Predicting Severe Toxicity of Targeted Therapies in Elderly Patients With Cancer
Conditions: Cancer
Sponsor: Institut Bergonié

 
RES_PRETOXE_V4.0 dated 01/02/2018 
 
Page 1 of  5 
 
 
PREDICTING SEVERE TOXICITY OF TARGETED 
THERAPIES IN ELDERLY PATIENTS WITH CANCER 
 
Pre-ToxE Summary 
 
VERSION No. 4.0 dated 01/02/2018 - No.: IB 2015-02  
 
ClinicalTrials.gov ID: NCT02751827 
 
This study is supported by the National Medicines Safety Agency (ANSM) as part of the 2014 Call for Young 
Researchers' Research Projects  
 
 
 
 
Coordinating investigator 
Antoine ITALIANO, MD, PhD                                                                         Department of medical oncology 
Medical oncologist                                                                                                      Bergonié 
Institute                       
 
Institut Bergonié 
 
229, cours de l’Argonne – 33076 BORDEAUX Cedex, France 
 
Tel.: +33 (0)5.56.33.78.00 - Fax: +33 (0)5.56.33.04.85 - Email: a.italiano@bordeaux.unicancer.fr  
 
 
 
Clinical Research and Epidemiology Unit 
Simone MATHOULIN-PÉLISSIER, MD, PhD  
Institut Bergonié, Bordeaux 
Head of department 
 
Carine BELLERA, PhD 
Institut Bergonié, Bordeaux 
Biostatistician 
 
Caroline LALET, 
Institut Bergonié, Bordeaux 
Clinical studies manager 
 
 
 
 
 
 
 
 
 
SPONSOR 
INSTITUT BERGONIÉ 

Institut Bergonié 
Pre-ToxE Protocol 
 
RES_PRETOXE_V4.0 dated 01/02/2018 
 
Page 2 of  5 
S U M M A R Y  O F  T R I A L  
 
Study title 
Predicting severe toxicity of targeted therapies in elderly patients with cancer 
Abbreviation  
Pre-ToxE 
Sponsor  
Institut Bergonié, Comprehensive Cancer Center 
Coordinating 
investigator 
Professor Antoine ITALIANO 
Number of centres 
Multi-centre 
Number of patients 
250 patients 
State of the question 
Purpose of the research 
The incidence of cancer in elderly subjects is constantly increasing and improving their 
management by taking into account their specific needs is one of the objectives of the 3rd 
cancer plan published in February 2014. New anti-cancer molecules are placed on the 
market after validation by clinical trials in which elderly subjects are under-represented. 
There is therefore little data available on the toxicity of these new molecules in elderly 
patients. Tyrosine kinase inhibitors (TKIs) are indicated in different types of metastatic 
cancer. Several elements suggest that their toxicity is higher in elderly subjects than in 
younger subjects: firstly, the pharmacokinetic modifications, drug interactions and more 
fragile ground, making these toxicities more severe. As the geriatric population is 
heterogeneous, identifying those subjects most at risk of complications is a crucial issue. It 
is also a major socio-economic issue, the occurrence of adverse events being the source of 
a significant additional cost. Our study will evaluate prospectively (cohort) among geriatric 
(G8 screening score, ADL, IADL, MNA, comorbidities, Performance Status, Get up and Go 
Test, visual or verbal fatigue scale), biological, pharmacokinetic and pharmacogenomic 
data, those prognostic factors of severe TKI toxicity in the elderly. The primary objective of 
this study is to predict severe toxicity (defined as the occurrence of treatment-related 
adverse events resulting in either discontinuation of more than 3 weeks of treatment, 
permanent discontinuation of treatment, hospitalisation, or death, i.e. disability or 
significant or lasting incapacity) of TKIs prescribed in the context of the Marketing 
Authorisation (MA) in subjects over 70 years of age. The secondary objectives are the rate 
of non-progression at 6 months (percentage of patients with complete response, partial 
response or stable disease according to RECIST v1.1 criteria), progression-free survival and 
the correlation between the pharmacogenomic data and the rate of non-progression at 6 
months. 
Target population 
This study concerns patients aged 70 and over with cancer and treated with a TKI 
prescribed in the context of the Marketing Authorisation and having signed an informed 
consent. 
Method of observation 
This is a non-interventional, multi-centre, prospective research study with collection of 
biological samples, in which 250 elderly cancer patients should be included for 24 months 
at several centres. Once the patient has signed the informed consent, the investigator will 
collect clinical data before the start of treatment. The investigator or the geriatric nurse 
will carry out a geriatric evaluation and take an initial blood sample to perform 
pharmacogenomic analyses. During treatment, the investigator will collect data 
concerning the type of treatment, toxicities and tumour response. A second blood sample 
will be taken at the end of the first month of treatment in order to perform 
pharmacokinetic analyses. A geriatric evaluation will be carried out after 2 months of 
treatment, either during a telephone interview or in consultation, in order to assess any 
toxic effects on the patient's general condition.  
Once treatment has been stopped, patient follow-up data will be collected along with a 
final geriatric evaluation. 

Institut Bergonié 
Pre-ToxE Protocol 
 
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Information collected 
The investigator sends to the Institut Bergonié coordinating clinical research assistant 
(CRA) the inclusion form including the number of the centre, the name of the principal 
investigator, the first letter of the patient's last name and the first letter of their first 
name, their age on inclusion, the eligibility criteria, identification of the treatment with 
TKI, the date of signature of the consent form, along with the date scheduled for the start 
of treatment. Each patient's personal data will be confidential (data protection act of 6 
January 1978 amended by the act of 6 August 2004). On the case report form or any other 
study document, patients will be identified by their initials (first letter of last name and 
first letter of first name) and an inclusion number. The investigators should, however, 
keep a patient identification list in their binder. 
Collection of blood 
samples 
As part of this protocol, two blood samples (2 * 5 ml = 10 ml) will be taken for each 
patient. An initial sample will be taken before the start of treatment upon inclusion and a 
second sample will be taken at the end of the first month of treatment. Each sample will 
be anonymised and the following information will appear on the tubes: name of the study, 
number of the study centre, number of the patient in this centre, date of sample and type 
of analysis carried out (pharmacokinetics and pharmacogenomics). At the end of the 
study, blood samples intended for pharmacokinetic analyses will be sent to the 
pharmacology department of the Bordeaux University Hospital headed by Prof. Mathieu 
Molimard, while the samples intended for pharmacogenomic analyses will be sent 
quarterly (according to the rhythm of inclusions) to the biological resources centre of 
Institut Bergonié. These samples will be accompanied by the sample routing form on 
which the date of signing of the sample preservation consent will be indicated. These 
biological samples will never be linked to nominative data and will be used for research 
purposes only. Any samples not immediately used will remain stored for future use to help 
researchers advance their knowledge of oncology and pharmacology. 
Study duration 
Enrolment period: 24 months 
Follow-up: 12 months 
Total duration: 36 months 
Information collection 
methods 
After checking the eligibility criteria, and once the informed consent has been signed, 
eligible patients will be registered centrally at Institut Bergonié by the study coordinator 
CRA (request by fax from each participating centre). A confirmation of inclusion with an 
inclusion number will be returned to the investigator. The patient's enrolment in the study 
will not be effective until the inclusion number has been assigned. 
Data analysis method 
Primary endpoints: prediction of severe toxicity (defined as the occurrence of adverse 
events attributable to treatment resulting in either discontinuation of more than three 
weeks of treatment, permanent discontinuation of treatment, hospitalisation, death, 
disability or significant or lasting incapacity) of TKIs prescribed in the context of the 
Marketing Authorisation in patients aged 70 years or over with cancer. Secondary 
endpoints: description of toxicities, non-progression rate at 6 months and progression-free 
survival at one year.  
Analysis of toxicity: The severe toxicity rate, along with the incidence rates for toxicities 
grades 1-4 will be reported according to the eligible and evaluable population. These 
endpoints will be described using frequency, percentage and 95% confidence interval. The 
toxicity rate will also be reported by subgroup of patients according to the TKI. Prognostic 
factors of severe toxicity will be evaluated using logistic regression analyses.  
Non-progression analysis: The non-progression rate at 6 months will be reported 
according to the eligible and evaluable population, but also by subgroup of patients 
according to the TKI used. This endpoint will be described using frequency, percentage and 
95% confidence interval. Prognostic factors (clinical and geriatric) of 6-month non-
progression rates will be evaluated using logistic regression analyses.  
Analysis of PFS: PFS will be analysed using the Kaplan-Meier method. Median survival will 
be presented with a 95% confidence interval. Median follow-up will be calculated using 
the reverse Kaplan-Meier method. Multivariate analyses will be performed according to 
the Cox proportional hazards model after verifying the risk proportionality assumption. 
Intermediate statistical analysis: 
After the inclusion of the first 150 patients, an intermediate statistical analysis will be 
performed. 

Institut Bergonié 
Pre-ToxE Protocol 
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Number of subjects 
In this study, we predict that approximately 30% of patients will experience severe 
toxicity. A population of 250 eligible and evaluable patients will allow us to estimate this 
proportion with an accuracy of ±5%, leading to a 95% confidence interval (24.3%; 35.7%). 
Subgroup analyses will also be carried out. Subgroups of patients will therefore be defined 
according to the TKI treatment received (pazopanib, regorafenib, sorafenib, etc.). 
Assuming that 50 patients are included in a subgroup with a toxicity rate of 30%, the 
resulting precision will be ±12%, for a 95% confidence interval (17.3% ; 42, 7%). 
 

Institut Bergonié 
Pre-ToxE Protocol 
 
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STUDY FLOWCHART 
 
 
 
TREATMENT 
 
 
 
SCREENING 
Start of 
treatment 
D1 
Month 1 
(D28, ±2 days) 
Month 2 
(D56, ±2 days) 
Month N 
Discontinua
tion of 
treatment 
(within 28 
days) 
Follow-up 
(Beyond 28 days 
after TKI 
discontinuation 
and up to 12 
months after TKI 
initiation) 
TKI 
Information 
..................................... MA ……………………………… 
 
 
 
Consultation 
X 
X 
X 
 
 
 
X 
Eligibility criteria 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
…………….………………………………….. X …………………………………………….. 
 
History of the disease / 
Medical history / Previous 
treatments 
X 
 
 
 
 
 
 
Performance status (ECOG) 
X 
X 
X 
 
 
 
 
Biological assessment 
X1 
 
 
 
 
 
 
Tumour evaluation  
X2 
 
……………………………………… According to the centre's routine practice ……………………………… 
................. 
Geriatric evaluation 
X3 
 
 
X4 
 
X4 
 
Blood sample  
for pharmacogenomics 
 
X 
 
 
 
 
 
Blood sample for 
pharmacokinetics 
 
 
X 
 
 
 
 
Toxicities 
 
………………………………..…. X ……………………………………. 
X5 
 
Concomitant treatments 
……………..………………………..…. X …………………………………………. 
X5 
 
Vital status 
 
 
 
 
 
 
X6 
 
1 Within 7 days before D1 of treatment initiation (same day possible): Haematology (CBC, platelets), Biochemistry (sodium, potassium, calcium, magnesium, 
phosphorus, glucose, LDH, urea, creatinine, ASAT, ALAT, Alkaline Ph. , total bilirubin, albumin, total protein), Coagulation (INR, PT, aPTT), Thyroid function (free 
T4, TSH). 
2 Within 4 weeks before D1 of treatment initiation (same day possible). 
3 Within 7 days before D1 of treatment initiation (same day possible): G8, Charlson, Cardiovascular diseases, ADL, IADL, ECOG, Get Up and Go Test, verbal or 
visual fatigue scale, MNA. 
4 Evaluation method during a consultation or telephone interview: % weight loss over the past few months, falls, verbal fatigue scale, ADL, IADL. 
5 To be collected for 28 days after discontinuation of treatment. 
6 Follow-up according to the centre's routine practice.