investigator will decide whether further 
DT infusions should be performed or definitively stopped, taking into account the benefit/risk 
ratio.  
Infusion could be delayed by up to 4 weeks. In case of grade 3 or 4 related adverse events, dose 
reduction is  authorized as described in section 6.6.1.   
The maximum authorized cumulative dose of  doxorubicin is 550 mg/m2 (or its equivalent for 
other anthracyclins). 
 
7.6.5 Any other adverse events   
In case of any other grade 3-4 toxicity at the time of next infusion, the infusion should be 
delayed by up to 4 weeks until AE decreases to grade  2. In case of persisting grade 3-4 AE, 
the study treatment will be definitively stopped. 
In case of life-threatening serious AE related to DT, the treatment will be stopped and the patient 
will not be re-administered DT. 
 
 


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8 
SAFETY CRITERIA 
The investigator is responsible for monitoring the safety of subjects who have been enrolled in 
the study. All adverse events occurring during the conduct of the study will be captured on the 
eCRF. All serious adverse events (related or not related) must be reported to Onxeo (formerly 
known as BioAlliance Pharma) Pharmacovigilance Department (Cf. section 8.7). 
 Any study drug-related AE (Cf. definition section 8.1) or any related or not related 
SAE (Cf. definition section 8.3) is to be followed until resolution or until mutually 
agreed by the investigator and an Onxeo (formerly known as BioAlliance Pharma) 
physician to discontinue reporting; 
 All AEs and SAEs will be reported until 30 days after the last infusion of study-drug; 
 Any respiratory SAE either related or not related to the study or to the study drug 
must be reported to Onxeo (formerly known as BioAlliance Pharma) 
Pharmacovigilance Department within 24 hours of the knowledge of the occurrence. 
Periodic review of the safety data will be conducted by an independent data safety monitoring 
board. 
Subjects must be carefully monitored for AE. AEs should be assessed in terms of their 
seriousness, severity, and relationship to the study drug. 
8.1 
Adverse Events 
The term AE is defined as any unfavorable and unintended sign, symptom, or disease (including 
an abnormal laboratory finding) temporally associated with the use of a medicinal 
investigational product, whether or not considered related to the investigational medicinal 
product.  
AEs associated with the use of a drug in humans, whether or not considered drug related, 
include the following: 
− An AE occurring in the Cycle of the use of a drug product in professional practice 
− An AE occurring from an overdose whether accidental or intentional 
− An AE occurring from drug abuse 
− An AE occurring from drug withdrawal 
− An AE where there is a reasonable possibility that the event occurred purely as a 
result of the patient’s participation in the study must also be reported as an AE even 
if it is not related to the investigational product. 
The clinical manifestation of any failure of expected pharmacological action will not be 
recorded as an AE if it is already reported as efficacy criteria in the e-CRF. If, however, the 
event fulfils any of the criteria for a SAE, it must be recorded and reported as such. 
Underlying conditions (existing prior to the trial) which become aggravated or recur after 
resolution during a clinical trial must be reported as an AE. An AE may be deemed serious if it 
meets any of the seriousness criteria given in Section 8.3. 
 


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8.2 
Unexpected Adverse Event Definition 
An unexpected AE is any event, the nature, specificity or severity of which is not consistent 
with the current Investigator’s Brochure. Also, reports which add significant information on 
specificity or severity of a known, already documented AE constitute unexpected AEs. For 
example, an event more specific or more severe than described in the investigator’s Brochure 
would be considered unexpected. Specific examples would be as follows: (a) acute renal failure 
as a labeled AE with a subsequent new report of interstitial nephritis, and (b) hepatitis with a 
first report of fulminant hepatitis. 
 
8.3 
Serious Adverse Events 
An AE is classed as being “serious” during a clinical trial if it: 
− Results in death  
− Is life-threatening  
− Results in persistent or significant disability or incapacity 
− Requires in-patient hospitalisation or prolongation of existing hospitalization 
− Is a congenital anomaly, or birth defect 
− Is a suspected transmission of an infectious agent 
− Is an important medical event (requires medical intervention to prevent outcomes 
listed above). 
Life-threatening: The term “life-threatening” in the definition of “serious” refers to an event 
in which the patient or 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 were more severe. 
Hospitalisation: Any event leading to hospitalisation or prolongation of hospitalisation will be 
considered as serious, unless at least one of the following exceptions is met: 
− 
The admission results in a hospital stay of less than 12 hours 
− 
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to 
the start of the study) 
− 
The admission is not associated with an AE (e.g., social hospitalisation for purposes 
of respite care). 
However, it should be noted that invasive treatment during any hospitalisation may fulfill the 
criteria of medically important and, as such, may be reportable as a SAE depending on clinical 
investigator’s judgment. In addition, where local regulatory authorities specifically require a 
more stringent definition, the local regulation takes precedent. 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
Important Medical Event: Any AE may be considered serious because it may jeopardize the 
patient and may require intervention to prevent another serious condition. As guidance for 
determination of important medical events, refer to the WHO Adverse Reaction Terminology 
“Critical Terms List”, these terms either refer to or might be indicative of a serious disease state. 
Such reported events warrant special attention because of their possible association with a 
serious disease state and may lead to more decisive action. 


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Note: previous studies have identified acute respiratory distress syndrome (ARDS) as 
SAE. In order to prevent the occurrence of ARDS, a decrease of SaO2 below 90% will be 
considered as SAE. 
 
Pregnancy : 
Any pregnancy that occurs from date of informed consent to six (6) months after end of therapy 
must be reported to Onxeo (formerly known as BioAlliance Pharma) immediately and followed 
up until after delivery on the Pregnancy report form. Pregnant patients will be withdrawn from 
the trial and will be advised to present at a center specialized in human genetics for genetics 
councelling. In case of still birth, spontaneous abortion/miscarriage, or congenital 
malformation/abnormality, a Pregnancy report form must be provided as well. 
8.4 
Severity Assessment 
The NCI CTC AE v4.0 classification should be used to determine and to grade the severity of 
AEs. 
For AEs not specified and detailed in the NCI CTC, severity will be categorized as mild 
corresponding to grade 1, moderate corresponding to grade 2, severe corresponding to grade 3 
or life-threatening corresponding to grade 4, according to the following NCI CTC definitions:  
Mild is defined as usually transient in nature and generally not interfering with normal 
activities. No medical intervention/therapy required. 
Moderate is defined as sufficiently discomforting to interfere with normal activities. No or 
minimal medical intervention/therapy required. 
Severe or medically significant is defined as prevents normal activities. Some assistance is 
usually required, medical intervention/therapy required, hospitalization possible. 
8.5 
Causality Assessment 
The assessment of the relationship of an AE to the administration of study drug is a clinical 
decision based on all available information at the time of the completion of the e-CRF. 
Related adverse events are those that are judged unlikely, possibly, probably or definitely 
related to the study or to the study drug by the investigator. 
Unrelated adverse events are those that are judged to be not related to the study or to the study 
drug by the investigator. 
An assessment of “No relation to study drug” would include: 
− The existence of a clear alternative explanation (i.e., mechanical bleeding at surgical 
site) or 
− Non plausibility (e.g., the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event, cancer 
developing a few days after the first drug administration). 
An assessment of “Yes, related to study drug” indicates that there is a reasonable suspicion that 
the AE is associated with the use of the investigational drug. 
Factors to be considered in assessing the relationship of the AE to study drug include the 
following: 


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− The temporal sequence of the event related to the time of drug administration. The 
event should occur after the drug is given. The length of time from drug exposure to 
event should be evaluated in the clinical context of the event. 
− Recovery from the event on discontinuation (dechallenge), recurrence on 
reintroduction of the drug (rechallenge) should be evaluated. Patient’s response after 
drug discontinuation (dechallenge) or patients response after drug reintroduction 
(rechallenge) should be considered in the view of the usual clinical course of the 
event in question.  
− Underlying, concomitant, concurrent diseases. Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the patient may have. 
− Concomitant medication or treatment. The other drugs the patient is taking or the 
treatment the patient received should be examined to determine whether any of them 
may be suspected in the cause of the event in question. 
− The pharmacology and pharmacokinetics of the test drug: The pharmacokinetic 
properties (absorption, distribution, metabolism, and excretion) of the test drug(s), 
coupled with the individual patient’s pharmacodynamics, should be considered. 
 
8.6 
Withdrawal Due to Adverse Events  
(See Subject Premature Withdrawal, section 4.4 and End of treatment Notification, section 
7.2.3). 
8.7 
Reporting Requirements 
8.7.1 
Non-Serious Adverse Event Reporting Requirements 
All AEs occurring after the patient has signed the informed consent must be fully recorded in 
the patient’s e-CRF. Documentation must be supported by an entry in the patient’s file. A 
laboratory test abnormality considered clinically relevant (e.g., causing the patient to withdraw 
from the study, requiring treatment or causing apparent clinical manifestations, or judged 
relevant by the investigator) should be reported as an AE. Each event should be described in 
detail along with start and stop dates, severity, relationship to investigational product, action 
taken and outcome. 
For all adverse events, the investigator has to pursue and obtain adequate information to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as non serious or SAE requiring immediate notification to the Sponsor (see 
below). Follow-up of the AE, even after the date of therapy discontinuation, is required if the 
AE or its after-effects persist. 
Follow-up is required until the event or its after-effects are resolved or stabilized at a level 
acceptable to the investigator and the Sponsor. For subjects withdrawn from the study and 
subjects experiencing AE at the end of the study and within 30 days following the last treatment 
day, the investigator will arrange for appropriate follow up (if required until the AEs are 
resolved or attributed to a cause other than the study drug). 
 




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The head of the Drug Safety Department will inform the Health Authorities in writing in 
accordance with current regulations and the Clinical Department will take care of the Ethics 
Committees information. 
8.7.3 
Progression of underlying malignancy 
Progression of underlying malignancy is not reported as an AE if it is clearly consistent with 
the suspected progression of the underlying cancer as defined by RECIST or mRECIST criteria 
or based on clinical progression assessed by the investigator. 
Death or hospitalization due solely to the progression of underlying malignancy should NOT 
be reported as a SAE. 
Clinical symptoms of progression may be reported as AEs if the symptom cannot be determined 
as being exclusively due to progression of the underlying malignancy, or does not fit the 
expected pattern of progression for the disease under study. 
Progression could be evident in the patient’s clinical symptoms, and the investigator may elect 
not to perform further disease assessments. In such cases, the progression is based on 
symptomatic deterioration and considered as a clinical progression. As far as possible, these 
evaluations should be a rare exception and every effort should be made to document the 
progression. 
If there is any uncertainty about an AE or SAE being due ONLY to the progression of the 
underlying malignancy, it should be reported as an AE or SAE. 
 
 




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of the survival time within each treatment group leads to predictions of the 2-year survival rate 
of 24.2% for Control and of 51.4% for Doxorubicin, respectively and to predictions of median 
survival times of 356.7 days and 760.4 days, respectively.  
Actually the population expected in the ReLive study will be markedly different from the 
population observed in the DOTAHCC1 study. Patients are expected to be more severe and 
consequently the median survival time of the control group should be markedly lower. A 
Korean study conducted on a population closer to the one expected for ReLive study has 
reported a median survival time of 187 days (Woo H.Y., 2011[50]). Under an exponential 
distribution, a median survival time of 187 days would correspond to a 1-year survival rate of 
25.8% (2-year survival rate of 6.7%). A French cohort study conducted on 1287 naive patients 
with HCC reported that only 187 patients were eligible for Sorafenib treatment and 103 received 
Sorafenib in whom a 1-year survival of 16% was reported (Rosa L., 2011[27]). Under an 
exponential distribution, a 1-year survival rate of 16% would correspond to a median survival 
time of 138 days and to a 2-year survival rate of 2.6%. 
Following the publication of the positive RESORCE regorafenib phase 3 study in Child Pugh 
A patients tolerant and progressing under sorafenib, the SAP was revised in order to handle the 
potential risk of lack of power. Analysis of efficacy and safety of the pooled DT groups versus 
BSC group was chosen as primary analysis and a more realistic OS in the control group of 
8 months instead of 6.6 months (200 days) and an HR of 0.69 instead of 0.60 were considered. 
Following the recent data of prospective non interventional studies showing that the Child Pugh 
status is a strong prognostic factor for OS in patients treated by sorafenib (median OS of 13 
months in Child Pugh A patients versus 5 months in Child Pugh B), analysis of efficacy and 
safety in this homogeneous population of Child Pugh A patients from whom the clinical benefit 
is expected to be higher has been added.  An OS in the control group of 9 months and an HR of 
0.68 were considered in this population. 
The hierarchical sequential closed test procedure will be used to control the overall type I error 
rate of 5% to evaluate first the primary endpoint OS in the ITT population, then if statistically 
significant the primary endpoint OS in the ITT Child Pugh A population and then if statistically 
significant the main secondary endpoints (PFS and OOR) in the ITT Child Pugh A population.  
The following sequence will be followed: 
• OS in the overall ITT population 
• OS in the ITT Child Pugh A population 
• PFS in the ITT Child Pugh A population 
• ORR in the ITT Child Pugh A population 
Overall population: 
Under the assumptions of a median survival of the control group of 8 months and a hazard ratio 
of 0.69, the required total sample size to achieve a 85% power to compare the experimental 
groups (pooled DT 20mg/m2 and DT 30mg/m2) versus BSC and performed at a significance 
level of 2.5% one sided is 348 patients in the ITT population (116 patients in the BSC group 


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and 232 patients in the DT group). It is expected 10% of patients will be lost to follow-up; this 
leads to a calculated total sample size of 390 randomised patients. 
Child Pugh A population (85% of the patient population): 
Under the assumptions of a median survival of the control group of 9 months and a hazard ratio 
of 0.68, the required total sample size to achieve a 80% power to compare the experimental 
group (pooled DT 20mg/m2 and DT 30mg/m2 groups) versus BSC with a significance level of 
2.5% one sided is 291 patients in the ITT Child Pugh A population (97 patients in the BSC 
group and 194 patients in DT groups). It is expected that 10% of patients will be lost to follow-
up; this leads to a calculated total sample size of 324 ITT Child Pugh A randomised patients. 
Thus the study will be completed once a total of 390 patients will have been randomized. The 
analysis will be performed when 285 events have occurred (corresponding to 230 events in the 
ITT Child Pugh A population). 
 
9.1.3 
General conventions 
Descriptive statistics for parameters of interest will be provided by treatment group (pooled DT 
groups, DT 20 mg/m2 alone, DT 30 mg/m2 alone and BSC control group) and overall.  
The baseline value will be defined as the last available value prior to first DT infusion for 
patients in tested dose groups or prior to first BSC administration for patients in BSC. 
The type I () error will to be 5% (two-sided) for all analyses.  
From a statistical point of view, this study will not be comparative between the two doses of 
DT. So comparison of confidence intervals between each DT group versus BSC will be 
exploratory in order to define the benefit-risk ratio for each dose (see 9.6).  
9.1.4 
Disposition of patients 
The number of screened, included, randomised and treated patients will be given overall and 
according to the group which they belong to (if appropriate). 
Eligibility criteria of treated patients will be checked. The number of treated patients who will 
complete or discontinue the study will be provided. Reasons for study discontinuation will be 
provided with detailed patient information. 
9.1.5 
Protocol deviations 
Protocol deviations will be examined relative to criteria of inclusion and exclusion, and to 
compliance with the protocol with regard to administration of treatment and prohibited 
medications. 
Major deviations will be defined, listed and summarized in the final statistical analysis plan 
issued prior to database lock. 
 


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9.2 
Population to be analyzed 
The Safety Population is defined as all included subjects receiving at least one DT infusion or 
at least one anti-cancer therapy or supportive care as  BSC. For safety analyses, patients will 
be affected to the group of treatment they actually received. 
The following populations are planned for the efficacy analyses:  
- 
The Intent To Treat (ITT) Population : all randomized patients. In this population, 
patients will be analysed in their randomisation group whatever the treatment they 
received. 
- 
The Per Protocol (PP) population includes all the patients of the ITT population without 
any major protocol deviation. Patients terminating the study prematurely will be 
included in the PP population provided that there is no protocol deviation. Before 
locking the database, the precise reasons for excluding patients from the PP dataset will 
be fully defined and documented by the Blind Review Committee. 
 
9.3 
Subjects characteristics 
Subjects’ characteristics will be evaluated according to demographic characteristics, physical 
examination, medical history and previous and concomitant treatments. 
Demographic data will be summarized with usual descriptive statistics. Previous and 
concomitant treatments will be organised according to the WHO Drug dictionary. Parameters 
that cannot be easily organised by class will be listed individually. 
 
 
9.4  
Efficacy endpoints 
9.4.1 Primary endpoint 
The primary endpoint is overall survival (OS), defined as the time from the date of 
randomisation to the date of death from any cause. Patients without death at the time of the 
statistical analysis will be censored at the date they were last known to be alive.  
The primary endpoint will be analyzed in ITT population (primary analysis), with an additional 
analysis in PP population. 
Definition of date of death or censoring will refer to FDA guidelines for OS (definition 
including documented death only). 
OS will be estimated using the Kaplan-Meier method and plotted as curves by treatment 
group.  
The  comparison between groups (pooled DT groups versus BSC) will be made using the 
unstratified LogRank test. The analysis will be performed when 285 events have been observed. 
The hierarchical sequential closed test procedure for a comparison of pooled DT groups with  


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BSC in the ITT Child Pugh A population will be used to control the overall type I error rate of 
5%. 
In addition to the analysis not adjusted for baseline characteristics considered above, a 
sensitivity analysis will be conducted using a Cox model adjusting for geographical region and 
pre-defined selected prognostic factors as recently described in this population such as ECOG 
score, BCLC stage, macroscopic vascular invasion, extrahepatic spread and hepatic impairment 
(Child Pugh score, prothrombine time) (Marrero J.A., 2013[54], Reig M., 2013[55], Iavarone M., 
2015[56]). HR, median and mean survival and OS rates every 3 months will be given with the 
corresponding 95% confidence intervals. 
9.4.2 Secondary endpoints 
A sequential (closed) testing procedure will be used to control the overall type I error rate. 
Formal testing of the first secondary endpoint will be undertaken only if a statistically 
significant result is achieved on the primary endpoint of OS in the Child Pugh A population and 
formal testing of the second secondary endpoint will be undertaken only if a statistically 
significant result is achieved on the first secondary endpoint.  
1. Progression Free Survival (PFS): 
PFS is defined as the time from the date of randomisation to the date of the first documented 
progression or death from any cause. The assessment of progression will be done by an 
independent radiological review according to RECIST 1.1. Patients without progression or 
death at the end of study treatment period will be censored at the date of their last tumour 
assessment.  
PFS will be analyzed in the ITT Child Pugh A population with an additional analysis in ITT 
and PP  populations. 
Definition of date of progression or censoring will refer to FDA guidelines for PFS.   
PFS will be estimated using the Kaplan-Meier method and plotted as curves by treatment group. 
The  comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using LogRank test. 
HR, median and mean survival and PFS rates every 2 months will be given with the 
corresponding 95% confidence intervals. 
If the primary endpoint of OS is statistically significant for the pooled DT 20 mg/m2 and 
30mg/m2 groups versus BSC in the Child Pugh A population, PFS will be formally tested at 
significance level of 5% for the pooled DT 20 mg/m2 and 30mg/m2 group versus BSC in the 
Child Pugh A population. The analysis of the other comparison will be considered as 
exploratory. 
In addition to the analysis not adjusted for baseline characteristics considered above, a 
sensitivity analysis will be conducted using a model adjusting for geographical region and pre-
defined selected prognostic factors as recently described in this population such as ECOG score, 
BCLC stage and macroscopic vascular invasion, extrahepatic spread and hepatic impairment 


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(Child Pugh score, prothrombine time) (Marrero J.A., 2013[54], Reig M., 2013[55], Iavarone M., 
2015[56]). 
2. Objective Response Rate (ORR): 
ORR is defined as the proportion of patients whose best overall response is complete or partial 
response during the study treatment period. The assessment of tumour response will be done 
by an Independent Radiological Review according to RECIST 1.1.  
ORR will be analyzed in the ITT Child Pugh A population with an additional analysis in ITT 
and PP populations. 
The comparisons between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using chi-square test. 
If the PFS is statistically significant for the pooled DT 20mg/m2 and 30mg/m2 group versus 
BSC in the Child Pugh A population, ORR will be formally tested at significance level of 5% 
for the pooled DT 20mg/m2 and 30mg/m2 group in the Child Pugh A population. The analysis 
of the other comparison will be considered as exploratory. 
In addition to the analysis not adjusted for baseline characteristics considered above, a 
sensitivity analysis will be conducted using a model adjusting for geographical region and pre-
defined selected prognostic factors as recently described in this population such as ECOG score, 
BCLC stage and macroscopic vascular invasion, extrahepatic spread and hepatic impairment 
(Child Pugh score, prothrombine time) (Marrero J.A., 2013[54], Reig M., 2013[55], Iavarone M., 
2015[56]). 
9.4.3 Exploratory endpoints 
No adjustment for multiple testing will be performed in the analysis of exploratory endpoints 
and p-values will be interpreted as exploratory. 
All exploratory analyses will be conducted in ITT and ITT Child Pugh A population. 
1. PFS by the Independent Radiological Review according to mRECIST is defined as the time 
from the date of randomisation to the date of the first documented progression or death from 
any cause. Patients without documented progression or death at the end of study treatment 
period will be censored at the date of their last tumour assessment. 
PFS will be estimated by the Kaplan-Meier method and plotted as curves by treatment group. 
The comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using LogRank test. 
2. PFS by the investigator according to RECIST 1.1 (and mRECIST if possible) is defined as 
the time from the date of randomisation to the date of the first progression (documented or 
clinical) or death from any cause. Patients without progression or death at the end of study 
treatment period will be censored at the date of their last tumour assessment. 
PFS will be estimated by the Kaplan-Meier method and plotted as curves by treatment group. 
The comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using LogRank test. 


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3. ORR by the independent radiological review according to mRECIST is defined as the 
proportion of patients whose best overall response is complete or partial response during the 
study treatment period.  
The comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using chi-square test . 
4. ORR by the investigator according to RECIST 1.1 (and mRECIST if possible) is defined as 
the proportion of patients whose best overall response is complete or partial response during 
the study treatment period.  
The comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using chi-square test. 
5. Time To Progression (TTP): 
TTP is defined as the time from the date of randomisation to the date of the 1st documented 
progression or death related to tumour progression. The assessment of progression will be done 
by the independent radiological review according to RECIST 1.1 and mRECIST (if possible) 
and by the investigator according to RECIST 1.1 and mRECIST (if possible). Patients without 
progression at the end of study treatment period will be censored at the date of their last tumour 
assessment. 
Definition of date of progression or censoring will refer to FDA guidelines for TTP. 
TTP will be estimated by the Kaplan-Meier method and plotted as curves by treatment group. 
The comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using LogRank test. 
6. Best Overall Response and Disease Control Rate:  
The assessment of tumour response will be done by the Independent Radiological Review 
according to RECIST 1.1 and mRECIST (if possible) and by the investigator according to 
RECIST 1.1 and mRECIST (if possible).  
Best Overall Response is defined as the best response observed during the study treatment 
period (no requirement for confirmation). 
Disease Control Rate is defined as the proportion of patients whose Best Overall Response is 
complete response, partial response or stable disease during the study treatment period. 
The comparison between groups (pooled DT 20mg/m2 and 30mg/m2 versus BSC) will be made 
using chi-square test. 
7. Time to Objective Response: 
Time to Objective Response will be calculated from randomisation to the date to first 
documented objective response (CR or PR). Patients without documented response (CR or PR) 
at the end of study treatment period will be censored at the date of their last tumour assessment. 
The assessment of tumour response will be done by the Independent Radiological Review 
according to RECIST 1.1 and mRECIST (if possible) and by the investigator according to 
RECIST 1.1 and mRECIST (if possible).  


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8. Duration of Response:  
Duration of response will be calculated in the subpopulation of patients experiencing a response 
(CR or PR) from the time when objective response (CR or PR) is first met to the date of first 
documented progression. The assessment of tumour response and progression will be done by 
the Independent Radiological Review according to RECIST 1.1 and mRECIST (if possible) 
and by the investigator according to RECIST 1.1 and mRECIST (if possible). Patients without 
documented progression at the end of study treatment period will be censored at the date of 
their last tumour assessment.  
Duration of Response will be estimated only for patients achieving an objective response using 
the Kaplan-Meier method and plotted as curves by treatment group. 
9. Evolution in serum α-fœtoprotein levels (AFP): 
Serum AFP levels will be summarized by visit and by dose. Differences between AFP levels 
every other month and at baseline will be summarized as well. Comparisons between groups 
will also be made using non parametric tests. The number of patients with a decrease in AFP 
from baseline will be shown overall and by dose of DT. 
 
9.5 
Safety endpoints 
Safety analyses will be descriptive and conducted in the safety population.  
Descriptive data will  be provided for adverse events, laboratory values (biochemistry and 
hematology), vital signs (weight, blood pressure), clinical exams (normal/abnormal), and 
concomitant treatments.  
Patients with at least one AE, SAE, severe AE, AE leading to discontinuation, AE leading to 
dose reduction, and AEs of interest will be summarized. Adverse events will be coded using 
MedDRA.  
Respiratory:  
- Incidence and duration of reduction of SaO2 during DT infusion (in DT arms); 
- Incidence and severity of respiratory events; 
Cardiac: 
- Incidence and severity of cardiovascular events (including BP and HR); 
- ECG and LVEF change ; 
Overall: 
- Incidence and severity of all TEAEs and SAEs according to NCI-CTC v4.0 scale; 
- Biological (haematology and biochemistry analyses and particularly AST/ALT, WBC); 
- Child Pugh Score deterioration. 
Safety endpoints will be individually described per subject number, presenting: emergence, 
description, body system, preferred term, date and time of onset, date and time of last study 


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drug administration before AE, time from onset since last study drug administration, 
frequency, severity and seriousness, relationship to study drug, action taken (corrective 
treatment, hospitalisation…) required and outcome if any. 
The treatment emergent AEs (TEAEs), defined as those events that occurred or worsened after 
the first drug administration, will be summarized by body system and preferred term. The 
number of emergent AEs and the number of subjects reporting these emergent AEs will be 
presented by treatment group and overall. 
The same table presentation will be used for serious TEAEs, drug related TEAEs and drug 
related serious TEAEs. 
 
9.6 Determination of the optimal dose of DT  
 
The statistical analyses comparing the experimental group (pooled DT 20mg/m2 and 30mg/m2 
groups) versus BSC will also be conducted in the DT 20mg/m2 group alone vs BSC and DT 
30mg/m2 group alone vs BSC in the ITT population.  
Baseline demographic characteristics, exposure, efficacy, safety and adjustment for covariates 
(as described in Sections 9.3, 9.4 and 9.5 of the protocol) will be compared for each DT group 
versus BSC (as exploratory analysis). 
The selection of the optimal DT dose will be based on the benefit/risk ratio of each dose of 
DT, taking into account: 
 
− Benefit/Efficacy: The optimal dose of DT in term of efficacy will be the one which is 
associated with the best survival in comparison with the BSC group. 
This will be assessed through the measure of OS and tested by the unstratified log-rank 
test.   
The optimal dose for efficacy will be identified if one out of the 2 exploratory unstratified 
log-rank tests between the DT 30 mg/m2 versus BSC or DT 20 mg/m2 group versus BSC 
is statistically significant or if a clinically relevant difference is observed in favour of one 
DT group versus BSC (i.e. unstratified log-rank tests between the DT 30 mg/m2 versus 
BSC or DT 20 mg/m2 group versus BSC less than 15%).  
If there is no difference between the DT 30mg/m2 versus BSC and DT 20mg/m2 group 
versus BSC (i.e. unstratified log-rank tests between the DT 30 mg/m2 versus BSC or DT 
20 mg/m2 group versus BSC more than 15%), it will be concluded that DT 20 mg/m2 and 
DT 30 mg/m2 are similar in term of efficacy.   
 
− Risk/Safety: The optimal dose of DT in term of safety will be the one which is 
associated with the lowest incidence of treatment discontinuations due to adverse drug 
reactions and the lowest incidence of deaths due to adverse drug reactions.  
Difference between the two doses of DT (DT 30 mg/m2 versus DT 20 mg/m2) will be 
explored via two-sided Fisher exact tests on the incidence of treatment discontinuations 
and on the incidence of death due to adverse drug reactions.  
If at least one exploratory Fisher test leads to conclude to a statistically significant 
difference between the DT 30 mg/m2 group and the DT 20 mg/m2 group, or if a clinically 


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relevant difference is observed between groups (absolute difference of more than 5%), the 
optimal dose of DT for safety will be the one which is associated with the lowest 
incidence of study treatment interruptions or deaths due to adverse drug reactions. If there 
is no difference between the dose groups for these safety criteria, it will be concluded that 
DT 20 mg/m2 and DT 30 mg/m2 are similar in term of safety.   
 
In summary, the optimal DT dose will be the dose of DT associated with the best OS (if any). 
If OS is similar between the 2 doses of DT, the optimal DT dose will be the one associated 
with the best tolerance. If OS and safety are found to be comparable between doses, then the 
lowest dose (20mg/m2) will be selected.  
 
9.7 
Interim Efficacy Analysis 
No interim efficacy statistical analysis is planned. 
If futility analysis is performed by the independant DSMB, this analysis will not be considered 
as interim because of the absence of impact on the Type 1 error. 
 
9.8 
Risk estimation of any event according to drug exposure 
Safety data will be carefully and regularly reviewed by the DSMB every 75 patients, 
corresponding to the collection of data in around 25 patients per treatment group. Estimates of 
the risk of serious respiratory effects (or any other serious events) are given in the following 
table.  
 
The 95% and 90% (exact binomial) confidence intervals are presented for different sample 
sizes: 
Sample size 
0 respiratory SAE (ARDS) 
1 respiratory SAE (ARDS) 
25 
0/25 (0.00%) 
90%CI [0.00%, 11.29%] 
95%CI [0.00%, 13.72%] 
1/25 (4.00%) 
90%CI [0.20%, 17.61%] 
95%CI [0.10%, 20.35%] 
50 
0/50 (0.00%) 
90%CI [0.00%, 5.82%] 
95%CI [0.00%, 7.11%] 
1/50 (2.00%) 
90%CI [0.10%,   9.14%] 
95%CI [0.05%, 10.65%] 
75 
0/75 (0.00%) 
90%CI [0.00%, 3.92%] 
95%CI [0.00%, 4.80%] 
1/75 (1.33%) 
90%CI [0.07%, 6.17%] 
95%CI [0.03%, 7.21%] 
100 
0/100 (0.00%) 
90%CI [0.00%, 2.95%] 
95%CI [0.00%, 3.62%] 
1/100 (1.00%) 
90%CI [0.05%, 4.66%] 
95%CI [0.03%, 5.45%] 
A first approach assumes that the 'experimental unit' is the patient and that the risk considered 
is the risk to see a serious respiratory AE (i.e. ARDS) in a patient receiving a series of injections. 
In this first approach, the table above is interpreted as follows: 


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- 
seeing 0 serious respiratory AE in a series of 25 patients leaves a risk of 5% that the true 
incidence could be above 11.29% and a risk of 2.5% that the true incidence could be 
above 13.72%. 
- 
seeing 1 serious respiratory AE in a series of 25 patients leaves a risk of 5% that the true 
incidence could be above 17.61% and a risk of 2.5% that the true incidence could be 
above 20.35%. 
A second approach is to consider that the 'experimental unit' is the injection and that the risk 
considered is the risk to see a serious respiratory AE after an injection. In this situation, the risk 
remains the same at each injection and is not influenced by the injection being repeated in the 
same patient or being applied to a new patient. In this second approach, the table above is 
interpreted as follows: 
- 
seeing 0 serious respiratory AE in a series of 100 injections (e.g. 25 patients having had 
4 injections on average) leaves a risk of 5% that the true incidence could be above 2.95% 
and a risk of 2.5% that the true incidence could be above 3.62%. 
- 
seeing 1 serious respiratory AE in a series of 100 injections leaves a risk of 5% that the 
true incidence could be above 4.66% and a risk of 2.5% that the true incidence could be 
above 5.45%. 
Based on these assumptions, the probability to see 1 serious respiratory AE or more is presented 
for different sample sizes and possible true serious respiratory AE incidences: 
Sample size 
ARDS: 0.1% 
ARDS: 1% 
ARDS: 5% 
ARDS: 10% 
25 
0.0247 
0.2222 
0.7226 
0.9282 
50 
0.0488 
0.3950 
0.9231 
0.9948 
75 
0.0723 
0.5294 
0.9787 
0.9996 
100 
0.0952 
0.6340 
0.9941 
1.0000 
This table shows that in a series of 25 patients, if the true serious respiratory AE incidence is 
0.1%, there is a probability of 2.47% to see 1 serious respiratory AE or more (and a probability 
of 97.53% to see 0 ARDS). If the incidence is 10%, there is a probability of 92.82% to see 1 
serious respiratory AE or more (and a probability of 7.18% to see 0 ARDS). Sample size may 
apply to patients (either all patients treated with DT or patients belonging to one treatment 
group) or injections.  
On the basis of these assumptions, safety analyses will be performed when a total of 75 patients 
have been included. 
 
 
 


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10 
DATA QUALITY ASSURANCE 
10.1  
Data Collection 
The Investigator/coordinator at each site must enter the information required by the protocol 
into the electronic Case Report Form (eCRF) provided by Onxeo (formerly known as 
BioAlliance Pharma). These will be forwarded to the sponsor, Onxeo (formerly known as 
BioAlliance Pharma), and their representatives. All additions to the eCRF during the study and 
SAE forms must be forwarded to the sponsor. Details on responses need to be accurately 
documented in the patient's hospital records. 
10.2 
Study Monitoring 
Before study initiation at a site initiation visit, an Onxeo (formerly known as BioAlliance 
Pharma) representative will review the protocol and eCRF with the investigators and their staff. 
A Clinical Research Associate (CRA) will be appointed by the sponsor to monitor this study 
and periodically contact the study centre, including the conduct of site visits. 
Monitoring visits at the investigational site will be made regularly to ensure that all aspects of 
the protocol, Good Clinical Practice (GCP), and national and local requirements are observed. 
Source documents will be verified for consistency with the data on the eCRF. The investigator 
guarantees direct access to source documents by the sponsor. Source data verification is 
performed in accordance with data protection regulations and guidelines and all information 
reviewed will be kept confidential. 
The investigator is responsible for completing the eCRFs within five days of the patient’s visit 
and the Onxeo (formerly known as BioAlliance Pharma) monitor/representative is responsible 
for reviewing them in order to clarify and resolve any data queries. The completed and 
monitored eCRFs for completed visits will be locked by the monitor appointed by Onxeo 
(formerly known as BioAlliance Pharma) and data will be processed by the sponsor Data 
Management. At the end of the study, a copy of the completed eCRFs will be provided to the 
respective sites for retention with other study documents, such as the protocol, the investigator’s 
brochure and any protocol amendments, in a secure place. 
10.3 
Data Management 
Data Management will be performed under the responsibility of the Sponsor. 
Data from the eCRFs are entered into the study database using EDC (Electronic Data Capture).  
Subsequently, the information entered into the database is systematically checked  
- 
On line with automatic checks 
- 
Off line by Data Management staff 
Using error messages from validation programs or database listings.  
Error message will be entered on Data Clarification Forms and entered into the database by the 
investigator using EDC. Investigator will sign the final eCRF with electronic signature. This 


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process is followed until the lock of the database. Quality control audits of all key safety and 
efficacy data in the database will be made by the data-manager before locking the data-base. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List which employs the Anatomical Therapeutic Chemical classification system. 
Coexistent diseases and adverse events will be coded using MedDRA. 
 
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by joint written agreement 
between the Clinical Operations Manager and the Responsible of Biometry appointed by Onxeo 
(formerly known as BioAlliance Pharma). 
 
 


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11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Training of Investigators 
Training of Investigators will be performed during the Study Initiation Visit. During this visit, 
study protocol, study procedures, administrative and regulatory procedures, reporting of 
Serious Adverse Events and Good Clinical Practices Guidelines will be reviewed. 
11.2 
Training of Monitors – Clinical Research Associates (CRA) 
Monitors will be trained on study protocol, study procedures, administrative and regulatory 
procedures, monitoring guidelines (including handling of Adverse Events), Operating 
Procedures related to their activities and Good Clinical Practices Guidelines. 
11.3 
Standard Operating Procedures 
The study will be conducted according to Sponsor’s Standard Operating Procedures, or after 
Sponsor approval, according to CRO’s Standard Operating Procedures. 
11.4 
Monitoring 
Regular monitoring visits by CRAs at the Investigator’s site, prior to the start, during and at the 
end of the study will be done in order to assure compliance with the protocol, accuracy of the 
data collected and to follow the progress of the study. 
As source data verification is important for monitoring, the investigator and the institution allow 
access to source data (medical records, patient chart, CRF, pharmacy file, drug accountability 
log, etc.) in connection with the study. 
11.5 
Auditing the Trial by the Sponsor 
The Sponsor’s Quality Assurance will implement a specific audit plan/program for the study. 
This audit plan will detail all Quality Assurance activities related to the study. Audit plan will 
cover all critical aspects of the trial. 
Audits of selected clinical sites will be conducted in accordance with Sponsor’s written 
procedures, by appointed qualified auditors who will be independent of the clinical trial. 
In this respect, Investigator and institution will allow access to duly appointed representatives 
of the Sponsor, to all documentation and source data (medical records, patient chart, CRF, 
pharmacy file, drug accountability log, etc.) in connection with the study. 
11.6 
Auditing the Trial by Regulatory Authorities 
Regulatory Authorities may request to audit the trial at any time during and after the completion 
of the study.  
In this respect, Investigator and institution will allow access to duly appointed Regulatory 
Authorities Auditors to all documentation and source data (medical records, patient chart, CRF, 
pharmacy file, drug accountability log, etc.) in connection with the study. 


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12 
DATA HANDLING AND RECORD KEEPING 
12.1 
Case report form and Source Data 
In accordance with legislation concerning the protection of data relating directly or indirectly 
to named individuals, any data collected during a clinical trial will be treated confidentially in 
order to guarantee the rights of the subject. 
The investigator must agree to place source documents relating to the subject(s) at the disposal 
of the CRA during his monitoring visits. The CRA will verify the data recorded in the e-CRFs 
against the source documents wherever necessary. 
The clinical study may also be inspected by the appropriate regulatory authorities to verify that 
the study was conducted in accordance with protocol requirements as well as the applicable 
regulations and guidelines. 
Regulatory authorities, the IEC, and an auditor authorized by the Sponsor may request access 
to all source documents, e-CRFs, and other study documentation for on-site audit or inspection. 
Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. Medical records and other study documents may be 
copied during audit or inspection provided that subject names are obliterated on the copies to 
ensure confidentiality. 
 
12.2 
Monitoring Plan (visits) 
The clinical research assistant (CRA) will remain in regular contact with the investigator to 
assess if the data are recorded correctly in the e-CRF. 
It is the responsibility of the CRA to regularly check that the protocol is being adhered to and 
that the e-CRFs are being filled in correctly through comparison with the source data. 
The investigator agrees to cooperate with the CRA in order to resolve any problems identified 
by the latter following the outcome of each monitoring visit. 
The CRA will monitor the study progress at the following times: 
− Before the initiation of the study to visit the site and determine the site’s ability to 
conform with the requirements of the protocol ( as applicable); 
− At the initiation visit, the investigator may only enroll his first subject after the CRA 
has completed this visit; 
− During the study the number of monitoring visits will be adapted to suit recruitment 
at each centre; 
− A closing visit will be conducted at the end of the trial. 
 
12.3 
Archiving Clinical Trial Files 
The investigator shall maintain the essential clinical study documents (including e-CRFs, 
source documents, clinical drug-disposition records, signed subject ICFs, AE reports, and other 


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regulatory documents) as required by the applicable regulatory requirements. The investigator 
should take adequate measures to prevent accidental or premature destruction of these 
documents. In the event of accidental destruction, the investigator must notify Onxeo (formerly 
known as BioAlliance Pharma) immediately. The following essential clinical study documents 
must be maintained: 
− Signed informed consent documents for all subjects 
− Screening log and enrollment log 
− Record of all communication between the investigator and IEC 
− Composition of the IEC or other applicable statement 
− Record of all communications between the investigator and Sponsor/CRO  
− List of sub investigators and other appropriately qualified persons to whom the 
Principal Investigator has delegated significant trial-related duties, together with 
their roles in the study and their signatures 
− Copies of e-CRFs and of documentation of corrections for all subjects 
− Drug-accountability records 
− Record of any body fluids or tissues retained 
− All other source documents (i.e., subject records, hospital records, laboratory 
records, etc.) 
− All other documents as listed in Section 8 of the consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
Essential clinical study documents shall be retained for at least 15 years following the date a 
marketing application is approved for the drug with the indication for which it is being 
investigated, or, if no application is to be submitted or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and the appropriate 
regulatory authorities are notified. 
These documents shall be retained for a longer period, however, if required by additional 
applicable regulatory requirements or by an agreement with Onxeo (formerly known as 
BioAlliance Pharma). The investigator must, therefore, obtain approval in writing from the 
Sponsor prior to destruction of any records. 
The investigator shall notify Onxeo (formerly known as BioAlliance Pharma) prior to any 
change in the location or status of any essential, clinical-study documents. Onxeo (formerly 
known as BioAlliance Pharma) shall be responsible for informing the investigator when these 
documents no longer need to be retained.  
 
 


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13 
ETHICS, REGULATORY & LEGAL CONSIDERATION 
The study will be conducted in accordance with the Good Clinical Practice (GCP) and local 
country requirements, the recommendations of the Declaration of Helsinki, as amended from 
time to time and the rules of International Conference on Harmonisation (ICH). 
 
13.1 
Ethical aspects 
Research is designed to benefit society and Public Health by gaining new knowledge.  
There is no guarantee, though, that the individual participant will personally benefit from study 
participation. The study treatment may result in an improvement of the disease or there may be 
no improvement at all. This is clearly described in the participant information. 
Overall it is considered that the study does not cause undue constrain to the participants.  
On this basis it is considered that the potential usefulness of the study exceeds the 
inconvenience and risks, and is reasonable to implement the study. 
 
13.2 
Independent Ethics Committees (IEC) 
Documented approval from the appropriate IEC will be obtained for the participating centre 
prior to study initiation, according to GCP, local laws, regulations, and organizations. When 
necessary, an extension, amendment, or renewal of the IEC approval must be obtained and also 
forwarded to the Sponsor. The IEC must supply to the Sponsor, upon request, a list of the IEC 
members involved in the vote and a statement to confirm that the IEC is organized and operates 
according to GCP and applicable laws and regulations. 
 
13.3 
Ethical Conduct of the Study 
The procedures described in this protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor and investigator abide by 
GCP Guidelines and operate under the guiding principles detailed in the Declaration of 
Helsinki. The study will also be carried out in keeping with applicable local law(s) and 
regulation(s). This may include an inspection by the Sponsor representatives and/or regulatory 
authority representatives at any time. The investigator must agree to the inspection of study-
related records by the regulatory authority/Sponsor representatives, and must allow direct 
access to source documents by the regulatory authority/Sponsor representatives. 
Modifications to the study protocol will not be implemented by either the Sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation form or a change of the protocol to eliminate an immediate hazard(s) to the trial 
subjects without prior IEC/Sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol 


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amendment should be submitted to the IEC/Sponsor. Any deviations from the protocol must be 
fully explained and documented by the investigator. 
 
13.4 
Regulatory Authority Approvals/Authorizations 
Regulatory Authority approvals/authorizations/notifications, where required, must be in place 
and fully documented prior to study start. 
 
13.5 
Subject Information and Consent 
A core information and Informed Consent Form (ICF) will be reviewed with each subject. Prior 
to the beginning of the study, the investigator must have the IEC written approval of the written 
ICF and any other written information to be provided to patients. The informed consent should 
be in accordance with the current revision of the Declaration of Helsinki, current ICH and GCP 
guidelines, and Onxeo (formerly known as BioAlliance Pharma) policy. The written approval 
of the IEC together with the approved (signed and dated) patient information/ICFs must be filed 
in the study file. 
The principal investigator, or co-investigators licensed to do so, will provide the oral 
information and simultaneously will go through the written participant information and ICF. 
The conversation will be conducted in a quiet and undisturbed environment at the hospital. 
Appropriate time for reflection (ideally at least 24 hours) will be given. If needed or requested, 
the patient could have a second meeting or seek for another opinion before signing the inform 
consent form. 
Written ICF must be obtained from each subject before any study-specific procedures take 
place. Participation in the study and the date of informed consent given by the subject should 
be documented appropriately in the subject’s file. The ICF should be written in a language in 
which the subject is fluent. 
The investigator must explain to potential subjects the aims, methods, reasonably anticipated 
benefits, and potential hazards of the trial and any discomfort it may entail. Subjects will be 
informed that they are free to not participate in the trial and that they may withdraw consent to 
participate at any time. They will be told that refusal to participate in the study will not prejudice 
future treatment. They will also be told that their records may be examined by competent 
authorities and authorized persons but that personal information will be treated as strictly 
confidential and will not be publicly available. Subjects must be given the opportunity to ask 
questions. After this explanation and before entry into the trial, consent should be appropriately 
recorded by means of the subject’s dated signature. This document should be prepared in 
duplicate, one for the subject and the other for the investigator. The investigator must retain his 
copy in his archives for a period of 15 years in accordance with current legislation. The subject 
should receive a signed and dated copy of the ICF. The original signed ICF should be retained 
in the study files. The investigator shall maintain a log of all subjects who sign the ICF and 
indicate if the subject was enrolled into the study or the reason for failure to enroll. 
 


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13.6 
Amendment to the protocol 
Modifications to the clinical study protocol will be made as an amendment and must be 
approved by Onxeo (formerly known as BioAlliance Pharma) and the IEC prior to being 
implemented, unless an amendment is to eliminate an immediate hazard to the clinical study 
subjects. 
Neither the investigator nor Onxeo (formerly known as BioAlliance Pharma) may modify the 
protocol without the agreement of the other. Once the study has started, amendments may only 
be made in exceptional cases. The IEC will be notified of such amendments. Modifications 
must be made in writing and signed by all parties concerned. The modifications will become an 
integral part of the protocol. Onxeo (formerly known as BioAlliance Pharma) or their designee 
shall be responsible for notifying the regulatory authorities of any amendments to the protocol. 
 
14 
CONFIDENTIALITY 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. Subject names will not 
be supplied to the Sponsor. Only the subject number will be recorded in the e-CRF, and if the 
subject name appears on any other document (e.g., pathologist report), it must be obliterated 
before a copy of the document is supplied to the Sponsor. Study findings stored on a computer 
will be stored in accordance with local data protection laws. The subjects will be informed in 
writing that representatives of the Sponsor, IEC, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subject’s records to be identified for Health 
Authority inspections. 
 
15 
DOCUMENTATION AND SOURCE DOCUMENTS 
Study Documents 
The investigator is responsible for providing and maintaining essential study documents. 
Essential study documents are those documents that individually and collectively permit the 
evaluation of the conduct of the study and the quality of the data produced. These documents 
serve to demonstrate the compliance of the investigator and Onxeo (formerly known as 
BioAlliance Pharma) with the standards of GCP and with all applicable regulatory 
requirements. 
Essential study documents include regulatory documents as well as source documents which 
are original documents, data records of clinical findings, observations, and other activities in a 
clinical study necessary for the reconstruction and evaluation of the study. 


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Source Data corresponds to all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
Source data is documented in source documents.The following list gives examples of source 
documents where source data may be located: 
• 
medical records 
• 
laboratory reports 
• 
subject diaries 
• 
nurses’ notes 
• 
dispensing logs 
• 
electrocardiogram (ECG) print-outs 
• 
case report forms (CRF) 
• 
X-ray images 
• 
radiological reports, etc. 
As the location of source data could vary from one investigator site to another depending on 
the organisation of the site and/or the investigator, some source data may be recorded directly 
in the Case Report Form (CRF). This corresponds, for example, to specific data requested by 
the study protocol and/or in case of data usually not fully described and/or collected in routine 
practice (e.g. ethnic origine, classification of AE / pain / other according to specific scale, body 
mass index, body surface aera, calculated creatinin clairance, disease staging..). These data 
collected and validated in the CRF are considered as source document. 
In addition, all efforts have to be made to maintain the anonymity and confidentiality of medical 
records during this study as per local country regulation. 
 
Technical Documentation 
All information relating to the investigational drug, and to the strategy of Onxeo (formerly 
known as BioAlliance Pharma), such as the clinical indication of the drug, the method of 
preparation, and the scientific data supplied by Onxeo (formerly known as BioAlliance Pharma) 
and as yet unpublished, is confidential and remains the property of Onxeo (formerly known as 
BioAlliance Pharma). The investigator agrees to use this information only for conducting this 
study and not for any other purposes, except with the prior written agreement of the Sponsor. 
The e-CRFs completed in the context of the study remain the property of Onxeo (formerly 
known as BioAlliance Pharma). The investigator has to retain the documents pertaining to the 
study, the written ICFs, the list identifying the participants, and a copy of the e-CRFs for a 
period of 15 years. The medical records and source documents for the e-CRFs shall be kept for 
the maximum period allowed by the investigator’s centre. The Sponsor should be notified in 
writing before any files are destroyed at the centre. 
An in-house statistical and clinical report shall be prepared and signed jointly by the Principal 
Investigator and Onxeo (formerly known as BioAlliance Pharma).  
The results of the study are the property of Onxeo (formerly known as BioAlliance Pharma). 


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16 
PUBLICATION OF TRIAL RESULTS 
Data from the study will be published in an international peer-reviewed journal. Order of the 
authors will be agreed based on the contribution of each author in the definition, executing and 
writing stages.  
 
17 
FINANCIAL CONDITIONS 
This study is initiated by Onxeo (formerly known as BioAlliance Pharma).  
The study drug will be provided to participants at no cost. Patient will not be reimbursed for 
participation in this study. Actual reasonable travel reimbursement assistance may be available 
if needed after agreement of the sponsor. 
This research is funded by Onxeo (formerly known as BioAlliance Pharma). The researchers 
do not, however, hold a direct financial interest in the sponsor or in the outcome of the study.  
 
 


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Pepin, X., et al., On the use of ion-pair chromatography to elucidate doxorubicin 
release mechanism from polyalkylcyanoacrylate nanoparticles at the cellular level. J 
Chromatogr B Biomed Sci Appl, 1997. 702(1-2): p. 181-91. 
45. 
Nakajima, A., et al., Beneficial effect of cepharanthine on overcoming drug-resistance 
of hepatocellular carcinoma. Int J Oncol, 2004. 24(3): p. 635-45. 
46. 
Wang, B.L., et al., Clinical significance of mrp gene in primary hepatocellular 
carcinoma. Hepatobiliary Pancreat Dis Int, 2003. 2(3): p. 397-403. 
47. 
Chiannilkulchai, N., et al., Doxorubicin-loaded nanoparticles: increased efficiency in 
murine hepatic metastases. Sel Cancer Ther, 1989. 5(1): p. 1-11. 
48. 
Genne, P., Report PRT/00041.1. Antitumor activity study of doxorubicin-loaded 
polyisohexylcyanoacrylate nanoparticles (Doxorubicin transdrug) in BDIX rats 
bearing hepatic metastasis of rat colon tumor. 2007. 


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49. 
Vahid, B. and P.E. Marik, Pulmonary complications of novel antineoplastic agents for 
solid tumors. Chest, 2008. 133(2): p. 528-38. 
50. 
Woo, H.Y., et al., Clinical course of sorafenib resistant hepatocellular carcinoma 
patients. Departement of Internal Medicine, Pusan National University School of 
Medecine, Busan, 2011. 
51. 
Lencioni, R. and J.M. Llovet, Modified RECIST (mRECIST) assessment for 
hepatocellular carcinoma. Semin Liver Dis, 2010. 30(1): p. 52-60. 
52. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47 
53. 
Lencioni R., et al., GIDEON (Global Investigation of therapeutic DEcisions in 
hepatocellular carcinoma and Of its treatement with sorafeNib): second interim 
analysis. Int J Clin Pract, 2014 May, 68(5): p. 609-617. 
54 
Marrero J.A., et al., Final analysis of GIDEON (Global Investigation of Therapeutic 
Decisions in Hepatocellular Carcinoma [HCC] and of Its Treatment with Sorafenib 
[Sor]) in >3000 Sor-treated patients (pts): Clinical findings in pts with liver 
dysfunction. Clin Oncol 31, 2013 (suppl; abstr 4126) 
55 
Reig M., et al., Postprogression Survival of Patients With Advanced Hepatocellular 
Carcinoma:Rationale for Second-Line Trial Design. Hepatology 2013 Dec, 58(6): p. 
2023-2031 
56 
Iavarone M., et al., Predictors of Survival of Patients With Advanced Hepatocellular 
Carcinoma Who Permanently Discontinued Sorafenib, Hepatology 2015, 00(00): p.1-
8 
57 
Cheng AL, et al., Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: 
Results of a Randomized Phase III Trial. J Clin Oncol, 2013 Nov 10;31(32): p.4067-
75. 
58 
Llovet J.M., et al., Brivanib in Patients With Advanced Hepatocellular Carcinoma 
Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the 
Randomized Phase III BRISK-PS Study. J Clin Oncol, 2013 Oct 1;31(28): p.3509-16. 
59 
Johnson P.J., et al., Brivanib Versus Sorafenib As First-Line Therapy in Patients With 
Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized 
Phase III BRISK-FL Study. J Clin Oncol. 2013 Oct 1;31(28): p.3517-24. 
60 
Zhu A.X. et al., SEARCH: a phase III, Randomized, Double-Blind, Placebo-
Controlled Trial of Sorafenib plus Erlotinib in Patients With Advanced Hepatocellular 
Carcinoma. J Clin Oncol, 2015 Feb 20;33(6): p.559-66. 
61 
Zhu A.X. et al., Effect of Everolimus on Survival in Advanced Hepatocellular 
Carcinoma After Failure of Sorafenib: the EVOLVE-1 Randomized Clinical Trial. 
JAMA, 2014 Jul 2;312(1): p.57-67. 
62 
Cainap C. et al., Linifanib Versus Sorafenib in Patients with Advanced Hepatocellular 
Carcinoma: Results of a Randomized Phase III trial. J Clin Oncol, 2015 Jan 10;33(2): 
p.172-9. 
63 
Zhu A.X. et al., Ramucirumab versus placebo as second-line treatment in patients 
with advanced hepatocellular carcinoma following first-line therapy with sorafenib 
(REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol, 2015 
Jul;16(7): p.859-70. 


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64 
Bruix, J., et al., Regorafenib for patients with hepatocellular carcinoma who progressed 
on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, 
phase 3 trial. (2017). Lancet, 2017 Jan;389(10064): p.56-66. 
 
 


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19 
LIST OF APPENDICES 
Appendix I: HCC staging according to BCLC 
Appendix II: Child-Pugh score 
Appendix III: CLIP and MELD scores 
Appendix IV: ECOG performance status 
Appendix V : NHYA classification 
Appendix VI: DT protocol of reconstitution 
Appendix VII: Pharmacokinetic protocol 
Appendix VIII: Biomarkers protocol 
Appendix IX: RECIST 1.1 and  mRECIST criteria 
Appendix X: NCI CTC AE v4.0 classification 
Appendix XI : List of inhibitors and inducers of CYP3A4, CYP2D6 and P-gp  
Appendix XII : EQ- 5DTM Questionnaire 
 
 
 
 
 
 
 


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I. 
BCLC proposal for HCC staging 
 
 
 
 
Barcelona Clinic Liver Cancer (BCLC) classification in HCC (adapted from EASL-
EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma, J. 
Hepatol 2012) 


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II. 
Child-Pugh score 
 
 
 
 
1 point 
2 points 
3 points 
Encephalopathy 
Absent 
Asterixis 
Confusion 
Ascites 
Absent 
Mild/Moderate 
Severe/Refractory 
Albumin 
> 35g/L 
35-28g/L 
 
< 28g/L 
Total bilirubin 
< 35µM/L 
 2mg/dl 
35-50µM/L 
2-3 mg/dl 
> 50µM/L 
>3 mg/dl 
Prothrombin time rate 
(INR) 
> 50% 
(< 1.7) 
40-50% 
(1.7-2.3) 
< 40% 
(> 2.3) 
 
 
Class A: 5-6 points
Class B: 7-9 points
Class C: 10-15 points




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IV. 
ECOG Performance Status 
 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, (eg, light house work, office work) 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 
Dead 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
 
 


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V. 
Stages of Heart Failure – NYHA Classification  
 
 
The New York Heart Association (NYHA) functional classification system relates symptoms 
to everyday activities and the patient's quality of life: 
Class
Patient Symptoms
Class I 
(Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnoea (shortness of breath). 
Class II 
(Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnoea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnoea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 
 


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VI. 
Doxorubicin Transdrug™ protocol of reconstitution 
 
DOXORUBICIN TRANSDRUG™ 10 mg - POWDER FOR SUSPENSION FOR INJECTION 
PROTOCOL OF RECONSTITUTION AND ADMINISTRATION PROCEDURE 
 
1. DOSAGE FORM  
Doxorubicin Transdrug™ 10 mg (DT) is a powder for suspension for injection which contains 
doxorubicin, an antineoplastic agent as active drug. DT is a 
 for suspension 
for intravenous injection, presented in glass vials with a rubber cap and a flip-off seal. Each vial 
contains 10 mg equivalent doxorubicin and 
 
  
 
2. RECOMMENDATION FOR SAFE HANDLING  
The following information is intended for medical and healthcare professionals only. Caution 
should be exercised in the handling and preparation of DT. The reconstitution must be carried 
out under a laminar flow, by a suitably trained staff. The vials must never be opened before 
reconstitution. DT must be injected by strict intravenous route. If any signs or symptoms of 
extravasation have occurred, the infusion should be immediately stopped and restarted in 
another vein. The waste disposal must be performed with respect to each centre procedure for 
genotoxic and cytotoxic compounds.  
 
3. STORAGE 
Store  in the refrigerator (2°C-8°C).  
After reconstitution:  
Chemical and physical in-use stability has been demonstrated for 24h following initial 
reconstitution when stored at refrigerated conditions (2°C-8°C). 
All precaution should be taken during the reconstitution in order to avoid any microbiological 
contamination.  In-use storage times and conditions prior to use are the responsibility of the 
user and should not be longer than 24 hours at 2°C to 8°C. 
Do not store partially used vials for future patient use. 
 
4. MATERIAL FOR RECONSTITUTION 
 Vent needles dispensing pin 
 5 µm filters (green colour code) 
 1.2 µm filters (blue colour code) 
 30 ml Luer Lock Syringes 
 Needles 21G x 1 ½ " (0.8 x 38 mm)  
 250 ml sterile bag for injectable solution 
 2.5% sterile glucose solution for injection  
 
 
 


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5. RECONSTITUTION AND FILTRATION (Hospital Pharmacy, under laminar flow) 
It is important to read the entire content of this section prior to the preparation of this 
medicinal product. 
Aseptic technique must be strictly observed throughout handling of DT since no 
preservative is present. 
Caution should be exercised in the handling and preparation of DT. The use of gloves is 
required. 
The preparation for intravenous infusion of DT is performed according to two main steps 
(reconstitution and filtration) as described hereafter.  
 
Step 1 – Reconstitution of DT powder 
 Calculate the dose of DT and determine the number of vials needed, based upon the 
recommended dose and the patient’s body surface area (BSA), according to the tables 
below.  
 Get the vials for reconstitution out of the refrigerator.  
 Keep the vials for reconstitution at room temperature for at least 30 min before 
reconstitution. 
 Reconstitute each vial containing HCl Doxorubicin 10 mg with 25 mL of 2.5% glucose 
as follows : 
o Remove the flip-off seal of each vial. 
o Insert a vent needle through the rubber cap. 
o Open the vent needle protective cap. 
o Add 25 ml of sterile glucose 2.5% for injection using a 30 ml syringe to each 
DT vial, to yield a suspension containing 0.4 mg/ml of doxorubicin HCl. The 
addition of glucose may induce the formation of a foam;  
o Close the vent needle and shake each vial for a minimum of 10 seconds to 
completely disperse the DT. Visually inspect the vial for particulate matter and 
continue shaking until complete dispersion is obtained.  Once reconstituted the 
resulted nanoparticle suspension for infusion of DT is a red-orange 
homogeneous suspension. 
Step 2 - Double filtration of the DT suspension through 5 µm filter and 1.2 µm 
filter into a sterile bag  
Each individual vial has to be filtered using one unique set of 5 µm and 1.2 µm filters and 
30 mL syringe.  
 Carefully open the protective cap of the vent needle. 
 Withdraw the suspension of DT into a sterile 30 mL syringe. During the collection of 
reconstitued suspensions, pay attention to avoid the aspiration of the foam in the syringe 
 Remove the 30mL syringe with the suspension of DT.  
 Adapt on each 30 mL syringe containing the suspension of DT and in series according 
the following sequence : 
o one 5 µm filter provided (green colour code),  
o one 1.2 µm filter provided (blue colour code) and then, 


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o the sterile bag provided. 
 Instill the suspension of each syringe into the sterile bag. 
 Operate as above to reconstitute other vials intended for the preparation in order to 
obtain in the sterile bag the appropriate volume of DT 0.4 mg/mL as determined 
previously. 
 The total suspension of DT corresponding to the appropriate volume for the patient will 
be administered to the patient without any futher dilution. 
 Stick the label onto the bag and store it in a refrigerator at 2°C to 8°C.  
 If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and should not be more than 24 hours following preparation 
and should be stored at 2°C to 8°C.  
 Discard any unused portion of suspension of DT.  
 Do not futher dilute the reconstituted suspension of DT. 
 
 
6. ADMINISTRATION TO THE PATIENT 
1. Day 0 –  Oral premedication the Day before study treatment administration  
 The day before DT injection, patient will receive a premedication with 
methylprednisolone 32 mg p.o. (or equivalent) + cetirizine 20 mg p.o (or equivalent)  
2. Day 1 –  Study treatment administration  
 Get the suspension bag out of the refrigerator and leave it at room temperature for at 
least 30 min;  
 One hour before DT administration (H-1), patient will receive premedication with 
methylprednisolone 32 mg p.o. (or equivalent) and cetirizine 20 mg p.o (or equivalent);  
 Then, the suspension of DT will be infused over 6 hours through intravenous route using 
an infusion pump or a syringe-pump in order to insure a constant flow;  
 Patient will have a continuous SaO2 monitoring during infusion and then 24 hours after 
the infusion starts; 
 The duration of infusion must be increased (flow reduced by half) in case of occurrence 
of pulmonary toxicity (cf section 7.6: Urgent Safety Measures). Any modification in the 
infusion rate must be recorded in the e-CRF;  
 Fasting is not needed.  
3. Day 2 –  Oral premedication the Day after study treatment administration  
 The Day after DT administration (D2), patient will receive a premedication with 
methylprednisolone 32 mg p.o. (or equivalent) and cetirizine 20 mg p.o (or equivalent);  


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DT dosing table and volume to be administered at a dose of 20 mg/m² according to patient’s body surface area 
DOXORUBICIN TRANSDRUG™ - DOSE = 20 mg/m² 
Body surface area*  
1.5 m2 
1.6 m2 
1.7 m2 
1.8 m2 
1.9 m2 
2.0 m2 
2.1 m2 
2.2 m2 
2.3 m2 
Total dose per patient  
30 mg 
32 mg 
34 mg 
36 mg 
38 mg 
40 mg 
42 mg 
44 mg 
46 mg 
Number of vials (10 mg/vial)  to reconstitute** 
3 
4 
4 
4 
4 
4 
5 
5 
5 
Final volume of suspension obtained to be 
administered (0.4 mg/mL) 
75 ml 
80 ml 
85 ml 
90 ml 
95 ml 
100 ml 
105 ml 
110 ml 
115 ml 
 
DT dosing table and volume to be administered at a dose of 30 mg/m² according to patient’s body surface area 
DOXORUBICIN TRANSDRUG™ - DOSE = 30 mg/m² 
Body surface area*  
1.5 m2 
1.6 m2 
1.7 m2 
1.8 m2 
1.9 m2 
2.0 m2 
2.1 m2 
2.2 m2 
2.3 m2 
Total dose per patient  
45 mg 
48 mg 
51 mg 
54 mg 
57 mg 
60 mg 
63 mg 
66 mg 
69 mg 
Number of vials (10 mg/vial)  to reconstitute** 
5 
5 
6 
6 
6 
6 
7 
7 
7 
Final volume suspension obtained to be 
administered (0.4 mg/mL) 
112.5 ml 
120 ml 
127.5 ml 
135 ml 
142.5 ml 
150 ml 
157.5 ml 
165 ml 
172.5 ml 
 
DT dosing table and volume to be administered at a dose of 15 mg/m² according to patient’s body surface area 
DOXORUBICIN TRANSDRUG™ - DOSE = 15 mg/m² 
Body surface area*  
1.5 m2 
1.6 m2 
1.7 m2 
1.8 m2 
1.9 m2 
2.0 m2 
2.1 m2 
2.2 m2 
2.3 m2 
Total dose per patient  
22.5 mg 
24 mg 
25.5 mg 
27 mg 
28.5 mg 
30 mg 
31.5 mg 
33 mg 
34.5 mg 
Number of vials (10 mg/vial)  to reconstitute** 
3 
3 
3 
3 
3 
4 
4 
4 
4 
Final volume suspension obtained to be 
administered (0.4 mg/mL) 
56.5ml 
60 ml 
64 ml 
67.5 ml 
71.5 ml 
75 ml 
79 ml 
82.5 ml 
86.5 ml 
* Round off the Body surface area in the following way: 
From 1.50 to 1.54 m², round down to 1.5 m2 
From 1.55 to 1.59 m², round up to 1.6 m2 
**The number of vials to reconstitute could be over if the volume of suspension collected is not sufficient. 


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VII. 
Pharmacokinetic protocol 
 
During the previous HCC studies, preliminary pharmacokinetic parameters were evaluated and 
individual pharmacokinetic profiles have been determined. The data obtained pointed out a 
wide inter-individual variability, which require evaluation of the pharmacokinetic profile in 
patients with HCC.  
In this study, patients will be treated with doses at 20 or 30 mg/m² of Doxorubicin Transdrug™, 
repeated every 4 weeks until progression of the disease or unacceptable toxicity.  
The aim of pharmacokinetic evaluation is first, to determine the population pharmacokinetic 
parameters. Secondly, the objective is to analyse the pharmacokinetic / pharmacodynamic 
correlation with DT efficacy and toxicity, and to evaluate inter-Cycles AUC stability.  
 
Due to its specific formulation (
), late 
exposure (>48 hours after DT infusion) has to be evaluated  in order to be able to characterize 
the pharmacokinetic profile of doxorubicin and doxorubicinol. 
For this purpose, blood sampling will be performed at the first and third treatment Cycles. For 
patients still on study treatement after Cycle 3, an optional and limited pharmacokinetic blood 
sampling will be done at Cycle 4, Cycle 6 (e.g. every 2 cycles until the end of study treatment).  
Blood collection (10mL/sample) will have to be taken from a peripheral vein. DT will be 
infused at D1 of each cycle over 6 hours through intravenous route. 
At Cycle 1 and Cycle 3: 
Blood samples will be collected at the following times on D1, D2, D3, D4, D8, D14 and D28 
during the 1st and the 3rd Cycle of DT treatment, to perform total and free doxorubicin and 
doxorubicinol assays.  
D1 ( D1= DT administration) (in patient) 
D2 
(in 
patient) 
T0 
T30m
in 
T60m
in 
T2h 
T4h 
T6h 
T6h3
0 
T7h 
T7h3
0 
T8h 
T12h 
± 2h 
T24h 
± 2h 
T33h 
± 2h 
Befor
e 
infusi
on 
30mi
n 
after 
start 
of 
infusi
on 
60mi
n 
after 
start 
of 
infusi
on 
2h 
after 
start 
of 
infusi
on 
4h 
after 
start 
of 
infusi
on 
3 to 5 
min 
befor
e the 
end 
of 
infusi
on 
30mi
n 
after 
end 
of 
infusi
on 
1h 
after 
end 
of 
infusi
on 
1h30 
after 
end 
of 
infusi
on 
2h 
after 
end 
of 
infusi
on 
6h± 2 
hours 
after 
end 
of 
infusi
on 
24h± 
2 
hours 
after 
start 
of 
infusi
on 
33h± 
2 
hours 
after 
start 
of 
infusi
on 
- 
D1: T0: before the beginning of treatment injection,  
- 
D1: T30min, T60min, T2h, T4h after start of the infusion, T6h (3-5 min before the end of 
infusion), then T6h30min (30 min after the end of infusion), T7h (1 hour after the end of 
infusion), T7h30 (1 hour 30 after the end of infusion), T8h (2 hours after the end of infusion) 
and T12h ± 2h (6 ± 2 hours after the end of infusion ) 
- 
D2: T24h and T33h (24 ± 2 hours and 33 ± 2 hours after start of infusion); The time H33h 
has been taken in order to avoid blood sampling during night 


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- 
Then D3: T48h (48 ± 2 hours after start of infusion), D4: T72h (72 ± 2 hours after start of 
infusion), D8, D14 and D28 after DT administration.  
 
D3  
(in or outpatient) 
D4  
(in or outpatient) 
D8  
(outpatient) 
D14  
(outpatient) 
D28  
(in or outpatient) 
T48h ± 2h 
T72h ± 2h 
T7days 
T13days 
T27days 
48h± 2 hours after 
start of infusion 
72h± 2 hours after 
start of infusion 
7 days after  
infusion (morning 
or afternoon) 
13 days after  
infusion (morning 
or afternoon) 
27 days after  
infusion (morning 
or afternoon) 
 
At Cycle 4, Cycle 6, then every 2 cycles until the end of study treatment (optional): 
D1 (D1= DT administration) (in patient) 
D14  
(outpatient) 
D28  
(in 
or 
outpatient) 
T0 
T4h 
T6h 
T8h 
T13days 
T27days 
Before infusion
4h after start of 
infusion 
3 to 5 min 
before the end 
of infusion 
2h after end of 
infusion 
13 days after  
infusion 
(morning 
or 
afternoon) 
27 days after  
infusion 
(morning 
or 
afternoon) 
 
Blood Sampling procedures: 
The blood will be taken in 10 ml EDTA tubes. Blood samples will be immediately put into a 
glass of ice + water after sampling. Then,centrifugation will be performed immediately  at 
3000 rpm, at +4°C ± 2°C for 20 min, to separate out the plasma.  
The plasma will then be divided into 2 polypropylene cryotubes, each of which must contain 
at least 1.5ml of plasma, and then immediately frozen at -80°C; Plasma can be 
alternatively kept at -20°C if -80°C is not feasible.  
The samples may be centrifuged individually, after the sample is collected. 
Each sample shall be identified as follows, using a label that is resistant to the storage 
temperature of -80°C:  
- 
the protocol number BA2011/03/04, 
- 
the centre number, 
- 
the identification number of the patient, 
- 
the theoretical sampling time, 
- 
the date of sampling. 
A check-list will be kept, including the exact identification of each sample and the real sampling 
times.  
Onxeo (formerly known as BioAlliance Pharma) will ensure dispatching of samples to third 
parties in charge of doxorubicin and its metabolite dosage. Study samples will be transferred 


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periodically to the laboratory in charge of these dosages using a container filled with enough 
dry ice to ensure that samples will be kept deep frozen at about -80°C.  
 
 


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VIII. Biomarkers protocol 
 
The blood will be taken in a 10 ml K2EDTA tube. Immediately gently invert the tube 10 times, 
and store it at room temperature until centrifugation. 
 
Aliquoting and freezing should be completed within 60 min of specimen collection.  
 
1. Set the centrifuge at 6°C. Plasma is obtained by centrifugating the blood sample in a 
swing centrifuge at the speed =1300 g for 10 min under refrigerated conditions  
(2-6°C). 
a. NOTE: Ensure rotor is balanced. 
 
 
2. Using a pipette the resultant plasma is transferred (but not the white cells in the buffy 
coat) to a 15 ml conical bottom Falcon® tube.  
 
o Centrifuge the second plasma tube at 2400 g or rpm for 15 min under 
refrigerated conditions (2-6° C) to remove all potentially remaining 
cellular material. 
 
o Save the “buffy coat” containing white cells and the red blood cells 
(RBC), separately as a source of DNA. Using a pipette, transfer buffy 
coat aliquots and red blood cell aliquots into labelled 1.8 ml cryovials 
and freeze them at -70°C to -80°C. 
 
3. Transfer the resultant plasma after second centrifugation, into a new 15 mL conical 
bottom Falcon® tube, using a pipette. Pipette to approximately 10% from the bottom 
of the tube to ensure no cellular material is collected.   
The purpose of double spinning the plasma is to remove all cellular contaminants so 
that the plasma is suitable for plasma DNA analysis. It is extremely important, therefore, 
not to disturb the buffy coat after the first spin, and any pellet after the second spin. 
 
4. Gently mix the plasma and transfer 800-1000 µl aliquots into labeled 1.8 ml cryovials, 
without delay. Freeze the cryovials at -70°C to -80°C.  
 
 
 


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IX. 
RECIST1.1  and mRECIST Criteria (Lencioni and Llovet 2010[53]) 
 
Tumour response and progression will be assessed by CT scan or MRI according to Response 
Evaluation Criteria In Solid Tumors (RECIST) guideline version 1.1 and modified RECIST 
Critera for HCC (Eisenhauer 2009[54]).  
 
RECIST 1.1 Criteria 
Target lesions: the number of lesions to select as target lesions is a maximum of 2 lesions per 
organ and 5 lesions in total. Target lesions should be selected on the basis of their size (those 
with the longest diameter) and their suitability for accurate repeated measurements.  
At baseline, the sum of the diameters: longuest diameters (LD) for extra nodal target lesions 
and short axis diameters (SAD) for nodal lesions will be calculated and reported as the baseline 
sum LD. This baseline sum LD will be used as the reference by which to characterize the 
objective tumour response. 
Non target lesions: all other lesions should be identified as non-target lesions and should be 
recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout the study. 
 
RECIST 1.1 response criteria used to determine the response on target lesions: 
Evaluation of target lesions 
Complete Response 
(CR): 
Disappearance of all targets extra nodal lesions and the regression of all 
nodal lesions to < 10 mm SAD. 
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 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. The 
appearance of one or more new lesions is considered progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while 
on study. 
Evaluation of non-target lesions 
 
Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumour 
marker level. All lymph nodes must be non pathological in size ( < 10 
mm short axis) 


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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 of existing non-target lesions and/or 
appearance of one or more new lesions * 
*Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
 
Evaluation of overall response (RECIST 1.1) 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Modified RECIST: 
Modified RECIST (mRECIST) criteria are considered as the best criteria to evaluate the 
efficacy of treatment of HCC. mRECIST criteria are endorsed by EASL and AASLD societies 
and recently by the FDA (Lencioni and Llovet, 2010). The definitions used in the mRECIST 
are described below: 
Target lesions: the lesion should be located in the LIVER:  
− Be classified as a RECIST measurable lesion (in at least one dimension as 1 cm or 
more); 
− Be suitable for repeat measurement; 
− Show intratumoural arterial enhancement on contrast-enhanced CT or MRI. 
mRECIST response criteria used to determine the response on target lesions: 
− Complete response (CR) = Disappearance of any intratumoural arterial enhancement 
in all target lesions; 


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− Partial response (PR) = At least a 30% decrease in the sum of diameters of viable 
(enhancement in the arterial phase) target lesions taking as reference the baseline sum 
of the diameters of target lesions; 
− Progressive Disease (PD) = An increase of at least 20% in the sum of the diameters of 
viable (enhancing) target lesions, taking as reference the smallest sum of the diameters 
of viable (enhancing) target lesions recorded since treatment started; 
− Stable Disease (SD) = Any cases that do not qualify for either partial response or 
progressive disease.  
Note: Infiltrative–type HCC should be defined as non target lesion when the mass shows ill-
defined, not suitable for repeat measurements. The same applies for HCC lesions previously 
treated with local or systemic treatments. They may or not be considered as target lesions 
according to delineation and suitability for repeat measurements. 
mRECIST response criteria used to determine the response on non target lesions are the same 
as RECIST 1.1 response criteria. However, as for target lesions, tumour necrosis should be 
taken into account when assessing the response to nontarget lesions. The disappearance of any 
intratumoural arterial enhancement in nontarget lesions should be considered equivalent to the 
disapperance of nontarget lesions. Likewise, the persistence of intratumoural arterial 
enhancement in one or more nontarget lesions should be considered equivalent to the 
persistence of one or more nontarget lesions and therefore declared incomplete response/stable 
disease.  
Special recommendations can be made: 
− Portal vein thrombosis should be considered a non measurable lesion due to the 
difficulty in performing consistent measurements of the malignant thrombus during the 
course of the treatment; 
− Porta hepatis lymph node can be considered as malignant if the lymph node axis is at 
least 20 mm; 
− Pleural effusion or ascites: cytopathologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is required when the measurable 
tumour has met criteria for response or stable disease (peritoneal carcinomatosis is a 
rare event in HCC). 
New lesions are: 
− A newly detected hepatic nodule is classified as HCC when its longest diameter is at 
least 1 cm and the nodule shows the typical vascular pattern of HCC on dynamic 
imaging (hypervascularisation in the arterial phase with washout in the venous or late 
venous phase); 
− Liver lesions larger than 1 cm without typical vascular pattern with evidence of at least 
1 cm interval growth in subsequent scans; 


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− Individual radiological event will be adjudicated in retrospect as progression at the time 
it was 1st detected by imaging techniques even if strict criteria were fulfilled only on 
subsequent radiological testings.   
 
Overall tumoural response takes into account all possible combinations of tumoural responses 
on target and non target lesions. The guidelines for the evaluation of overall response are similar 
using RECIST 1.1 or mRECIST for HCC and as shown in table below. 
Evaluation of overall response (mRECIST for HCC) 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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X. 
NCI CTC classification  
The NCI Commun Terminology Criteria for Adverse Events version 4.0 is located on the 
internet at the following URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf 
 
 
 
 
 


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XI. 
List of inhibitors and inducers of CYP3A4, CYP2D6 or P-gp  
 
Non exhaustive list adapted from FDA recommendations on Drug development and Drug Interactions: table of substrates, inhibitors and 
inducers: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm 
Enzyme 
Inhibitor 
Inducer 
CYP3A4 
Class 
DCI 
Class 
DCI 
  
Antifungal drugs  
ketoconazole 
itraconazole 
Antibiotics 
rifampin 
  
  
posaconazole 
voriconazole 
  
nafcillin 
  
  
fluconazole 
  
  
  
  
Antibiotics 
clarithromycin 
telithromycin 
Antiepileptic drugs 
carbamazepine 
  
  
erythromycin 
ciprofloxacin 
  
phenytoin 
  
  
isoniazid 
  
  
rufinamide 
  
Antiviral drugs 
boceprevir 
telaprevir 
Antiviral drugs 
efavirenz 
  
  
ritonavir 
saquinavir 
  
etravirine 
  
  
indinavir 
lopinavir/ritonavir 
  
amprenavir 
  
  
ritonavir 
nelfinavir 
Others 
modafinil 
  
  
amprenavir 
atazanavir 
  
armodafinil 
  
  
darunavir/ritonavir 
fosamprenavir 
  
prednisone 
  
  
tipranavir/ritonavir 
  
  
bosentant 
  
Calcium channel blockers 
mibefradil 
diltaziem 
  
aprepitant 
  
  
verapamil 
amlodipine 
  
pioglitazone 
  
Antiarrytmics 
amiodarone 
ranozaline 
  
echinacea 
  
Antidepressant/Anxiolytic 
nefazodone 
alprozolam 
  
  
  
  
fluoxetine 
fluvoxamine 
  
  
  
Others 
cimetidine 
ranitidine 
  
  


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aprepitant 
atorvastatin 
  
  
  
  
cyclosporine 
oral contraceptives 
  
  
  
  
bicalutamide 
cilostazol 
  
  
  
  
imatinib 
nilotinib 
  
  
  
  
grapefruit juice 
ginkgo 
  
  
  
  
goldenseal 
  
  
  
Enzyme 
Inhibitor 
Inducer 
CYP2D6 
Antiarrytmics 
quinidine 
amiodarone 
  
none known 
  
  
propafenone 
  
  
  
  
Calcium channel blockers 
diltaziem 
verapamil 
  
  
  
Antidepressant 
fluoxetine 
bupropion 
  
  
  
  
paroxetine 
duloxetine 
  
  
  
  
desvenlafaxine 
escitalopram 
  
  
  
  
sertraline 
  
  
  
  
Antifungal drugs  
terbinafine 
  
  
  
 
Antibiotics 
telithromycin 
  
  
  
 
Antiviral drugs 
ritonavir 
  
  
  
  
Others 
methadone 
diphenhydramine 
  
  
  
  
cimetidine 
ranitidine 
  
  
  
  
oral contraceptives 
  
  
  
  
  
cinacalcet 
febuxostat 
  
  
  
  
hydroxychloroquine 
celecoxib 
  
  
  
  
gefitinib 
imatinib 
  
  
  
  
hydralazine 
echinacea 
  
  
P-gp 
Antifungal drugs  
itraconazole 
ketoconazole 
Antibiotics 
rifampin 
  
Antibiotics 
azithromycin 
clarithromycin 
Antiepileptic drugs 
carbamazepine 
  
  
erythromycin 
  
  
phenytoin 
  
Antiviral drugs 
lopinavir 
ritonavir 
Antiviral drugs 
tipranavir/ritonavir 


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Antiarrytmics 
amiodarone 
dronedarone 
  
  
  
  
carvedilol 
quinidine 
  
  
  
Calcium channel blockers 
diltaziem 
felodipine 
  
  
  
  
verapamil 
  
  
  
  
Others 
captopril 
ranolazine 
  
  
  
  
cyclosporine 
conivaptan 
  
  
  
  
quercetin 
  
  
  
 
 
 
 


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XII. 
EQ- 5DTM Questionnaire


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