Phase III Study Comparing Maintenance With Pemetrexed or Gemcitabine to a Surveillance in Elderly Patients (70 Years Old and More) With a Advanced Non Small Cell Lung Cancer Controlled by Induction Chemotherapy.
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer (Squamous or Non Squamous)
Sponsor: Intergroupe Francophone de Cancerologie Thoracique

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
1/54 
IFCT-1201 MODEL Protocol 
Maintenance vs. Observation after inDuction chemotherapy  
in non-progressing Elderly patients with advanced non-small cell Lung cancer  
 
Maintenance chemotherapy versus follow-up after 
carboplatin and weekly paclitaxel doublet 
chemotherapy in elderly patients with advanced 
nonsmall cell lung cancer (NSCLC): IFCT-1201 MODEL 
randomised phase 3 trial 
 
 
EudraCT No.: 2012-005520-15 
Sponsor 
 
10 rue de la Grange-Batelière 75009 PARIS - FRANCE 
Coordinating Investigator 
Prof. Elisabeth QUOIX 
Department of Pneumology - NHC [Nouvel Hôpital Civil (New Civilian Hospital)] HUS 
[Hôpitaux universitaires de Strasbourg (University Hospitals of Strasbourg)] (Strasbourg) 
 
 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
2/54 
Project code  
IFCT-1201 MODEL Protocol  
 
Sponsor 
Intergroupe Francophone de Cancérologie Thoracique [French Intergroup of Thoracic 
Oncology] (IFCT) 
10 rue de la Grange-Batelière 75009 PARIS 
 
Coordinating Investigator 
Prof. Elisabeth QUOIX 
Pulmonology Department 
New Civil Hospital 
1 place de l’Hôpital 
67091 Strasbourg cedex 
Tel.: + 33 (0)369550897 
Email: elisabeth.quoix@chru-strasbourg.fr 
 
 
Steering Committee 
E. Quoix, V. Westeel, F. Morin, MP. Lebitasy, B. Milleron, G. Zalcman 
 
Pharmacovigilance 
Dr Marie Paule Lebitasy 
Statistician 
Laurence Baudrin 
Clinical Operations Manager 
Elodie Amour 
Data Management 
Quân Tran 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
3/54 
APPROVAL AND SIGNATORIES TO THE IFCT-1201 MODEL PROTOCOL 
 
Maintenance chemotherapy versus follow-up after carboplatin and weekly 
paclitaxel doublet chemotherapy in elderly patients with advanced nonsmall 
cell lung cancer (NSCLC): IFCT-1201 MODEL randomised phase 3 trial  
 
SPONSOR 
IFCT 
Name 
date 
(dd/mm/yy) 
Signature 
Chairperson 
Gérard Zalcman 
20-12-12 
[signature] 
Director 
Franck Morin 
20-12-12 
[signature] 
Biostatistician 
Laurence 
Baudrin 
20-12-12 
[signature] 
 
Responsibilities 
delegated by the 
sponsor 
Name 
date 
(dd/mm/yy) 
Signature 
Coordinating 
Investigator 
Elisabeth 
Quoix 
20-12-12 
[signature] 
 
I hereby acknowledge that I have read the entire protocol  
EUDRACT:  
and undertake to conduct this trial in accordance with Good Clinical Practice, the Biomedical 
Research Law (4 August 2004) and as described in this document. 
COORDINATING INVESTIGATOR: 
Name: Elisabeth QUOIX  
 
Date: 20/12/2012 
Signature:  
[signature]

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
4/54 
 
Table of contents 
1. 
Study Rationale ........................................................................... 5 
2. 
Study Objectives ......................................................................... 10 
3. 
Study Design .............................................................................. 11 
4. 
Study Population ......................................................................... 12 
5. 
Schedule of Assessments and Procedures ............................................ 17 
6. 
Study Treatments........................................................................ 20 
7. 
Dose adjustment ......................................................................... 23 
8. 
Endpoints ................................................................................. 35 
9. 
Pharmacovigilance ...................................................................... 37 
10. Statistical methodology ................................................................ 39 
11. Administrative section .................................................................. 42 
12. Final Report and Publication .......................................................... 47 
13. A BIO-IFCT-1201 Ancillary study (Bio-MODEL) ....................................... 49 
14. References ................................................................................ 52 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
5/54 
1. Study Rationale 
1.1. Epidemiology of Non-Small Cell Lung Cancer  
The incidence of primary lung cancer was over 39,000 new cases in 2011 with a death rate 
of 29,100 in the same year (1). The incidence increases with age due to the significant 
increase in life expectancy at least in developed countries, with a median age at diagnosis 
currently close to 70 years (2,3).  
In most epidemiological studies, the threshold at which the elderly are referred to is 65 
years of age (4). In therapeutic trials for the elderly, the lower limit is generally set at 70 
years of age, which corresponds to the fact that no therapeutic adaptation is required in 
the majority of cases between 65 and 70 years of age. Most therapeutic trials for the 
elderly and subgroup analyses in trials not dedicated to the elderly have used this 
threshold (5,6,7,8,9). 
The treatment of patients over 70 years of age with lung cancer has therefore become a 
public health issue. Despite this, until the end of the 20th century, very few phase 3 trials 
specifically devoted to the elderly were carried out. Their participation in trials remains 
well below their representativeness in the general population of patients with primary lung 
cancer (2). Furthermore, a certain nihilism has meant that chemotherapy is rarely offered 
to elderly people with metastatic non-small cell lung cancer (NSCLC), at least in the 
United States (4) whereas a recent survey in France does not seem to show the same 
reluctance (10). 
1.2. Treatment of elderly patients with advanced NSCLC 
1.2.1. Chemotherapy 
Since the randomized study published in 1999 by the Italian group (5) showing both survival 
and quality of life benefit in patients aged 70 years and over treated with vinorelbine as 
monotherapy, compared to supportive care, the indication for chemotherapy in elderly 
patients with NSCLC stage IV is no longer disputed. Several other trials dedicated to the 
elderly have since been published. These trials first showed that single-agent 
chemotherapy was preferable to dual-agent therapy without platinum salts (6). The 
European guidelines published in 2010 were therefore to propose a single-agent therapy 
that could be vinorelbine, gemcitabine or even docetaxel (11). However, these guidelines 
mentioned that trials comparing a platinum salt doublet with single-agent chemotherapy 
were essential. Indeed, the analyses in subgroups of some Phase III trials suggest a benefit 
to the addition of a platinum salt in the elderly, of the same order as that in the general 
population (8,7,12). It is clear that the selection biases in such trials are significant, and 
that these results observed in specifically selected elderly patients could not be 
transposed to the entire elderly population. It is for this reason that the IFCT initiated in 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
6/54 
2006 a trial comparing the combination of carboplatin (AUC 6 every 4 weeks) + weekly 
paclitaxel (90 mg/m², D1, 8, 15), with gemcitabine monotherapy (1150 mg/m², D1, D8 
with D1 = D22) or vinorelbine (25 mg/m² D1, D8 with D1 = D22). The doublet had 
previously demonstrated its feasibility in a Phase II trial, demonstrating both efficacy and 
good tolerability (13). 
This Phase III trial showed a very significant and highly significant gain in overall survival 
and progression-free survival in patients aged 70 to 89 years, performance status (PS) 0 to 
2 with locally advanced non-irradiable or metastatic locally advanced NSCLC (14). The 
median age of 451 patients enrolled was 77 years. Median survival was 10.3 months in the 
doublet arm versus 6.2 months in the monotherapy arm (RR=0.64, 95% CI=0.52-0.78). The 
probability of survival at 1 year was 44.5% (95% CI=37.9-50.9) versus 25.4% (95% CI=19.9-
31.3). 
This trial dedicated to the elderly therefore confirmed the hypothesis resulting from the 
subgroup analyses, namely that elderly patients can benefit from a carboplatin-based 
doublet, in this case in combination with weekly paclitaxel. Current recommendations are 
therefore to administer a carboplatin-based doublet to elderly patients with advanced 
NSCLC (15). 
1.2.2. EGF-R TKI inhibitors in the second- or third-line in elderly patients 
 
There have been no therapeutic trials evaluating targeted therapies specifically for 
elderly patients. Subgroup analysis of the BR 21 trial evaluating erlotinib as a second- or 
third-line therapy after using a platinum salt doublet showed that the benefit obtained in 
patients 70 years of age and older was similar to that obtained in younger patients (9). In 
the previously mentioned IFCT randomised study (14), the second-line therapy was 
erlotinib, at a dose of 150 mg/day. The median progression-free survival observed with 
erlotinib was 2.6 months in the dual-agent arm compared to 2.2 months in the single-agent 
arm. Median survival from the start of erlotinib therapy was 6.8 and 4.6 months, 
respectively. The survival rates observed in the dual-agent arm were therefore very similar 
to those reported in the BR21 study (16). 
1.2.3. Maintenance treatment with cytotoxic therapy in the elderly 
Until very recently, therapeutic recommendations from learned societies (17) for patients 
with NSCLC in the metastatic stage, whose tumour is devoid of EGFR activating mutation, 
remained based on the “stop and go” or “watch and wait” strategy after a 1st line of 
chemotherapy (including a platinum salt and a 3rd generation cytotoxic agent), 
administered at a maximum number of 4 cycles in “stable” patients or 6 cycles in 
“responder” patients. Treatment was interrupted and resumed in the form of a second line 
(docetaxel, pemetrexed, erlotinib) only when disease progression was observed. The main 
risk of this strategy is to be confronted with a rapid progression of the disease during the 
free interval of any treatment, which may lead to clinical deterioration incompatible with 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
7/54 
the initiation of a new treatment. In fact, about one-third of patients whose disease is 
controlled after induction treatment do not receive any additional treatment with this 
type of strategy (18).  
The concept of therapeutic maintenance therefore seeks to optimize the use of active 
treatments in advanced NSCLCs over time to avoid these drawbacks of the “stop and go” 
therapeutic strategy. It is based on maintaining continuous therapeutic pressure on tumour 
disease, thereby delaying the emergence of chemoresistant clones, increasing progression-
free survival, with the gain in PFS expected to translate into overall survival gains. 
Maintenance therapy can thus be defined as the continuation of treatment after obtaining 
the maximum response to 1st line chemotherapy until disease progression. (19,20,21,22). 
This strategy is made possible by the availability of better-tolerated treatments, cytotoxic 
molecules or targeted biotherapies, that can be administered over a long period of time, 
without cumulative toxicity. The aim of maintenance therapy is to preserve the benefit 
obtained by the 1st line therapy, to increase the duration of disease control and thus to 
prolong patients’ survival without deteriorating their quality of life. The maintenance 
strategy seems all the more justified as the disease being treated is rapidly progressive, 
which is usually the case in advanced NSCLCs. 
Two maintenance options (20,21) were evaluated in advanced NSCLCs, after four cycles of 
chemotherapy combining a platinum salt and a 3rd generation cytotoxic agent: i) “true” or 
“continuation” maintenance, consisting in continuing the cytotoxic agent initially used in 
combination with the platinum salt until disease progression; ii) “switch” maintenance 
based on the introduction of a new treatment (generally a second-line validated efficacy 
monotherapy), upon the end of induction chemotherapy. This second option also aims to 
avoid the risk of disease progression that is inaccessible to any subsequent treatment and 
allows all patients to benefit from validated second-line treatment. These two 
maintenance options contribute to improving the treatment of advanced NSCLCs by 
optimizing the 1st treatment line with continuation maintenance on the one hand, or by 
optimizing patients’ exposure to several different treatments with the maintenance switch 
on the other. 
Some clinical trials have shown that continuation maintenance and switch maintenance 
statistically and clinically significantly increase the duration of disease control, (23,24,25), 
others have not (26). However, survival benefit has only been demonstrated in three trials, 
2 with pemetrexed for non-squamous carcinomas (25,27), the other with erlotinib (23).  
However, a meta-analysis of 8 maintenance trials, either switch or continuous, showed a 
significant benefit, both in progression-free survival and overall survival (28). 
This has led to the development of new ASCO guidelines available since September 2011 
that recognize “Switch maintenance” as a possibility for patients who respond or are 
stable after 4 cycles: immediate treatment with another monotherapy such as pemetrexed 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
8/54 
for non-squamous cell carcinomas or erlotinib (or even docetaxel) for all histological types, 
is considered an alternative therapeutic option validated for patients whose disease has 
been controlled by induction chemotherapy (29). 
The “PARAMOUNT” trial (25) evaluating continuation maintenance with pemetrexed 
confirmed an increase in progression-free survival. Thanks to its potency, this study was 
able to measure the real impact of this strategy on overall survival. At the recent ASCO 
congress, Paz-Ares et al. confirmed the overall survival gain from 11 months after 
randomization in the control arm to 13.9 months in the maintenance arm. The Marketing 
Authorization (MA) of pemetrexed has therefore recently been extended to maintenance, 
of course in non-squamous cell carcinomas.  
Like pemetrexed, gemcitabine has a safety profile that makes its use in a maintenance 
strategy possible; the absence of early cumulative toxicity other than haematological in 
nature allows for prolonged administration.  
Gemcitabine was studied in “continuation” maintenance in three phase 3 trials (24,30,31). 
In the first trial, 352 patients were treated with 4 cycles of cisplatin-gemcitabine 
combination; 206 patients considered stable or responders were randomized between the 
continuation of gemcitabine (1250 mg/m² at D1 and D8 of 3-week cycles) and simple 
monitoring, with TTP (Time To Progression) as the endpoint (24). Gemcitabine in 
maintenance therapy significantly prolongs the TTP with a quantitatively high but non-
significant survival benefit due to the lack of potency of the test (median survival of 13 
months in the maintenance arm versus 11 months in the “monitoring” arm, p=0.195; HR = 
0.84 [0.52-1.38]). Toxicity was moderate, particularly without any episodes of febrile 
neutropenia, despite 15% of cycles involving grade 3-4 neutropenia. The French IFCT-GFPC 
0502 trial (30) confirmed the significant impact of continuing gemcitabine in terms of PFS 
in patients controlled with cisplatin-gemcitabine chemotherapy (HR=0.56 [0.44-0.72]), 
without significant impact on overall survival (median survival increased from 10.8 to 12.1 
months; HR, 0.89 [0.69 to 1.15]), since the trial was not designed to evaluate an overall 
survival benefit. Nevertheless, the exploratory subgroup analysis shows that the survival 
gain appears to be limited to patients “responding” to cisplatin-gemcitabine induction 
chemotherapy, this benefit being quantitatively significant (median survival increased from 
10.8 to 15.2 months, HR=0.72 [0.51-1.04]) especially since almost all patients in the 
control arm received second-line treatment. The American maintenance trial with 
gemcitabine after induction therapy with carboplatin-gemcitabine, on the other hand, is 
entirely negative, but two-thirds of patients had a PS ≥ 2 at the time of randomization 
(31), confirming that continuation maintenance should only be offered to patients who 
maintain a correct general condition after induction chemotherapy. However, Trial 0501 
showed that the benefit of induction therapy with a doublet was also observed in the 27% 
of patients with PS=2 at baseline, with no clear deterioration in quality of life, which 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
9/54 
encourages these patients to remain in a maintenance strategy with “light” therapy 
compared to induction treatment. 
1.3. Rationale of the proposed trial 
No maintenance trials specifically dedicated to the elderly have been conducted to 
date. Sub-group analysis of the Paramount trial (25) in the 34% of individuals over 65 
years of age (92 patients aged 70 and over and 97 patients aged 65 to 69 years) 
shows that they benefit at least as much from continuation maintenance with 
pemetrexed as younger patients. 
In the JMEN trial (27), where 35% of patients were 65 years of age or older, there is no 
information available on survival by age. Finally, the IFCT-GFPC 0502 trial enrolled only 
patients under 70 years of age (30). As a result, there is only very limited data on 
maintenance treatment in the elderly. Thus, it is essential to verify whether maintenance 
strategies can be applied to elderly patients. 
It is likely that pemetrexed in maintenance is well tolerated in the elderly subject since 
the analysis of the elderly subjects (32) in Hanna study (33) comparing pemetrexed with 
docetaxel in patients 70 years of age and older in the second line, shows that there are 
12.5% of grade 3 to 4 cases of neutropenia (compared to 29.7% in the docetaxel arm) and 
only 2.5% of grade 3 to 4 cases of febrile neutropenia, comparable to what is observed in 
younger subjects. Gemcitabine was used in the Brodowicz (24) and Pérol maintenance 
trials (30). However, it should be noted that in the first trial, although the extreme ages 
are 77 years, the median age is 57 years, showing that there were probably few elderly 
people and it should be recalled that, in the second trial, the upper limit was 70 years 
(30). 
The overall efficacy and favourable safety data of the medicinal products proposed for this 
trial (paclitaxel, carboplatin, pemetrexed, gemcitabine, erlotinib) justify evaluating this 
maintenance strategy in elderly patients with stage IV non-small cell lung cancer.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
10/54 
 
2. Study Objectives 
2.1. Primary objective 
To compare the overall survival of patients whose disease is controlled after induction 
chemotherapy with 4 cycles of carboplatin and paclitaxel weekly from randomization 
maintenance versus observation. 
2.2. Secondary objectives 
 
To investigate the feasibility of maintenance (median number of maintenance cycles 
that can be administered without unbearable toxicity) 
 
To investigate progression-free survival 
 
To determine the duration of the response or stabilisation obtained from the 
maintenance therapy. 
 
To evaluate tolerance and quality of life during induction treatments (carboplatin + 
weekly paclitaxel), maintenance (gemcitabine, pemetrexed)  
 
To describe the percentage of patients who are randomised in each of the two arms 
accessing the second line with erlotinib and the efficacy of the second line (response 
rate according to RECIST 1.1, progression-free survival time, overall survival time from 
the time erlotinib is initiated). 
 
To identify clinical prognostic survival factors 
 
To evaluate the prognostic impact of the expression of DNA repair-regulating proteins 
and targets of administered cytotoxics (MSH2, RRM1, BRCA1, TS), or genetic or 
epigenetic markers (K-Ras mutation, RASSF1A methylation), already evaluated in 
previous IFCT studies. The predictive impact will be analysed in an exploratory manner. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
11/54 
 
3. Study Design 
3.1. Experimental plan  
This is a randomised, multicentre, open-label phase 3 trial to evaluate two management 
options in patients with controlled disease, one being monitoring and the other being 
maintenance with pemetrexed or gemcitabine with a second line fixed with erlotinib.  
Patients will be randomised by minimisation according to a 1:1 scheme and a random 
factor and with the following stratification: 
 
Response after 4 cycles of induction chemotherapy (objective response 
versus stabilisation) 
 
PS at the time of randomisation: 0-1 versus 2 
 
Histology (non-squamous versus squamous) 
 
Age (< or ≥ 80 years)  
 
Site 
 
Figure 1: study design 
 
 
 
 
 
 
 
 
 
 
3.2. Measures taken to avoid bias 
Centralized randomisation to limit screening bias. The intention-to-treat analysis will avoid 
attrition bias. 
Evaluation bias will be limited by the objectivity of the primary endpoint, overall survival. 
2ème ligne
Maintenance
Induction
Paclitaxel – Carboplatine
x 4 cycles
R*
A
B
Prog
épidermoïde
Non-
épidermoïde
Pemetrexed
Gemcitabine
Prog
Surveillance
Prog
Inclusion
Erlotinib
Enrolment
Induction 
Maintenance 
2nd line 
R*
Induction 
Induction 
Paclitaxel – Carboplatine 
X 4 cycles 
Monitoring 
Prog 
Prog 
Prog 
Non-squamous 
squamous 
Erlotinib 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
12/54 
Finally, concomitant treatments, as well as treatment discontinuation and protocol 
deviation will be documented in order to avoid follow-up bias. 
4. Study Population 
4.1. Inclusion criteria  
1. Histologically or cytologically proven Non-Small Cell Lung Cancer (NSCLC) with 
the greatest possible emphasis on obtaining histological evidence (detection of 
a mutation in the EGF-R gene and biomarker analysis).  
2. Non-operable and non-irradiable Stage III or Stage IV (7th UICC TNM 
classification 2009 [33]). Previously operated NSCLC metastatic relapses are 
included only in the absence of prior perioperative chemotherapy. 
3. No EGFR activating mutation (LREA deletion in exon 19, L858R or L861X 
mutation in exon 21, G719A/S mutation in exon 18) or mutation status of EGFR 
not determined.  
4. No EML4-ALK translocation or ALK status not determined. 
5. Presence of at least one measurable lesion in CT scan (RECIST v1.1): target 
over 10 mm in its largest diameter (15 mm of small axis for adenopathies), not 
previously irradiated and analysable by CT scan. 
6. Age ≥ 70 years and < 90 years. 
7. Mini-Mental Test Status (MMS) > 23. 
8. WHO performance index from 0 to 2. 
9. Normal liver function: bilirubin < LSN, GOT, GPT < 2.5 x LSN or < 5 x LNS in 
case of liver metastases. 
10. Renal function with creatinine clearance calculated ≥ 45 mL/min (MDRD 
formula).  
11. Normal haematological function (neutrophils ≥ 1.5 giga/l, platelets ≥ 100 
giga/l, haemoglobin ≥ 10 g/dl). 
12. Estimated life expectancy > 12 weeks. 
13. Written and signed informed consent. 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
13/54 
4.2. Exclusion criteria 
1. Carcinoma, small cell (including mixed), neuroendocrine carcinoma. 
2. Knowledge of an EGFR activating mutation or rearrangement of the ALK gene. 
The presence of a K-RAS mutation is not an exclusion criterion  
3. Progressive or symptomatic metastases of the central nervous system. Patients 
with a history of symptomatic metastases in the central nervous system or 
spinal cord compression may be enrolled if they have been treated (surgery or 
radiotherapy) and have become asymptomatic. Oral corticosteroids are 
allowed, subject to a stable dose for at least 4 weeks prior to the start of 
treatment. 
4. Superior vena cava syndrome except if they have been treated by placement of 
a superior vena cava prosthesis. 
5. Serum calcium > 2.70 mmol/l. Use the corrected serum calcium according to 
the formula: Corrected Ca (mmol/l= Measured Ca (mmol/l) + 0.02x(40-
albuminaemia in g/l). 
6. Previous anti-tumour treatment (any chemotherapy or EGFR inhibitor). 
7. MMS ≤ 23. 
8. Other concomitant severe conditions: congestive heart failure, unstable 
angina, significant arrhythmia or a history of heart attack within 6 months 
before entering the trial. 
9. Interstitial pulmonary pathology existing prior to lung cancer. 
10. Neurological or psychiatric disorders that prevent understanding of the trial. 
11. Uncontrolled infectious condition. 
12. Severe or uncontrolled systemic diseases, considered by the investigator to be 
incompatible with the proposed protocol. 
13. Grade 2 peripheral neuropathy. 
14. History or concomitance of any other cancer except basal cell skin cancer or in 
situ carcinoma of the treated cervix or any other cancer that has received 
curative treatment without chemotherapy and in remission for more than 5 
years. 
Patients with a history of prostate cancer under 5 years of age may be 
enrolled: 
 If the lung cancer is an undifferentiated adenocarcinoma or positive TTF1 
undifferentiated large cell carcinoma: in case of localized prostate cancer 
with a good prognosis according to Amico classification (≤ T2a and Gleason’s 
Score: ≤ 6 and PSA value (ng/ml): ≤ 10), and treated curatively (surgery or 
radiotherapy) without chemotherapy, 
 If the lung cancer is an undifferentiated adenocarcinoma or negative TTF1 
large cell carcinoma but PSA immunohistochemical labelling on the lungs is 
negative or if the same anatomopathologist confirms that the morphology is 
different (written report required): in case of prostate cancer with a good 
prognosis according to Amico classification (≤ T2a and Gleason Score: ≤ 6 and 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
14/54 
PSA value (ng/ml): ≤ 10) treated curatively (surgery or radiotherapy) without 
chemotherapy,  
 If the lung cancer is a squamous cell cancer: in case of prostate cancer 
considered as cured (≤ T2a and Gleason Score: ≤ 6 and PSA value (ng/ml): ≤ 10 
and treated curatively by surgery or radiotherapy), without chemotherapy. 
15. Allergy to any of the treatments or excipients. 
16. Combination with yellow fever vaccine (pemetrexed) or CYP3A4 inducers 
(erlotinib)  
17. Sexually active male, with a partner in genital activity who refuses to use an 
effective contraceptive method during the study and for 6 months after the 
last dose of the treatment. 
18. Impossibility to submit to the medical follow-up of the trial for geographical, 
social or psychological reasons. 
19. Patient under legal protection. 
4.3. Maintenance Treatment Eligibility Criteria 
1. Patients with objective or stabilised response (according to RECIST 1.1) after 4 
cycles of first-line chemotherapy with carboplatin AUC 6 every 4 weeks and 
paclitaxel 90 mg/m² weekly.  
2. PS 0, 1 or 2 after induction chemotherapy. 
3. Normal liver function: bilirubin < LSN, GOT, GPT < 2.5 x LSN or < 5 x LNS in 
case of liver metastases.  
4. Creatinine clearance ≥ 45 ml/min (MDRD). 
5. Recovery of sufficient haematological function (polynuclear neutrophils ≥ 1.5 
giga/l, platelets ≥ 100 giga/l). 
6. 
No concomitant radiotherapy, except in the case of localized bone radiation 
therapy for palliative purposes, other than spinal, with a 2-week delay between 
the administration of gemcitabine and the start of the radiation therapy or the end 
in the case of radiation therapy before treatment begins, this period may be 
reduced to eight days if the patient’s clinical condition so requires. In the case of 
spinal irradiation, any irradiation should be avoided as much as possible within 4 
weeks of gemcitabine administration. 
4.4. Concomitant Treatments 
4.4.1. Cancer treatments 
No other cancer treatment (including bevacizumab) is allowed during the trial period, 
except for the use of analgesic radiation therapy on bone damage. This radiation therapy 
should only be performed within a two-week period between the administration of 
gemcitabine and the start or end of the radiation therapy and the administration of 
gemcitabine. Only an emergency such as spinal cord compression can be considered to 
reduce this period to 8 days.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
15/54 
4.4.2. Other Concomitant Treatments 
The use of other symptomatic medications (steroids, anti-emetics, analgesics) will be at 
the discretion of the physician in charge of the patient. Any need for a significant increase 
in symptomatic treatment should be investigated and documented for possible disease 
progression. 
The use of non-steroidal anti-inflammatory agents is not recommended on the days before 
and two days after the administration of pemetrexed. 
Hematopoietic Growth Factors will not be used in primary prevention. However, they can 
be used as secondary prevention or curative measures. 
Erythropoiesis Stimulating Agents may be used during chemotherapy, provided that the 
haemoglobin is < 10 g/dl, with a maximum therapeutic target of 11 g/dl haemoglobin 
levels, as recommended in each study site. In addition, an iron profile (including, in 
addition to the blood count, the determination of ferritin, serum iron and transferrin 
saturation coefficient associated with an inflammation marker: CRP) will be performed in 
principle before the start of treatment and at the time of randomisation. 
Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides, loop diuretics, 
NSAIDs) may potentially decrease the clearance of pemetrexed or potentiate the 
nephrotoxicity of chemotherapy. These combinations should be used with caution. 
Creatinine clearance will be evaluated before each chemotherapy treatment course.  
Concomitant administration of substances also secreted at the tubular level (e.g., 
probenecid, penicillin) may decrease the clearance of pemetrexed. Precautions should be 
taken when these drugs are combined with pemetrexed. 
4.5. Criteria for Early Discontinuation and Withdrawal from Trial 
4.5.1. Withdrawal 
The study is conducted with the intention-to-treat (ITT) and therefore, a patient is 
followed whether or he is per-protocol or not. Withdrawal from a trial is not synonymous 
with the end of the study. 
The reasons for withdrawing from the trial are: 
-withdrawal of consent, 
Patients have the right to withdraw their consent and ask to leave the study at any time 
and for any reason (which they are not required to explain). This should not in any way 
affect their right to subsequent care. However, the investigator should make every effort 
to ensure that the non-medically justified withdrawal of patients is avoided.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
16/54 
4.5.2. Early discontinuation of treatment  
In case of: 
- tumour progression during treatment, 
- toxicity requiring discontinuation of the study treatments, 
- intercurrent disease, 
- protocol violation 
- non-compliance,  
- administrative reasons  
- patient’s decision. 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
17/54 
5. Schedule of Assessments and Procedures  
5.1. Patient inclusion 
 
Complete physical examination (weight, height, body surface area, SP, history 
collection, geriatric assessment (MMS, IADL, geriatric depression scale, INCA G8 
oncode score) within 7 days. 
 
Biological assessment carried out within 7 days prior to enrolment: blood count and 
platelets, CRP, serum electrolytes, serum calcium, serum albumin, serum 
creatinine with calculation according to MDRD of creatinine clearance, GOT, TGP, 
alkaline phosphatases, serum bilirubin, ferritin and transferrin saturation 
coefficient. 
 
Tumour imaging performed within 4 weeks prior to enrolment: chest x-ray, chest CT 
with sections on adrenal areas, abdominal ultrasound and/or abdominal CT, CT or 
brain MRI.  
 
In case of pain suggestive of bone metastases, if access to PET scan is not possible, 
standard X-ray, MRI or CT and/or bone scan imaging will be performed.  
 
Electrocardiogram (ECG), cardiac ultrasound if there is a history of heart disease 
that may impair left ventricular function. 
5.2. Patient Randomisation 
 
Complete physical examination (weight, height, body surface area, SP, history 
collection, geriatric assessment (geriatric depression scale, CNIB G8 oncode score). 
 
Biological assessment: blood and platelet count, CRP, serum electrolytes, blood 
calcium, albuminemia, creatinine with calculation according to MDRD of creatinine 
clearance, GOT, PGT, alkaline phosphatases, serum bilirubin, ferritin and 
transferrin saturation coefficient. 
 
Tumour imaging: chest CT with adrenal sections, abdominal ultrasound and/or 
abdominal CT, brain CT or MRI.  
 
5.3. Treatment period 
5.3.1. Evaluation before each cycle 
 
Complete physical examination (weight, height, BMI, body surface area, PS). 
 
Biological assessment: blood count and platelet count, serum creatinine with 
clearance calculation according to MDRD, AST, ALT, serum bilirubin and alkaline 
phosphatase. 
 
Collection of adverse events and follow-up of these events until adequate 
resolution or explanation is provided, even if the patient has completed the study 
treatment. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
18/54 
5.3.2. Evaluation on D8, D15 of each cycle and D21 during induction  
 
Biological assessment: blood and platelet count, serum creatinine levels. 
5.3.3. Evaluation imaging examinations 
During the 1st line (induction and maintenance), an evaluation report will be prepared 
after 2 cycles, after 4 cycles. Every two cycles for the first two maintenance evaluations 
(EVA4 and EVA5). Then the evaluations will be done every 3 cycles in both arms. 
 
A chest CT with adrenal sections is the minimum required for each evaluation. 
 
repetition of examinations to determine the initial measurable lesion(s). 
 
any examination necessary to confirm the appearance of a new lesion in the event 
of clinical suspicion of disease progression. 
 
The PET scan will only be repeated before randomisation if it was performed before 
induction because of the risk of qualifying any lesion first revealed by the PET scan 
as a progression. 
5.3.4.  Evaluation of quality of life  
This will be done during randomisation and then at each evaluation assessment 
after randomisation.  
The scale used is the Lung Cancer Symptom Scale of Quality of Life (LCSS, Appendix 
6)  
5.3.5. Minimum and maximum time limits 
 
The maximum time between enrolment and the start of induction therapy is 2 
weeks. 
The maximum time between D1 of the 4th induction treatment cycle and D1 of 
maintenance is 42 days.  
The 2nd line must start no later than 3 weeks after the evaluation showing 
progression. 
5.3.6. Second-line treatment 
During the second line, an evaluation report will be prepared (similar to that done during 
induction treatment) every 2 cycles for the first 3 evaluations and then every 3 cycles:  
 
repetition of examinations to determine the initial measurable lesion(s). 
 
any examination necessary to confirm the appearance of a new lesion in the event 
of clinical suspicion of disease progression. 
5.4. Follow-up period 
A follow-up will be carried out after the study is completed: 
 
Collection of subsequent cancer treatments. 
 
Collection of tolerance and adverse events (only target AEs and SAEs that may be 
related to the study treatments or the research) and follow-up of these events until 
adequate resolution or explanation is provided, even if the patient has completed 
the study treatment.

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
19/54 
Summary table of investigations (Flow-Chart) 
 
Induction 
Maintenance/Monitoring 
 
Enrolment 
Cycle 1 
Cycle 2 
VAS2 
Cycle 3 
Cycle 4 
VAS3 
Cycle 1 
Cycle 2 
VAS4 
Cycle 3 
Cycle 4 
VAS5 
Every cycle 
Every three cycles 
Informed consent 
signed  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
Adverse events 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
Concomitant 
treatments 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
Geriatric assessment 
(IADL, MMS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Geriatric depression 
scale  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Oncodage 
Questionnaire 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
LCSS questionnaire 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Haematological 
assessment 
X 
X1 
X1 
 
X1 
X1 
 
X1 
X1 
 
X1 
X1 
 
X1 
 
Biochemical assessment 
X 
X2 
X2 
 
X2 
X2 
 
X2 
X2 
 
X2 
X2 
 
X2 
 
Hepatic assessment 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
Iron profile and CRP 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest and 
supramesocolic CT scan 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Abdominal and pelvic 
CT scan or ultrasound 
X 
 
 
X3 
 
 
X 
 
 
X3 
 
 
X3 
 
X3 
Brain CT or MRI 
X 
 
 
X3 
 
 
X 
 
 
X3 
 
 
X3 
 
X3 
PET scan (optional) 
X 
 
 
 
 
 
X4 
 
 
 
 
 
 
 
 
1 To be performed also on D8 and D15 of each cycle as well as on D21 during induction except for patients under supervision 
2 Serum creatinine (MDRD) to be performed also on D8 and D15 of each cycle as well as on D21 during induction except for patients under supervision 
3 If target initially present or in case of a clinical sign 
4 To be performed if PET scan performed during the inclusion assessment 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
20/54 
6. Study Treatments 
Patients will be enrolled before the 1st cycle of induction chemotherapy but randomisation 
will only take place after induction treatment in responders or stabilised patients after the 
4 cycles. 
Premedication with pemetrexed will be in accordance with its MA:  
- 
Corticosteroid therapy the day before, the day after and the day after 
administration with a dosage equivalent to 50 mg of prednisolone per day. 
- 
Oral folic acid (350 to 1000 µg/day) at least 5 doses within 7 days before the first 
injection, then throughout the treatment and for 21 days after the last dose. 
- 
Intramuscular vitamin B12 (1000 µg) in the week before the 1st dose and then once 
every 3 cycles.  
Primary preventive treatment of the emetic risk should be implemented during induction 
chemotherapy. The choice of treatment is left to the investigator’s discretion.  
Since the protocol uses medicinal products used in routine practice, chemotherapy 
products will not be provided. The reconstitution of cytotoxic products must be carried out 
in a centralised reconstitution unit. 
Doses will be capped at 400 mg/m² for carboplatin and 2 m² of body surface area in 
general. 
In both arms, maintenance therapy should be started no later than 42 days after D1 of the 
last induction chemotherapy. 
Patients who meet the eligibility criteria will be randomised after induction chemotherapy 
to one of the following 2 arms: observation or maintenance with Pemetrexed or 
gemcitabine depending on histology (non-squamous vs squamous) 
6.1. Induction chemotherapy 
4 cycles of carboplatin AUC6 (D1= D29) + paclitaxel 90 mg/m² D1, D8, D15; cycles 
repeated every 28 days.  
The calculation of the dose of carboplatin will be done using the Calvert formula.  
Before being infused, Paclitaxel must be diluted with aseptic techniques. The following 
infusion solutions may be used for dilution: 0.9% sodium chloride infusion solution, 5% 
glucose infusion solution, 5% glucose infusion solution containing 5% glucose and 0.9% 
sodium chloride, 5% glucose infusion solution in a Ringer solution, for a final concentration 
of 0.3 to 1.2 mg/ml.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
21/54 
The physicochemical stability of the diluted solutions was demonstrated at 5°C and 25°C 
for 7 days when diluted in 5% glucose solution and 5% glucose solution in Ringer’s solution 
for infusion, and for 14 days when diluted in 0.9% sodium chloride solution for injection. 
From a microbiological point of view, the product must be used immediately. If not used 
immediately, the conditions and shelf life before use are the responsibility of the user and 
should normally not exceed 24 hours between 2° and 8°C.  
During preparation, the solutions may show some turbidity attributed to the excipient of 
the product. This turbidity is not removed during filtration. To reduce the risk of 
precipitation, the dilution of Paclitaxel actavis for infusion should be used as soon as 
possible after dilution. A filter should be placed on the infusion line insofar as a small 
number of fibres (within the USP Particulate Matter Test for LVP limits) have been 
observed. PVC bags should be avoided as the EL* Cremophor could attack them. This 
consideration also applies to the equipment used during reconstitution. Only glass or 
polyolefin bags and polyethylene tubing have been validated. 
All patients should be pre-medicated with corticosteroids, antihistamines and H2 receptor 
antagonists before paclitaxel is administered:  
Medication  
Dosage  
Administration before paclitaxel  
Dexamethasone 
20 mg 
per os or IV  
Oral administration:  
approximately 12 and 6 hours  
IV Administration:  
30 to 60 minutes  
Diphenhydramine* 
50 mg IV  
30 to 60 minutes  
Cimetidine  
300 mg IV  
30 to 60 minutes  
or ranitidine  
50 mg IV  
* or 5 mg of DEXCHLORPHENIRAMINE 
 
Growth factors  
Given the expected dose adjustments, the use of haematopoietic growth factors is not 
recommended for primary prophylaxis. Their use as secondary prophylaxis or for curative 
purposes is possible. Administration from D3 to D5 has been described with a weekly 
cisplatin paclitaxel combination (34) and this regimen could be used in the context of 
secondary prevention (granocyte* or neupogen*).  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
22/54 
Subsequent treatment: 
 
In case of disease progression (RECIST 1.1) and only in case of progression: 
treatment with erlotinib 150 mg/day as second-line treatment 
6.2. Study design 
After 4 cycles of induction chemotherapy, in case of controlled disease (RECIST 1.1) and 
eligibility for maintenance treatment:  
- 
For patients with squamous cell carcinoma: after 4 induction cycles: Maintenance switch 
with gemcitabine monotherapy (1150 mg/m² on D1, D8, cycles repeated every 21 days) 
until progression or unacceptable toxicity; in case of documented disease progression, 
second-line therapy with erlotinib 150 mg/day.  
- 
For patients with non-squamous cell carcinoma: after 4 induction cycles: maintenance 
switch with pemetrexed 500 mg/m2 every 3 weeks until progression or toxicity; in case of 
documented disease progression, second-line therapy with erlotinib 150 mg/day.  
Anti-emetic treatment will be decided by each investigator, knowing that steroids and 
apepritant are not recommended for this indication (corticosteroids, on the other hand, 
are recommended for pemetrexed for anti-allergic use).  
Any patient who is required to discontinue induction or maintenance therapy for 
toxicity reasons is monitored in accordance with the protocol without starting second-
line therapy. This is only initiated in case of objective disease progression. 
The patient should receive his first course of induction chemotherapy within 14 days of 
enrolment. 
After documented disease progression during first-line treatment, randomized patients 
should start second-line treatment (erlotinib) within a maximum of 3 weeks. After this 
time, the patient will have to be withdrawn from the study.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
23/54 
7. Dose adjustment 
7.1. Induction chemotherapy with Paclitaxel - Carboplatin (4 cycles) 
7.1.1. Dose reduction ranges for Paclitaxel/carboplatin 
 
 
0 (starting dose) 
-1 
-2 
Paclitaxel (mg/m²) 
90 
80 
70 
Carboplatin (AUC) 
6 
5 
4.5 
 
Dose adjustments on D1 depending on the greatest haematological toxicity 
observed during the past cycle 
On D1 the doses of carboplatin and paclitaxel will be reduced by one level if the 
following toxicities have been observed:  
-Grade 4 neutropenia (PNN < 500/mm3) for at least 7 days 
-Grade 3 or 4 febrile neutropenia (PNN < 1000/mm3 with temperature >= 38°5C) 
[sic] 
-Grade 4 anaemia (< 6.5 g/dl) 
-Grade 4 thrombocytopenia (< 25000/mm3 or bleeding that required a transfusion 
7.1.2. Time of administration on D1 based on haematological and non-
haematological toxicities observed on the day of rechallenge:  
To receive chemotherapy, the patient must have:  
PNN >= 1500/mm3 
Platelets >=100000/mm3 
Return of all non-haematological toxicities to a grade <=1. 
A period of two times a week may be proposed. If D1 cannot be administered on 
D43, chemotherapy is discontinued, with exceptions to be discussed with the 
principal investigator. 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
24/54 
7.1.3. Changes in Paclitaxel/Carboplatin doses on D1 based on the non-
haematological toxicities observed during the past cycle:  
Organ or tissue 
Toxicity 
Grade 
Action 
Ear 
Hearing/Internal 
ear 
>=2 
Discontinuation of carboplatin 
Continuation 
of 
Paclitaxel 
according to the investigator’s 
choice 
Cardiovascular  
Asymptomatic sinus 
bradycardia 
Ventricular 
Arrhythmia 
Asymptomatic  
 
1 
 
 
 
 
No adjustment 
ECG before each cycle 
 
 
Symptomatic 
ventricular 
arrhythmia 
Atrioventricular 
block (except 1st 
degree) 
Other blocks 
>=2 
Discontinuation of 
chemotherapy 
Gastrointestinal 
Mucositis 
>=3 
1 reduction level for both drugs 
Liver 
Bilirubin > 3 x LSN 
AST/ALT (> 2.5 x 
LSN) 
In case of hepatic 
metastases: >= 5 
>=3 
>= 2 
Discontinuation of 
chemotherapy 
Infection 
Infection 
without 
neutropenia 
>=3 
1 reduction level for both drugs 
Nervous system 
Sensory neuropathy 1 
2 
 
*2 
No adjustment 
One reduction level for both 
drugs 
*If persistence despite dose 
reduction, 
second 
reduction 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
25/54 
 
 
 
>=3 
level 
 
 
Discontinuation of 
chemotherapy 
Pain 
Arthralgia/myalgia 
 
 
for more than 7 
days 
>= 3 
 
 
>=3 
One level of dose reduction for 
Paclitaxel only 
 
Discontinuation of 
chemotherapy (2 drugs) 
Kidneys 
clearance 
< 
30 
ml/min 
> 2 
Discontinuation of carboplatin 
Continuation of paclitaxel at 
the investigator’s discretion 
Toxicity affecting other organs except 
nausea, vomiting and fatigue 
>=3 
2-level dose reduction or 
discontinuation of 
chemotherapy at the 
investigator’s discretion 
7.1.4. Dose adjustment/administration time for paclitaxel on D8 and D15 
The patient must meet the following criteria to receive paclitaxel on D8 and D15:  
PNN >= 1500/mm3 
Platelets >= 100000/mm3 
The dose of Paclitaxel will then be the same as on D1 unless non-haematological 
toxicity requiring a dose reduction had occurred between D1 and D8 or between D8 
and D15. 
As mentioned above, if D8 is postponed, this dose is cancelled, similarly, if D15 
cannot be administered, the dose is cancelled. If D8 and D15 must be cancelled, 
the same procedure is repeated on D29, while respecting the dose-level reduction 
rules described above. 
7.1.5. What to do if there is a hypersensitivity reaction 
Cases of severe hypersensitivity characterised by hypotension, dyspnoea, 
angioedema or generalised urticaria have been described in 2% of patients 
receiving paclitaxel. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
26/54 
In the event of a hypersensitivity reaction, appropriate measures should be taken 
by the investigator depending on the severity of the event. 
CTC Grade 1: transient rash, fever < 38°C: continued infusion, monitoring. No 
treatment required. 
CTC Grade 2: urticaria, fever >= 38°C and/or symptomatic bronchospasm: 
discontinuation 
of 
paclitaxel 
infusion, 
administration 
of 
2.5 
mg 
of 
dexchlorpheniramine and methylprednisolone 60 mg. Resume paclitaxel infusion 
after 
sedation 
of 
symptoms 
at 
a 
slower 
flow 
rate: 
20 
ml/h 
for  
15 minutes then 50 ml/h for 15 minutes then if there are no other symptoms at the 
initial flow rate until the end of the infusion. Special attention with controlled 
monitoring should be exercised during the next administration of paclitaxel. 
CTC Grade 3 or 4: severe or even life-threatening symptoms: major bronchospasm 
requiring intravenous treatment with or without urticaria, oedema/angioedema, 
anaphylactic shock: discontinuation of paclitaxel infusion. Administration of 
diphenhydramine 
and 
methylprednisolone 
as 
above. 
Add 
adrenaline 
or 
bronchodilators by aerosol or IV route if necessary. Mention the incident as a 
Serious Adverse Event (SAE). Do not resume chemotherapy. 
 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
27/54 
7.2. Maintenance with pemetrexed 
To receive chemotherapy, the patient must have:  
PNN >= 1500/mm3 
Platelets >=100000/mm3 
Dose adjustment based on haematological toxicity 
Nadir 
Pemetrexed dose 
PNN ≥ 500/mm3 
Platelets ≥ 50,000/mm3 
100% of the preceding 
dose 
PNN < 500/mm3  
Platelets ≥ 50,000/mm3 
75% of the preceding 
dose 
Platelets < 50,000/mm3  
Irrespective of PMN levels 
75% of the preceding 
dose 
Platelets < 50,000/mm3 with 
bleeding ≥ Grade 2 
Irrespective of PMN levels 
50% of the preceding 
dose 
 
The occurrence of Grade 3 or 4 neutropenia or thrombocytopenia after two dose 
reductions results in the permanent discontinuation of pemetrexed. The patient will be 
monitored according to the protocol with second-line erlotinib treatment upon relapse. 
The use of white-line growth factors (G-CSF) is allowed. 
Dose adjustment based on non-haematological toxicity 
The dose should be adjusted to the most significant non-haematological toxicity observed 
during the previous cycle as shown in the diagram below: 
Toxicity 
Grade 3 or 4 diarrhoea or diarrhoea 
requiring hospitalisation. 
75% of the preceding dose 
Treatment postponed until diarrhoea is resolved 
 
Grade 3 or 4 stomatitis 
50% of the preceding dose 
Study withdrawal after recurrence of a Grade 3-4 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
28/54 
after 2 dose reductions 
 
Renal failure 
Creatinine clearance (MDRD) must be > 45 
ml/min 
before 
any 
administration 
of 
pemetrexed. The cycle can be postponed for up 
to 35 days. If creatinine clearance remains < 45 
ml/min after this time, pemetrexed will be 
permanently stopped. 
 
Any other Grade 3 or 4 toxicity  
75% of the preceding dose 
Treatment postponed until the toxicity is 
resolved. Study withdrawal after a maximum of 
two dose reductions. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
29/54 
7.3. Maintenance with gemcitabine 
Dose adjustment of gemcitabine on D1 of the cycle 
 based on the blood count prior to each cycle (the day before or the day of chemotherapy) 
FBC before D1 of each cycle  
 
Polynuclear 
Neutrophils (/mm3) 
Platelets 
(/mm3) 
Dose and postponement 
 
 1,500 
and  100,000 
Treatment 
within 
the 
scheduled 
time, 
dose 
adjustment based on nadir 
< 1,500 
and/or < 100,000 
Treatment postponed for one 
week*, dose adjusted to the 
nadir of the previous cycle 
* maximum postponement of twice a week; beyond that, withdrawal from the trial. 
 Dose adjustment based on the Nadir at each cycle 
Nadir 
 
Polynuclear 
Neutrophils (/mm3) 
Platelets 
(/mm3) 
Dose at next cycle 
 
 500 
and  50,000 
No adjustment 
< 500 less than 5 days without 
fever 
and  50,000 
No adjustment 
< 500 for > 5 days and/or 
febrile neutropenia 
and/or < 50,000 
Reduce by one dose level* 
* Dose levels: 
Level -1: reduction of the gemcitabine dose to 1000 mg/m2.  
Level -2: reduction of the gemcitabine dose to 750 mg/m² 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
30/54 
Adjustment of gemcitabine doses on D8 based on FBC 
Polynuclear 
Neutrophils (/mm3) 
Platelets 
(/mm3) 
Gemcitabine (% dose) 
 
> 1,500 
> 100,000 
100% 
of 
the 
dose 
given on D1 
1,000 to 1,500 
or 75,000 to 
100,000 
75% of the dose given 
on D1  
< 1,000 
 or < 75,000 
0* 
* injection cancelled and not postponed 
 
Dose adjustment based on hepatic toxicity 
Serum bilirubin (mol/l) 
NCI grade 
Gemcitabine (% dose) 
< ULN 
0 
100 
> ULN-1.5 ULN 
1 
100 
> 1.5 ULN 
2, 3, 4 
75 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
31/54 
7.4. Erlotinib in second line 
Treatment will be temporarily discontinued in the event of Grade 3 or 4 toxicity until 
return to Grade 2. The maximum interruption period is 14 consecutive days. When 
treatment is resumed, a dose reduction in 50 mg levels is envisaged (2 possible 
reductions). In the event of a new Grade 3 or 4 toxicity despite appropriate treatment, 
erlotinib treatment will be permanently stopped, the patient should be withdrawn from 
the study.  
Dermatological toxicity 
 
This is the most common side effect (75% of patients observed in the BR 21 trial). 
However, a Grade 3 or 4 toxicity was only observed in 9% of patients in the BR 21 trial.  
It is important to distinguish between the rash observed during treatment with erlotinib 
and acne. Therefore, this rash must be treated differently from acne: retinoid ointments 
are not indicated.  
Identification/evaluation of the grade:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Recommendations for physicians in case of rash:  
Primary management of rash  
Treatment option 
 
Consider early topical treatment (from Grade 1) with topical corticosteroids. 
 
An analgesic may be beneficial: consider it before reducing doses of erlotinib 
GRADE 1 
Rash pouvant être associé à la prise de Tarceva 
GRADE 2 
GRADE 3  
GRADE 4 
Éruption papulaire ou 
maculaire, ou 
érythème, légers. 
Pas de symptômes 
associés 
Éruption papulaire ou 
maculaire ou érythème, 
modérés. 
Prurit ou autres 
symptômes associés 
Éruption papulaire , 
maculaire ou vésiculaire, 
ou érythrodermite 
généralisée, sévères. 
Dermatite exfoliante, 
ulcérante ou bulleuse, 
généralisée 
Pas de modifications de doses 
sauf si grade 2 intolérable pour le 
patient 
Réduction des doses  
par paliers de 50 mg pour 
revenir à un grade ≤ 2. 
Rash that can be associated with the use of Tarceva 
GRADE 1 
GRADE 3 
GRADE 3 
GRADE 4 
Papular or macular rash, 
or erythema, mild. 
No associated symptoms 
Papular or macular rash, or 
erythema, moderate. 
Pruritus or other associated 
symptoms 
Papular or macular or vesicular 
rash, or generalized 
erythrodermatitis, severe. 
Exfoliating, ulcerative or 
bullous dermatitis, generalised 
No dose adjustments unless Grade 2 is 
intolerable for the patient 
Dose adjustments in 50 mg 
levels to return to a grade ≤ 2 
GRADE 2 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
32/54 
 
Topical retinoids and other treatments for acne are not recommended. They 
could even exacerbate the rash. 
 
A dermatological opinion will be sought if necessary 
General Recommendations  
 
Evaluation of the effectiveness of the treatment after one week and continue 
for another week. Discontinue if there is no improvement after 2 weeks.  
 
Use topical agents with caution, especially in cases of severe rash: efficacy may 
be limited if there is little penetration into the deep layers of the skin. 
 
Secondary management of infected rash 
 
Treatment options 
 
Consider the use of local topical antibiotics. 
 
Consider the use of rapid treatment with oral antibiotics such as doxycycline. 
 
Recommendations for patients in case of rash: 
 
Make-up  
 
The rash can be covered with make-up without risking aggravating the 
symptoms. Dermatologically approved make-up is preferable.  
 
Use a mild make-up remover. 
Moisturising cream  
 
Use a hypo-allergenic emollient cream to prevent and soothe dry skin, such as 
Dexeryl®.  
Sun exposure 
 
Avoid exposure to the sun, or use good protection. 
Other treatments  
 
Do not use acne treatments as this may aggravate symptoms. 
 
 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
33/54 
Gastrointestinal toxicity  
 
 
Changed doses and recommendations if diarrhoea  
 
Grade per 
toxicity scale 
NCI-CTC v3 
Adjustment of 
erlotinib doses 
Recommendations for the management  
Grade 1 
No 
Consider Loperamide (4 mg for the first dose, followed by 2 mg 
every 2 - 4 hours until diarrhoea is stopped for 12 hours) and 
rehydrate appropriately. 
Grade 2 
No 
Loperamide (4 mg for the first dose, followed by 2 mg every 2 - 
4 hours until diarrhoea is stopped for 12 hours) and rehydrate 
appropriately. 
Grade 3 
Discontinuation 
Discontinue treatment and provide appropriate rehydration, 
monitor diuresis and renal function until resolution at Grade  1; 
resume treatment at a reduced dose. 
Grade 4 
Withdrawal from 
the study 
If treatment is ineffective: withdraw the patient from the study. 
Ophthalmological toxicity 
 
Patients with dry eyes will initially be treated with artificial tears. If the symptom persists, 
a consultation with the ophthalmologist should be arranged. 
Vascular toxicity 
 
Elevations of the International Normalized Ratio (INR) and bleeding (including 
gastrointestinal) have been reported in clinical studies, in some cases in combination with 
warfarin or an NSAID. In patients treated jointly with warfarin or a coumarin derivative, 
prothrombin time or INR should be regularly monitored. 
Nausea/Vomiting 
Vomiting < 30 minutes after taking erlotinib:  
new dose of 150 mg of erlotinib 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
34/54 
Other toxicities 
Liver function monitoring with AST/ALT transaminases, bilirubin, alkaline phosphatases 
assay every 4 to 6 weeks is recommended. If the hepatic profile is disturbed, the benefit of 
continued erlotinib therapy should be reassessed. 
Pulmonary toxicities found in the BR21 trial are less than 1%31 and not significantly 
different from the placebo arm. As a precaution, special monitoring of respiratory 
symptomatology should be carried out with a chest x-ray or even a chest scan if there is 
any doubt, and erlotinib should be discontinued pending the results of the diagnostic 
assessment of respiratory symptomatology. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
35/54 
8. Endpoints 
8.1. Eligibility and patient evaluation 
Any patients enrolled will be evaluated for overall survival and progression-free survival. 
Any patient who has received at least one dose of one of the study treatments will be 
evaluated for toxicity. Response rates will be expressed in terms of intention to treat 
(ratio of the number of responders to the total number of patients enrolled in each arm).  
8.2. Toxicity evaluation 
It will be carried out according to the NCI-CTC criteria version 4.0. 
8.3. Definition of evaluation targets 
The evaluation will be carried out according to RECIST 1.1 [24] (See Appendix 1) by each 
investigator. 
8.4. Evaluation of biomarkers: Bio-1201 MODEL  
Biomarkers evaluated by immunohistochemistry (IFCT centralisation): MSH2 (human 
MutS homolog 2), TS (Thymidylate synthétase), RRM1 (Ribonucleoside-diphosphate 
reductase large subunit), BRCA1 (breast cancer 1, early onset). 
A collection of paraffin-embedded tumour blocks will be collected from all the patients 
enrolled in the clinical study. For each patient, the minimum requirement is 5 white slides 
(+1 HES slides). tumour blocks, or failing this, 5 freshly cut white slides (precise cutting 
date: 4 slides for IHC + 1 slide if labelling fails), whose tumour content has been verified 
on adjacent HES section, will be sent to IFCT (with HES section), for the performance of 
these IHC labelling by the IFCT teams having already performed these analyses for Bio-
IFCT0002 studies (Zalcman et al. WCLC 2011) and PREDICT (Histology Laboratory of the 
CHU [University Hospital] of Caen, Dr Levallet; Anatomy and Pathology Laboratory of the 
CHU [University Hospital] of Tenon, Paris, Dr Martine Antoine). The interpretation of 
immunolabelling and their quantification will be carried out by the ana-pathological group 
of the IFCT according to the methodologies validated in the above-mentioned studies.  
Genetic biomarkers: The findings of the K-Ras mutation research carried out by 
the regional molecular genetics platform labelled by the iNCA will be collected by 
the IFCT. In case of any remaining DNA material after the mandatory genetic study 
of the platforms, a DNA collection will be carried out by the IFCT from the 
platforms for the centralized methylation research of RASSF1A using the MS-PCR 
technique validated in bio-IFCT 0002 study (35) by the Inserm de Caen [Institut 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
36/54 
national de la santé et de la recherche médicale (French National Institute for 
Health and Medical Research)] UMR 1086 team (Dr G. Levallet, Prof. G. Zalcman) 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
37/54 
9. Pharmacovigilance 
9.1. Toxicity evaluation 
All the patients who received the protocol treatment regardless of the duration of the 
treatment will be evaluable for toxicity.  
9.2. Non-serious adverse events 
An adverse event is defined as a harmful and unintended event in a clinical trial 
participant, regardless of whether the event is related (effect) or not to the research or 
product being investigated. 
This may be a symptom, a group of symptoms, a laboratory abnormality or a temporarily 
associated intercurrent disease. 
9.3. Serious adverse events 
9.3.1. Regulatory definition  
A serious adverse event is defined as an event occurring in a patient participating in a 
clinical study, whether therapeutic or not, regardless of whether it is related to the 
purpose of the clinical study (in particular a medicinal product under analysis) and which 
corresponds to the following definition: 
 
death  
 
life-threatening 
 
hospitalisation or prolongation of hospitalisation (a scheduled hospitalisation is 
not a SAE, for whatever reason) 
 
persistent handicap/disability or severe temporary disability 
 
congenital abnormality/malformation or abortion 
 
a medically significant event or new fact (clinical event or laboratory result 
considered serious by the investigator and that does not meet the severity criteria defined 
above).  
Examples: overdose, second cancers, significant increase in the frequency of a known 
adverse event, etc. 
Deaths related to the obvious progression of the cancer disease will not be reported as a 
SAE. The cause of death must be carefully recorded in the source file. If the patient dies 
during unscheduled hospitalisation, the hospitalisation will be reported as a SAE. 
A serious adverse event is also not considered to be hospitalisation < 24 hours unless it is a 
life-threatening event resulting in death on the same day (cause other than cancer). 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
38/54 
9.3.2. Time limit for notification to the sponsor 
All SAEs must be reported to the study sponsor. This reporting is a legal requirement. 
Serious adverse events should be reported on a special form (see Appendix 2) within 24 
business hours from the time the investigator becomes aware of them, by fax to the trial 
coordination (IFCT fax: 01.44.83.01.51). They will be updated if necessary (monitored 
until the event is resolved).  
Any serious adverse event occurring within 30 days of the end of the administration of any 
of the study treatments should be subject to the above procedure. After this period, only 
events for which a causal link to any of the study products is suspected (late toxicity) will 
be reported as SAEs. 
9.3.3. Unexpected serious adverse events  
An unexpected serious adverse event is considered to be any event not mentioned or 
different in nature, intensity or frequency from the reference document. The reference 
document is the investigator’s brochure (IB) or the summary of product characteristics 
(SmPC) for medicinal products with a marketing authorisation.  
In this study, the reference documents will be the SmPC for cisplatin, pemetrexed and 
gemcitabine since they all have the MA. 
The sponsor will inform investigators about the occurrence of all unexpected serious 
adverse events within the notification time described above.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
39/54 
10. Statistical methodology 
10.1. Calculation of the number of subjects required 
The median survival rate of patients who received 4 cycles of carboplatin + paclitaxel in 
the IFCT-0501 study and had control of their disease at the end of these 4 cycles was 10.2 
months from the end of the induction treatment.  
To demonstrate a 4-month gain in overall survival in the maintenance arm (median survival 
at 14 months from baseline (or 10 months from randomisation) in the maintenance arm 
with a 5% bilateral alpha risk and a 20% beta risk, with a 4-year baseline period and a 
minimum 3-year follow-up period), 328 patients should be randomised, i.e., enrol 546 
patients, assuming that 60% will be responders or stabilised. 
Randomisation will be carried out via extranet using a minimisation technique already 
widely used in our previous trials. 
10.2. Analysis population  
Any patients enrolled will be evaluated for progression-free survival and survival. Any 
patient who has received at least one dose of one of the study treatments will be 
evaluated for toxicity. Response rates will be expressed in terms of intention to treat 
(ratio of the number of responders to the total number of patients enrolled in each arm).  
- The tolerance analysis population will be defined as all patients who received one dose of 
treatment. 
- The Intention-to-Treat (ITT) population will include all enrolled and randomised patients. 
- The population of eligible patients will be ITT patients who do not have any deviations 
considered as major on the inclusion and non-inclusion criteria. 
Deviations from the protocol will be reviewed by the principal investigators, then classified 
as minor or major deviations, and listed. 
10.3. Analysis of study data  
Analyses will be carried out on the ITT population and on the population of eligible 
patients if relevant for the analysis of the primary endpoint. The safety analysis will be 
carried out on the safety population. 
10.3.1. Analysis of the primary endpoint 
Overall survival is defined as the time between the date of randomisation and death from 
any cause. It will be estimated using the Kaplan-Meier method. The number of patients 
who died during the study will be described by arm. The comparison between the 2 arms 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
40/54 
will be carried out using a bilateral Log-Rank test. The median overall survival and its 95% 
confidence interval will be presented. The overall survival curves will be tracked. 
10.3.2. Analysis of secondary endpoints 
 
The feasibility of maintenance will be studied and reported according to the 
median number of maintenance cycles that can be administered without 
unacceptable toxicity. 
 
Progression-free survival is defined as the time between the date of randomisation 
and progression or death from any cause. It will be estimated using the Kaplan-
Meier method. The number of patients who progressed will be described. The 
comparison between the 2 treatment arms will be carried out using a bilateral Log-
Rank test. The median progression-free survival and its 95% confidence interval will 
be presented. The progression-free survival curves will be tracked. 
 
The response (complete+partial) will be measured according to RECIST 1.1. The 
duration of the maintenance response will be defined as the time between the 
evaluation date of the EVA3 response and progression on maintenance. The 
duration of the control (response+stabilisation) will also be analysed.  
 
Tolerance will be analysed on induction, maintenance treatments (gemcitabine, 
pemetrexed) and relapse (erlotinib). Adverse events will be coded using MedDRA 
coding. The number of patients for whom at least one adverse event has been 
reported will be presented in each arm, as well as the number of events itself, 
depending on the relationship to the treatment, the intensity, and the cycle of 
onset. 
 
Exposure to treatments will be evaluated by the length of time the study 
treatments were taken in each arm. 
 
The percentage of patients randomised in each of the 2 arms accessing the second 
line with Erlotinib will be presented with its 95% confidence interval. 
 
The efficacy of the second will be analysed according to response rate, overall 
survival and progression-free survival.  
 
The response will be evaluated after 2 and 4 maintenance cycles. Patients for 
whom the response is not evaluable will be considered as failures. Response rates 
will be compared using the exact Fisher test. 
 
Overall survival and progression-free survival of the second line will be based on 
the first dose of erlotinib and will be analysed in the same way as in the first line. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
41/54 
10.3.3. Investigation for prognostic and predictive factors 
A multivariate analysis using the Cox proportional risk model will be performed to 
investigate prognostic factors for survival. A procedure for selecting the step-by-step 
downward variables will be used to keep the independent survival factors in the model. All 
statistically significant basal variables at the 20% threshold will be introduced into the 
initial model.  
An exploratory analysis will study the effect of treatments in each of the modalities of the 
variables selected in the final model. 
An exploratory analysis of the prognostic value of the biomarkers studied will be 
performed with a multivariate analysis using the same methodology. The prognostic model 
that may be identified will be validated by a bootstrap technique that reproduces all the 
steps of this analysis. The predictive value of biomarkers will be investigated using 
interaction tests between the maintenance arm (overall for MSH2, BRCA1, K-Ras) and the 
observation arm, and for RRM1 between patients receiving gemcitabine and patients in the 
observation arm, for TS between patients receiving pemetrexed and those in the 
observation arm. 
10.4. Monitoring analysis  
A monitoring analysis will be performed after enrolling half of the randomised patients, 
i.e. 164 patients. The objective of the monitoring analysis will be to ensure the overall 
quality of the trial, i.e. enrolment rate, treatment compliance, protocol deviations, as 
well as adverse event monitoring. In particular, the feasibility of maintenance treatment 
in this elderly population will be analysed and reported according to the median number of 
maintenance cycles that can be administered without unacceptable toxicity.  
The Independent Data Monitoring Committee will be composed of one statistician and 
three physicians qualified in oncology.  
Its operating rules will be formalised in the IDMC charter drawn up by the IFCT and the 
Steering Committee and submitted to the IDMC for approval. 
The charter will cover administrative, operational and methodological aspects and will be 
finalised before the enrolment of the first patient in the trial. 
 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
42/54 
11. Administrative section 
11.1. Obligations of the sponsor 
11.1.1. Before the trial 
The sponsor: 
 
shall complete the regulatory formalities prior to the conduct of the trial; 
 
shall ensure all administrative procedures with the management of each associated 
institution 
 
shall provide the complete protocol and its appendices, the adverse event report 
form, the positive opinion of the EC, the certificate of insurance and the authorisation of 
the Competent Authority (ANSM). 
The sponsor or its representatives: 
 
shall provide the research sites with the necessary instructions and documents for 
the proper conducting of the trial (protocol, case report forms, investigator’s brochure), 
 
shall organise an introductory meeting to train investigators and study coordinators 
(during this meeting, all the sections of the protocol will be discussed, how to complete 
the case report forms will be explained, as will the study procedures) 
11.1.2. During the trial 
The sponsor or its representatives: 
 
shall conduct regular visits to the research sites 
 
shall be available at any time for consultation and shall remain in contact with 
research site personnel by letter, telephone and/or fax. 
 
shall review and evaluate the data in the case report forms and investigate 
potential data collection errors 
In consultation with the principal investigator, the sponsor shall provide the investigators 
involved in the study with any new information likely to interfere in the conducting of the 
trial. 
11.1.3. At the end of the trial  
The sponsor is responsible for ensuring that the end of trial procedures are carried out. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
43/54 
11.2. Obligations of the investigator 
The investigator undertakes to conduct the study in accordance with the 1974 version of 
the Declaration of Helsinki, revised in 1975 and 1989, Good Clinical Practice, and the 
applicable laws and regulations. 
Regarding the latter, the investigator at each site undertakes to collect the informed 
written consent of each patient included in the trial. A copy of the written consent 
shall be given to the patient, and another will be kept in the patient’s medical file. 
Patients must be able to give their informed consent and therefore not be under 
guardianship or suffering from a neuropsychic pathology that affects their judgement. 
They also undertake to complete the case report forms required for the monitoring of the 
study. 
Furthermore, the investigator undertakes to: 
 
Report any serious or unexpected adverse events occurring during the trial to 
the sponsor within the time frame described in Chapter 7.1 using the 
appropriate form. 
 
Agree to the monitoring with access to source documents to validate the data in 
the case report forms and, if necessary, to accept an internal or external audit 
requested by the sponsor or a representative of the regulatory authorities. 
 
Archive the trial documents (copy of the case report form pages, informed 
consent) for a period of at least 15 years. 
 
Include at least one patient during the first six months following the 
implementation of the trial. 
 
Ensure no interference with another trial with the same indications. 
 
Respect the confidentiality of documents that are provided. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
44/54 
11.3. Ethical considerations 
11.3.1. Participant information and consent 
Prior to the conduct of this biomedical research on a human subject, the free, informed 
and express consent of the latter must be obtained after having been informed of the 
objective of the research, the conduct and duration of the study, the benefits, potential 
risks and constraints of the study as well as the nature of the study product and the 
opinion given by the Ethics Committee (Art. L. 1122-1 of the French Public Health Code 
(CSP)). 
The consent form shall be dated and signed personally by the patient and the investigator 
or the physician representing them (original archived by the investigator, a copy will be 
given to the patient or their legal representative). 
11.3.2. Request for CNIL (Commission Nationale de l’Informatique et des 
Libertés [French Data Protection Authority]) authorisation to process 
computerised data:  
This biomedical research shall result in the production of information for scientific 
purposes. This directly or indirectly personal and encoded information is covered by a legal 
framework for the use of files (Law no. 78-17 of 6 January 1978 and Law no. 94-548 of 1st 
July 1994). 
The sponsor (IFCT) has an authorisation (No. 1227585) relating to the processing of 
personal data for the purpose of biomedical research on medicinal products and 
pathologies pursuant to the law of 20 December 1988 as amended by law No. 2004-806 of 9 
August 2004. 
Insofar as this biomedical research is conducted within the framework of strict legislative 
and regulatory requirements (“Huriet-Sérusclat” law of 20 December 1988 as amended by 
law No. 2004-806 of 9 August 2004) in accordance with standardised methodologies. The 
CNIL has adopted a reference methodology (MR001 in accordance with Article 54 of the 
amended law of 6 January 1978) which now covers all processing of personal data carried 
out in the context of biomedical research - including pharmacogenetic trials. 
11.3.3. Procedures for amendments and addenda 
Any substantial amendment to the protocol shall be proposed by the study sponsor. This 
will have to be the subject of an amendment submitted to the EC and the ANSM. The 
amendment may only be made with the agreement of the EC and the ANSM (if applicable). 
The sponsor shall inform each investigator and send them the amendment and related 
authorisations. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
45/54 
11.4. Quality control and assurance 
eRegulatory considerations: The medical procedures in this trial are consistent with the 
most recent recommendations of the Declaration of Helsinki and public health law No. 2004-
806 from 9 August 2004 on the protection and safety of human subjects. 
Confidentiality: The Protocol and its appendices, as well as all data, shall be confidential as 
indicated at the beginning of the Protocol. 
Data monitoring: The IFCT Clinical Research Unit will monitor this trial to ensure the 
collection of accurate, complete and reliable data, as well as logistical support for the 
research sites. An inspection mandated by the Regulatory Authorities by employees who are 
bound by professional secrecy may be required to ensure that all the necessary source 
documents are available, and that the clinical trial is conducted in accordance with Good 
Clinical Practice and the law of 09/08/2004. 
11.5. Study schedule 
The protocol is expected to start in May 2013, with a projected recruitment period into the 
trial of 4 years, and a follow-up of 3 years, with the trial expected to be completed in 
April 2020.  
Early termination of the study 
Any early termination of the study will be made by the sponsor in contact with the 
coordinating investigator. It will be notified in writing by the sponsor. This letter will be 
sent to the Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM) 
and to each investigator as well as to the EC. 
11.6. Commitment Statement 
New investigators 
Investigators may only participate in the trial after a written request to the sponsor. It should consist of 
the following elements: 
 
the estimated number of patients he/she will be able to include in the 
protocol per year, 
 
a recent curriculum vitae with medical board number. 
Site opening 
Before starting the inclusions, a site must be officially opened, i.e., the name of the 
investigator, his/her institution, phone number, fax number, email address, must be duly 
submitted to the sponsor, the EC, and the ANSM. The investigator must be in possession of all 
the documents necessary for the proper conducting of the trial (protocol, investigator’s 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
46/54 
brochure, case report forms). He/she must have obtained the agreement of the institution’s 
pharmacist for the distribution of treatments and, in case of difficulty, resolve the problem 
with the study coordinator. They must have, by means of a letter, informed their institution’s 
director of their participation. An agreement shall be signed between the director of their 
institution and the sponsor. 
11.7. Organisation of the study 
The Steering Committee takes all decisions concerning the implementation, execution, 
analysis and report of the study. It will meet 2 times per year, and periodically send 
information on the conducting of the study to the investigators.  
It is composed of members of the editing committee, study statisticians, and a representative 
of the sponsor. 
The Coordinating Site shall be the Clinical Research Unit (CRU) of the IFCT, located at “10 rue 
de la Grange-Batelière, 75009 PARIS”. Its role is to ensure the proper conduct of the trial as 
provided for in the protocol: inclusion management, data collection, data management, SAE 
management, organization of investigator and various committee meetings. It shall inform the 
Steering Committee of all elements concerning the conduct of the trial. 
Furthermore, the Steering Committee reserves the right of regularly organising an 
investigators’ meeting where the files of the included patients will be reviewed. The purpose 
of this review panel will be to jointly check that the eligibility criteria and therapeutic 
modalities required by the protocol are respected and properly understood.  
 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
47/54 
12. Final Report and Publication 
Once the study ends, a clinical trial report will be published by the principal investigators 
and the statistician responsible for the study. The coordinating investigator will sign the 
final version of the clinical trial report for this study, hereby indicating their agreement 
with the analyses, the results, and the conclusions of the report.  
The key players in a clinical study are the coordinating investigator, investigators, 
members of the IFCT staff team and members of the boards of directors and scientists, all 
of whom collaborate to varying degrees from the design of the trial to the final writing of 
the findings. The order of signatories will be governed by the IFCT rules 
(http://www.ifct.fr): 
1. The coordinating investigator has the choice between first and last place. In both cases, he 
or she must have been extensively involved in the design of the trial, inclusions and drafting 
of the article. 
2. If he/she chooses the first place, the last place is reserved for the President, one of the 
secretaries or one of the other elected members of the Board of Directors (BOD) or the 
Secretary of the Scientific Council (SC). The latter must be chosen on the basis of his or her 
participation in the design of the trial, inclusions and the drafting of the article. In the 
event of any difficulty in choosing this person, a secret ballot of the Board of Directors will 
determine the outcome. 
3. If he/she chooses the last place, the second to the last place goes to the Chairperson, one 
of the Secretaries or one of the other elected members of the Board or the Secretary of the 
SC under the same conditions, unless the latter takes the first place if, in agreement with 
the principal investigator, he/she drafts the article. In the event of any difficulty in 
choosing this person, a secret ballot of the Board of Directors will determine the outcome. 
4. Investigators are listed in order of inclusion of eligible patients. All other investigators 
should be listed in an appendix. 
5. Two members of the same team may not sign the same article unless one of them appears 
as the coordinating investigator or member of the Board or secretary of the signatory SC as 
such in first, last or second last place. 
6. IFCT staff team members play an essential role in clinical studies. As such, those involved in 
the design of the trial, its management or the drafting of the article must systematically 
appear in the acknowledgements or as signatories. Their names will be listed by the 
Director to the Coordinating Investigator. If they appear as signatories, they must not 
appear in the first 6 or last 2 positions. They may not exceed two if the number of 
signatories is above 10, 1 if it is equal to or below 10. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
48/54 
7. If a university statistician has collaborated in the development and processing of trial data, 
he/she may sign in agreement with the principal investigator (coordinator) at a position 
defined between them by consensus (usually 3rd or 4th position). 
8. Under no circumstances shall anyone request a signature for having provided care for a 
patient for routine care that is not research-related. 
9. all investigators (1 per IFCT research site) will be listed following each article in a table that 
may also include anatomopathologist, surgeon, radiotherapist from the site depending on 
the article, so that this citation induces a Medline occurrence. 
10. For ancillary studies (biological, radiological or other), in the case of an article or abstract 
with a maximum of 10 signatures, the principal investigator (coordinator) of the biological 
study has the choice between the first and the last place. In both cases, he or she must 
have been extensively involved in the design of the trial, its funding, inclusions and drafting 
of the article. The above rules apply for the last place if he or she chooses the first place. 
The second-to-last place may be reserved for the head of the research laboratory that made 
the most decisive contribution to the study. The third-to-last place may be reserved for the 
Principal Investigator (coordinator) of the clinical study if he/she is not the PI (CI) of the 
biological research study. The first four places may be occupied by the scientists or 
physicians, members or not of the IFCT, who have contributed the most to the ancillary 
study, including, where applicable, the university statistician upon proposal by the CI and 
the Board Bureau and validation by the Board. If a maximum of 10 signatories, 3 to 4 central 
places will be reserved for the best 3 to 4 clinicians (in the sense that they have contributed 
most in terms of anatomical/pathological sampling). In the case of articles with 20 
signatures, 2 to 3 places will be reserved for the pathologists who contributed most to the 
study (either in the collection of specimens or in the review of the IFCT Anapath Panel). All 
biology labs participating in the study should be represented by one signatory, the 
remaining signatory places should be reserved for clinicians according to the above rules, 
including 1 member of the IFCT permanent team who contributed most to the study 
(Decision of the CI + Director+ Chairperson), and the clinical study CI. 
11. All articles shall be marked “...on behalf of IFCT” at the end of the list of signatories and 
shall include the acronym IFCT-XXYY in their title of the clinical trial from which the 
ancillary study was derived. 
12. IFCT may need to be assisted in the formatting of an article in English, but shall under no 
circumstances delegate the actual writing to an agency or industry. 
These rules were developed and validated by the IFCT Board of Directors in September 
2010 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
49/54 
13. A BIO-IFCT-1201 Ancillary study (Bio-MODEL) 
13.1. Biological samples (tumour block) 
This trial proposes a design to test 4 of the biomarkers determined on the tumour 
samples taken at baseline: 
 
biomarkers of sensitivity or resistance to the platinum salt used in the induction 
phase doublet (MSH2, BRCA1),  
 
biomarkers of sensitivity or resistance to compounds used during the RRM1 
maintenance phase for gemcitabine (M1 subunit of ribonucleotide reductase), TS 
(thymidylate synthetase) and folate carriers for pemetrexed, 
 
biomarker of sensitivity or general resistance to chemotherapy (or poor prognosis: 
K-Ras mutation, 
 
biomarkers of poor prognosis and sensitivity or resistance to paclitaxel used in 
induction: RASSF1A methylation. 
A collection of paraffin-embedded tumour blocks will be performed on all patients enrolled 
in the clinical study. For each patient, the minimum requirement is to obtain 5 white 
slides (4 antibody labels + 1 in case of failure) centralised with the adjacent locally 
produced HES slides. 
The detection of K-Ras mutations tumour biopsy is now routinely performed by molecular 
genetic platforms. In order not to carry out this analysis in duplicate, the case report form 
includes an item to specify the result obtained from the platform. Any remaining residue 
at the platform level will be collected by IFCT for the centralised search for RASSF1A 
methylation by MS-PCR, and the unused DNA will then be returned to the platform.  
13.2. Statistics 
13.2.1. Statistical power consideration 
Statistical power considerations were made for a univariate logistic regression modelling 
the probability of death at 1 or 2 years based on a dichotomised biomarker score. 
It is assumed that biomarker results will be collected for 80% of the patients enrolled, i.e. 
437 patients.  
The following assumptions are based on the results of IFCT-0002 trial: Randomized trial 
comparing two preoperative chemotherapy regimens in clinical Stage I and II NSCLC. Since 
patients aged 70 and older in this trial represent only 15%, the results are based on the 
entire biological sample. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
50/54 
For the RRM1 biomarker, it is assumed that the proportion of patients who will die within 
one year of starting treatment will be 12%. 
 
RMM1 biomarker:  
Proportion of patients who will have negative RRM1 labelling (first quartile 
threshold Q1, <Q1): 23% 
Proportion of patients who will die within the year knowing that they will have a 
negative RRM1 label: 19% 
Under these assumptions, this would correspond to an Odds Ratio of 2.1, 95% CI 
[1.2; 3.9]. 
For the MSH2 and BRCA1 biomarkers, it is assumed that the proportion of patients 
who will die within two years of starting treatment will be 26%. 
 
for the MSH2 biomarker, the parameters are as follows: 
Proportion of patients who will have a positive biomarker value (median threshold 
Q2, ≥Q2): 53% 
Proportion of patients who will die within 2 years knowing they will have a positive 
biomarker: 30% 
Under these assumptions, this would correspond to an Odds Ratio of 1.6, 95% CI 
[1.0; 2.4]. 
 
for the BRCA1 biomarker, the parameters are as follows: 
Proportion of patients who will have a negative biomarker value (median threshold 
Q2, <Q2): 42% 
Proportion of patients who will die within 2 years knowing they will have a negative 
biomarker: 33%  
Under these assumptions, this would correspond to an Odds Ratio of 1.9, 95% CI 
[1.2; 2.9]. 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
51/54 
For TS markers whose positivity threshold appears to be more variable and random in 
comparison with past studies, such as RASSF1A methylation (positive in 21% of patients 
with early stage NSCLC (35)) whose study will depend on the availability of unused DNA on 
genetic platforms and whose size cannot therefore be predicted with reliability (possibly 
less than 50% of the initial size), the study will be purely exploratory and will not allow for 
the development of power assumptions a priori. 
13.2.2. Statistical analysis plan 
The main objective of the ancillary study is to assess the prognostic value of biological 
markers using Cox’s survival model, adjusted to the clinical and biological factors of the 
trial. 
The secondary objective is to evaluate the predictivity of these markers: RRM1 versus 
gemcitabine, TS versus pemetrexed, and the remaining markers versus one of the two 
treatments. 
 
Descriptive analysis 
Biological markers will be analysed in a quantitative and qualitative manner 
(dichotomisation according to a threshold defined by past studies). 
Their association with clinical and biological factors will be assessed using Chi2 and ANOVA 
tests, or using the Fisher and Mann-Whitney non-parametric tests if necessary. 
Prognostic analysis of response and survival 
The prognostic value of biological markers will be evaluated using a logistic model and a 
Cox model.  
The markers will be analysed continuously and discretely. 
As a second step, clinical factors associated with response and overall survival will be 
identified, using univariate logistic and Cox models, significant variables at p<0.2 will be 
entered in multivariate models to which a variable selection procedure will be applied.  
Markers with a p of less than 0.2 will be entered into the clinical model to determine an 
optimal model. 
 
 
 
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
52/54 
Validation study 
In order to confirm the prognostic role of the biological markers identified in this trial, a 
validation study will be carried out using a bootstrap method. 
Predictive analysis of response and survival 
The predictivity of biological markers will be evaluated using an interaction test between 
each marker and treatment in both the logistic and Cox models.  
The markers will be analysed continuously and discretely. 
The following strategy will limit the number of analyses: 
The predictive value of the markers will be tested in a logistic and Cox model each 
containing the treatment, the marker and the treatment* marker interaction term.  
The second step will be to identify the clinical factors associated with response and overall 
survival. To do this, univariate logistic and Cox models will be performed and the 
significant variables at p<0.2 will be entered in the multivariate models to which a 
variable selection procedure will be applied.  
Finally, markers for which the p of the interaction term is less than 0.2 will be entered 
into the clinical model to determine an optimal model. 
14. References 
1.  
HCL/InVS/INCa/Francim/Inserm. Projection de l’incidence et de la mortalité par cancer en 
France en 2011  
2.  
Jennens RR, Giles GG, Fox RM. Increasing underrepresentation of elderly patients with 
advanced colorectal or non-small-cell lung cancer in chemotherapy trials. Intern Med J. 2006 
avr;36(4):216-20.  
3.  
Blanchard EM, Arnaoutakis K, Hesketh PJ. Lung cancer in octogenarians. J Thorac Oncol. 2010 
juin;5(6):909-16.  
4.  
Davidoff AJ, Tang M, Seal B, Edelman MJ. Chemotherapy and survival benefit in elderly 
patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 2010 mai 1;28(13):2191-7.  
5.  
Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-
small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J. Natl. 
Cancer Inst. 1999 janv 6;91(1):66-72.  
6.  
Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly 
patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the 
Elderly Study (MILES) phase III randomized trial. J. Natl. Cancer Inst. 2003 mars 5;95(5):362-
72.  
7.  
Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, et al. Single-agent 
versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and 
leukemia group B (study 9730). J. Clin. Oncol. 2005 janv 1;23(1):190-6.  
 

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
53/54 
8.  
Ansari RH, Socinski MA, Edelman MJ, Belani CP, Gonin R, Catalano RB, et al. A retrospective 
analysis of outcomes by age in a three-arm phase III trial of gemcitabine in combination with 
carboplatin or paclitaxel vs. paclitaxel plus carboplatin for advanced non-small cell lung 
cancer. Crit. Rev. Oncol. Hematol. 2011 mai;78(2):162-71.  
9.  
Wheatley-Price P, Ding K, Seymour L, Clark GM, Shepherd FA. Erlotinib for advanced non-
small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada 
Clinical Trials Group Study BR.21. J. Clin. Oncol. 2008 mai 10;26(14):2350-7.  
10.  Quoix E, Monnet I, Scheid P, Hamadouche A, Chouaid C, Massard G, et al. [Management and 
outcome of French elderly patients with lung cancer: an IFCT survey]. Rev Mal Respir. 2010 
mai;27(5):421-30.  
11.  Pallis AG, Gridelli C, van Meerbeeck JP, Greillier L, Wedding U, Lacombe D, et al. EORTC 
Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology 
(SIOG) experts’ opinion for the treatment of non-small-cell lung cancer in an elderly 
population. Ann. Oncol. 2010 avr;21(4):692-706.  
12.  Belani CP, Fossella F. Elderly subgroup analysis of a randomized phase III study of docetaxel 
plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of 
advanced nonsmall cell lung carcinoma (TAX 326). Cancer. 2005 déc 15;104(12):2766-74.  
13.  Pujol J-L, Milleron B, Molinier O, Quoix E, Depierre A, Breton J-L, et al. Weekly paclitaxel 
combined with monthly carboplatin in elderly patients with advanced non-small cell lung 
cancer: a multicenter phase II study. J Thorac Oncol. 2006 mai;1(4):328-34.  
14.  Quoix E, Zalcman G, Oster J-P, Westeel V, Pichon E, Lavolé A, et al. Carboplatin and weekly 
paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with 
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 sept 
17;378(9796):1079-88.  
15.  Ganti AK, deShazo M, Weir AB 3rd, Hurria A. Treatment of non-small cell lung cancer in the 
older patient. J Natl Compr Canc Netw. 2012 févr;10(2):230-9.  
16.  Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib 
in previously treated non-small-cell lung cancer. N. Engl. J. Med. 2005 juill 14;353(2):123-32.  
17.  Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, et al. American Society of Clinical 
Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung 
cancer. J. Clin. Oncol. 2009 déc 20;27(36):6251-66.  
18.  Gerber DE, Rasco DW, Le P, Yan J, Dowell JE, Xie Y. Predictors and impact of second-line 
chemotherapy for advanced non-small cell lung cancer in the United States: real-world 
considerations for maintenance therapy. J Thorac Oncol. 2011 févr;6(2):365-71.  
19.  Stinchcombe TE, Socinski MA. Maintenance therapy in advanced non-small cell lung cancer: 
current status and future implications. J Thorac Oncol. 2011 janv;6(1):174-82.  
20.  Pérol M, Arpin D. [Maintenance therapy in advanced non-small cell lung cancer: A new 
paradigm?]. Presse Med. 2011 avr;40(4 Pt 1):404-14.  
21.  Fidias P, Novello S. Strategies for prolonged therapy in patients with advanced non-small-cell 
lung cancer. J. Clin. Oncol. 2010 déc 1;28(34):5116-23.  
22.  Socinski MA. Re-evaluating duration of therapy in advanced non-small-cell lung cancer: is it 
really duration or is it more about timing and exposure? J. Clin. Oncol. 2009 juill 
10;27(20):3268-70.  
23.  Coudert B, Ciuleanu T, Park K, Wu Y-L, Giaccone G, Brugger W, et al. Survival benefit with 
erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) 
according to response to first-line chemotherapy. Ann. Oncol. 2012 févr;23(2):388-94.  

IFCT-1201 MODEL 
 Version 1.6 dated 20/11/2015 
 
 
 
54/54 
24.  Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, et al. Cisplatin and 
gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive 
care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 
mai;52(2):155-63.  
25.  Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol J-L, Bidoli P, et al. Maintenance therapy 
with pemetrexed plus best supportive care versus placebo plus best supportive care after 
induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell 
lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet 
Oncol. 2012 mars;13(3):247-55.  
26.  Westeel V, Quoix E, Moro-Sibilot D, Mercier M, Breton J-L, Debieuvre D, et al. Randomized 
study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer. J. 
Natl. Cancer Inst. 2005 avr 6;97(7):499-506.  
27.  Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Maintenance 
pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-
cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 oct 
24;374(9699):1432-40.  
28.  Zhang X, Zang J, Xu J, Bai C, Qin Y, Liu K, et al. Maintenance therapy with continuous or 
switch strategy in advanced non-small cell lung cancer: a systematic review and meta-
analysis. Chest. 2011 juill;140(1):117-26.  
29.  Azzoli CG, Temin S, Aliff T, Baker S Jr, Brahmer J, Johnson DH, et al. 2011 Focused Update of 
2009 American Society of Clinical Oncology Clinical Practice Guideline Update on 
Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J. Clin. Oncol. 2011 oct 
1;29(28):3825-31.  
30.  Perol, M, Chouaid C, Milleron BJ. Maintenance with either gemcitabiene or erlotinib versus 
observation with predefined second-line tretament after cisplatin-gemcitabine induction 
chemotherapy in advanced NSCLC : IFCT-GFPC 0502 phase III study. J Clin Oncol. 28(Suppl 
15):540S.  
31.  Belani CP, Waterhouse DM, Ghazal H, Ramalingam S, Bordoni R, Greenberg R et al. Phase III 
study of maintenance gemcitabine and best supportive care versus best supportive care 
following standard combination therapy with gemcitabine-carboplatin for patients with 
advanced non-small cell lung cancer. J Clin Oncol. 28(18S):A7506.  
32.  Weiss GJ, Langer C, Rosell R, Hanna N, Shepherd F, Einhorn LH, et al. Elderly patients benefit 
from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of 
pemetrexed compared with docetaxel in patients with previously treated advanced non-small-
cell lung cancer. J. Clin. Oncol. 2006 sept 20;24(27):4405-11.  
33.  Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized 
phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer 
previously treated with chemotherapy. J. Clin. Oncol. 2004 mai 1;22(9):1589-97.  
34.  Frasci G, Comella P, D’Aiuto G, Budillon A, Barbarulo D, Thomas R, et al. Weekly paclitaxel-
cisplatin administration with G-CSF support in advanced breast cancer. A phase II study. Breast 
Cancer Res. Treat. 1998 mai;49(1):13-26.  
35.  De Fraipont F, Levallet G, Creveuil C, Bergot E, Beau-Faller M, Mounawar M, et al. An 
apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial. Clin. 
Cancer Res. 2012; 18(10): 2976-86.