D I T E P 2 0 1 8 01 Gustave Roussy is one of the largest phase - - PDF document

01

2 0 1 8 D I T E P

3

• Dr. Christophe Massard

Head of DITEP

Gustave Roussy is

• ne of the largest

phase 1 centre, with more than 450 patients included per year in phase 1 trials. The mission of the DITEP is to accelerate the development

• f new anticancer

drugs, to build an ambitious cancer research program (precision medicine, immunotherapy and new targets), and also to give a new hope to patients facing cancer battles.

Created on September 1st, 2013 to strengthen the therapeutic innovation and the early clinical trials at Gustave Roussy. In 2018, this medical department carries the ambition to be one of the top international players in early drug development, precision medicine and immunotherapy.

OUR STRATEGIC VISION AND MISSIONS

Oncology has become in the last decade an exciting therapeutic area bridging new scientifjc concepts and major clinical breakthroughs for the patients and their families. Our ambition is to foster a new era of cancer care and treatments by:

Promoting innovation and multidiscipli- nary collaborations to achieve higher rates of treatment effjcacy based on streamlined molecular analyses and predictive tools generated from our precision medicine programs, as well as innovative imaging methods. Facilitating patients’ inclusion in phase I/II studies at an earlier stage of the disease to acknowledge the early clinical trial as a true therapeutic

• pportunity within an integrated cancer

care management structure. Positioning cancer immunotherapy and the novel immunomodulators as early as possible as potential backbone therapies for combinations with other approaches. Continuously developing the medico- scientifjc expertise of our investigators team and the skills and performance

• f our clinical operations staff through

fruitful collaborations and partnerships with pharma and biotech companies. Pursuing

• ur

quality assurance management in the context of ISO- 9001 certifjcation.

OVERALL ORGANIZATION OF THE DITEP

September 2006 September 2008 October 2010 February 2015 September 2016 September 2017 May 2015 November 2016 September 2007 July 2011 September 2013

Early drug development and clinical trials identifjed as a strategic orientation of Gustave

• Roussy. Prof Soria appointed as the leader
• f a working group for therapeutic innovation

and early clinical trials expansion. Creation of the « SITEP » (Service des Innovations Thérapeutiques et Essais Précoces), fjrst hospitalization unit in France fully dedicated to early clinical trials in oncology (fjrst-in-human administration, phase I trials, phase I/II extension cohorts) with 8 beds and 6 out- patient seats. Recognition granted by the french National Cancer Institute (INCA, 4 years)

• f SITEP as an early trials center (CLIP²)

Renewal of the CLIP² label by INCA (4 years) Renewal of the ARS certifjcation for fjrst-in-human trials Dr Massard appointed as Head of the DITEP New premises gathering all the DITEP teams

• n one fmoor (4th)

Establishment of the early clinical trial pluridisciplinary committee (RCP-150) Certifjcation of the french Health Regional Agency (ARS, 5 years) for fjrst-in-human trials Creation of the DITEP as a full medical department of Gustave Roussy , headed by Prof. Soria.

DITEP

ISO 9001 accreditation N°2016/72604.1

DITEP KEY STEPS

09

Headed by Dr. Christophe Massard, in 2018 the DITEP encompasses 150 full-time equivalents dedicated to early clinical trials, translational research and precision medicine programs. Since November 2016, the DITEP has obtained the ISO 9001v2015 certifjcation (Quality Management System) for its activities of access to therapeutic innovations, management of early clinical trials, and scientifjc outreach.

CARE WARDS & FACILITIES

• A conventional week-hospitalization unit (4th fmoor) headed by Dr Antoine Hollebecque: 13

single-patient beds. This unit receives patients who require full-time hospitalization as per protocol or for safety surveillance due to side effects over the week.

• An out-patient care unit (4th fmoor) headed by Dr Andrea Varga: 16 armchairs (whose 2

dedicated to PK). This outpatient unit is operational every day from Monday to Friday from 7:00 am to 7:00 pm (including PK sampling on Saturdays). This unit also receives patients who require nursing and related cares.

• A consultation platform facility
• An early phase clinical operations unit (4th fmoor) headed by Mrs Guylène Chartier gathering

all staff in the same new premises that host all MDs offjces, a local laboratory dedicated to the processing of biological samples, as well as confjdential monitoring spaces dedicated to the trials sponsors.

PLURIDISCIPLINARY CLINICAL RESEARCH AND DECISION-MAKING COMMITTEES

• The early clinical trial multi-disciplinary tumor board (RCP-150), headed by Dr Vincent

Ribrag, encompasses all DITEP experts in medical oncology, radiotherapy, hematology, immunotherapy, as well as experts in biopathology and imaging. This weekly committee is in charge of the validation of all patients’ referral to our phase I programs, and for the review of all on-going trials and medical decisions regarding any complex situations of safety or experimental treatment decisions.

• The molecular pluridisciplinary committee (RCPM-150), dedicated to the weekly review
• f the molecular tumor profjles performed within our precision medicine programs

aims at including each phase I-eligible patient in the most adapted clinical trial based

• n actionable molecular abnormalities.
• A monthly Protocol Review Committee (PRC) to address the scientifjc value and

feasibility of new trials proposals.

MEDICAL AND CLINICAL OPERATION TEAMS

• Principal investigators and sub-investigators: 6 MD-PhD, 7 MDs (see CV p.28-40)
• Medical and academic assistants & Managers: 13
• Clinical research nurses & Managers: 40
• Head of clinical operation unit: 1
• CRA managers: 2
• Project managers: 7
• Study coordinators: 26
• Clinical research technicians & sample managers: 17
• Schedulers: 3
• Medical research assistants & helpers: 7
• Quality assurance: 1
• Administrative & contracting: 3
• Chief scientifjc offjcer: 1

09

• Dr. C. Massard

• E. Netzer

J.Florance

• D. Aubry

Dr A. Hollebecque

• L. Daley
• S. Lancereau

B.Thuillier

Dr A. Varga Dr R.Bahleda Dr C. Baldini

1 Head nurse (day) 25 nurses S.Rodrigues 4 Nurse helpers Dr A.Gazzah Dr J.M.Michot Dr S. Champiat

• P. Dielenseger

7 nurses (night) 1 Head nurse (night)

• K. Willinger

• G. Bernal-

Trinel

4 Medical clinical research assistants + 3 helpers AMR 3 schedulers 2 Data Managers 1 assistant 1 Finance coordinator 1 Contract coordinator 26 study-co 10 data-managers 5 Sample managers

• M. Ngo Camus
• C. Nicotra
• S. Fahrane
• N. Hainault

• N. Imam
• E. Toubiwou
• E. Zedouard
• H. Pousse

• S. Orange

5 MA + 2 Medical Administrative Secretaries + 1 professional training contract

• H. Zouhri
• N. Meunier
• G. Chartier

ORGANIZATION CHART

DITEP KEY FIGURES

806 34 11,2

patients recruited in precision medicine programs

104 460 2.080

early clinical trials opened for inclusions patient’s referrals for inclusion in early clinical trials patients recruited in early clinical trials

3.946 3.504

stays (Conventional Hospital and Day Hospital) medical consultations publications on early clinical trials results and precision medicine programs as the average journal Impact Factor

2017 KEY FIGURES

13

96

2011 2010 2012 2013 2014 2015

41 55 68 70 88

2016 2017

91 104

Early clinical trials, as of January 2018 (in dose escalation and in organ-oriented extension cohorts)

3 Cell cycle & Apoptosis 41 Immune Checkpoints & Immunomodulators 18 Tyrosine Kinase Inhibitors 10 Antibody Drug Conjugates & Bispecifjc Monoclonal Antibodies 6 Epigenetic & metabolic Inhibitors 8 Other

86

EARLY CLINICAL TRIALS

Yearly number of ongoing early clinical trials

MAIN ACTIVITY INDICATORS

Patients recruited in DITEP trials Patients treated in early clinical trials in 2017

Patients treated in our early clinical trials (inclusions in our precision medicine programs excluded) Patients recruited in our studies (early clinical trials and precision medicine programs)

Gastrointestinal Hematology Gynaeco Lung GenitoUrinary Breast HNSCC Skin Brain Neuroendocrine Other Sarcoma

32% 1% 1% 2% 2% 5% 5% 5% 10% 11% 12% 14%

460

PATIENTS

DITEP RESEARCH ACTIVITES

MTAs

• Mol. Profiling/Serial Biopsies

Targeted panel WES/RNASeq/ctDNA

EDD in Hematological Malignancies PRECISION MEDICINE IMMUNOTHERAPY NEW MOLECULAR ENTITIES FIHs Dose Escalation (All comers) Dose Extensions (All indications) Basket / Umbrella Trials Combos with Radiotherapy Local Immunomodulation Intratumoral Injections Neoadjuvant Settings / WoO Trials

DESIGNS FIELDS OF INTEREST

DITEP Research Axis

ICB FIH & combos ADCs - BiTEs Cancer Vaccines CAR-T cells DNA repair Epigenetic Metabolism SPECIFIC EXPERTISES

DITEP RESEARCH AXIS

17

This Gustave Roussy-sponsored biomedical research exploited the extensive molecular and immunological characterization of on-purpose fresh biopsies of metastatic sites in relapsed and refractory phase I-eligible patients in order to orient these patients to the most adapted molecular targeted or immune-based therapy. In the fjrst part of this program, named MOSCATO-01, over 1011 patients were included between November 2011 and March 2016. Four hundred eleven patients had an “actionable” molecular abnormality (identifjed on NGS gene panel, CGHa, IHC analyses and more recently WES/RNASeq) and 199 out them have been treated with an ad hoc targeted molecule. The

• bjective of the study was to demonstrate that

the progression-free survival of the fjrst line

• f oriented treatment (PFS2) was signifjcantly

superior to the progression-free survival of the last treatment line before inclusion (PFS1). This judgment criterion was fully achieved with a PFS2/PFS1 ratio > 1.3 in 33% (IC95 PFS ratio: 26-39%) of the patients with a disease control rate of 62% and a median overall survival of 11.3 months. With these results, MOSCATO-01 is the fjrst trial demonstrating a clinical benefjt in advanced cancer patients by a large-scale molecular screening and precision medicine approach. The second part of the program, named MOSCATO-02, was launched in March 2016 by Dr . Antoine Hollebecque. It is an extension of the fjrst part and now includes, on top of the molecular profjling, an immune contexture characterization and an evaluation of the mutational load (WES) for the orientation of the patient to immunotherapy. PUBLICATION Massard C, et al. High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial. Cancer Discov. 2017 Jun;7(6):586-595.

1168 554

patients enrolled in MOSCATO-01 patients enrolled in MOSCATO-02

(as of February 2018)

MOSCATO program (“Molecular Screening for Cancer Treatment Optimization”)

PRECISION MEDICINE PROGRAMS

The MATCH-R trial started in 2014 (PI : Prof. Benjamin Besse, Head of the Medical Oncology Department). It is a two-centre prospective trial sponsored by Gustave Roussy which aims at characterizing the evolution of clonal architecture of tumors from patients treated with molecular targeted therapies. It is designed to collect fresh tumor biopsies at relapse/recurrence in patients treated with molecular targeted agents (either approved

• r in early clinical trials of the DITEP portfolio
• f studies). Eligible patients are patients in

progressive disease who previously experienced a signifjcant benefjt to a targeted molecules (objective response or long-lasting disease stabilization > 6 months) and availability of an archived initial tumor material. This MATCH-R program also includes several sub-studies :

• The Bégin Hospital and Gustave Roussy have

collaborated to establish one focusing on cancer

• f the prostate (Dr

. Yohann Loriot) in patients resistant to enzalutamide and abiraterone.

• The MATCH-R IMMUNO is a prospective study

that aims at identifying molecular mechanisms

• f resistance to immunotherapies in patients

with unresectable or metastatic cancers. Eligible patients in this trial are patients eligible for a treatment with an anti-PD-1 or anti-PD-L1 monoclonal antibody , either in monotherapy or in combination.

FRESH TUMOR

biopsy Max 21 calendar days pathological control CGH Array & NGS/WES/RNAseq ctDNA

MOLECULAR SCREENING ACTIONABLE TARGET IMPROVE OUTCOME RELEVANT TARGETED THERAPY CLINICAL DECISION TREATMENT

MATCH-R program Precision medecine scheme

PUBLICATION Planchard D, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015 Oct;26(10):2073-8.

223

patients enrolled

• Prof. BESSE

19

PUBLICATION Planchard D, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015 Oct;26(10):2073-8. Jovelet C, et al. Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial. Clin Cancer Res. 2016 Jun 15;22(12):2960- 8. Koeppel F, et al. Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients. PLoS

• One. 2017 Nov 21;12(11):e0188174.

The « Liquid Biopsy » Program is based on the detection in the blood of circulating tumor residues, such as circulating tumor cells (CTC), nucleic acids (ctDNA or ctRNA) using specifjc highly sensitive and specifjc assays. The general goal of this approach is to monitor , through a repeatable and safe blood sampling, the clonal evolution of tumors at the cellular and molecular levels under the pressure of targeted therapies and to characterize resistance mechanisms. This program is currently deployed across multiple indications, with a focus on lung cancers, for the tracking of already known (in initial tumor biopsies) molecular aberrations (i.e. mutations, amplifjcations, translocations) on

• ncogeneic drivers (EGFR, ALK, MET, FGFR…)

and to evidence any new one that could be associated to primary or secondary resistance (e.g. to immune checkpoints blockers or specifjc tyrosine-kinase inhibitors).

LIQUID BIOPSY program

1221

patients enrolled (CTC)

Recent years have seen the emergence of new immunotherapies fjnally effective. These new molecules, mainly monoclonal Antibodies (mAbs), present a novel mechanism of action: by blocking co-inhibitory receptors expressed by T cell they unleash their effector functions. The fjrst generation of these immune-targeted mAbs are blocking immune checkpoint receptors such as CTLA4* and PD1 ** and have revolutionized the treatment of melanoma with metastatic response rates and survival exceptionally increased. The PD1/PD-L1 blocking mAbs also give very encouraging results in cancers of the kidney, lung and other advanced cancers are currently being explored. A new generation of treatments against cancer is born!

* CTLA4: cytotoxic T-lymphocyte-associated protein 4 ** PD1: Programmed cell death protein 1

In 2015, Gustave Roussy launched an institutional program dedicated to immunotherapy: GRIP (Gustave Roussy Immunotherapy Program). This program aims at strengthening translational research on these new treatments, and accelerating the clinical development

• f immunotherapy

, in order to give access to these treatments to the largest number of patients. Initiated by Professor Alexander Eggermont, General Director of Gustave Roussy , the GRIP program is under the clinical direction of Dr . Aurélien Marabelle and under the scientifjc direction of Professor Laurence Zitvogel. By reactivating the immune system against cancer cells, these immunotherapies may sometimes provoke auto-immune reactions. These reactions are new and necessitate specifjc management. In addition, some rare toxic effects are potentially severe and require early detection. As part of the GRIP, Gustave Roussy has implemented a program designed to manage the adverse effects of immunotherapies. This program has 4 components: a network of organ specialist, institutional management guidelines, the REISAMIC pharmacovigilance registry (Registry of Severe Adverse Effects of Immunomodulating Monoclonal Antibodies in Oncology), and dedicated multidisciplinary team (MDT) meetings.

Clinical Research in immunotherapy A program dedicated to immunotherapy: GRIP

Number of active Immunotherapy Trials Number of patients treated in Immunotherapy Trials

IMMUNOTHERAPY

21 21

RADIOTHERAPY

Radiotherapy combinations

The link between development of new anticancer drugs and radiation therapy has been part of the activity of DITEP since its creation. Combination

• f

radiotherapy with nanoparticles, therapies targeting DNA repair mechanisms and immunomodulatory agents are under study. A signifjcant portion of this activity is at the interface with the preclinical research activity developed at Gustave Roussy. The combination of radiotherapy with other anticancer agents is therefore part of a comprehensive development strategy. For these studies, academic funding is of special importance notably in the case of combinations

• f antiviral agents and radiotherapy.

Radiomics

The Radiomics team of the INSERM U1030 unit (led by Prof. Eric Deutsch) has established a very fruitful collaboration with the group of Pr Nikos Paragios (Centrale Supelec INRIA), bringing world- renowned expertise in imaging analysis and artifjcial intelligence. Medical image processing and analysis (i.e. radiomics) is a promising and rapidly growing

• discipline. This new approach consists of the analysis
• f high dimensional data (typically > 1000 features

per volume of interest) extracted from standard medical imaging such as CT-scans, PET or MRI. The underlying assumption is that imaging refmects not only the architecture of the tissues, but also their cellular and molecular composition. The end goal

• f radiomics is to generate imaging biomarkers as

decision support tools for clinical practice and to better understand cancer biology. One of the axes

• f research is the use of radiomics as a predictor of

lymphocytic tumor infjltration and thus of the effjcacy

• f immunotherapies.

HEMATOLOGY

With 19 trials

• pen

for hematological malignancies, the DITEP has emerged as a key player in hematology drug development. More than 90 patients were enrolled in these trials in 2016 with myeloid and lymphoid diseases. First in man studies targeting epigenetics (IDH2 and EZH2) open new areas for treating patients and now will enter in phase II and III drug development given the high level of activity

• bserved in trials where the DITEP was largely

involved. On the

• ther

hand, targeting immune checkpoints proved to be extremely effective in lymphomas such as Hodgkin disease. During the recent years, a dedicated hematology team within the translational research laboratory has been created and offers now the opportunity to add biological cellular collection and a molecular profjle of the patient’s tumors. This molecular profjle is implemented for patient’s screening. Our aim will be to characterize more precisely the patient’s tumors and more effjciently propose the relevant trial to the patients according to this updated molecular characterization.

• Prof. DEUTSCH

SPECIFIC EXPERTISES

DITEP COLLABORATIONS

1 338 national external referrals in 2017

Soft Tissues – Bone

• C. Honoré

Thoracic Pathology

• B. Besse

Gastro-digestive

• D. Malka

Endocrine Tumours É. Baudin Dermatology

• C. Robert

Cervico-facial Pathology

• I. Breuskin

Urology

• L. Albigès

Neurology

• F. Dhermain

Haematology

• S. De Botton

Breast

• S. Delaloge

Gynecology

• P. Pautier

Paediatric Pathology

• J. Grill

Genetical Oncologist

• O. Caron

Active file of patients in 2016

EXTERNAL INTERNAL

Gustave Roussy Tumor Boards (RCP) DITEP Experts & Referents to RCP

• R. Bahleda
• A. Gazzah
• A. Varga
• V. Ribrag
• JM. Michot
• A. Marabelle
• C. Massard
• A. Hollebecque

2 268 2 198 2 818 4 330 4 749 4 198 4 204 826 3 550 10 651 3 351 2 448 972

Organ-oriented expertise with all other tumor boards and medical departments for the patient referral and facilitation of the transition between early and late phase clinical trials. Most of the DITEP physicians are also organ-specialists partially affjliated to different organ-oriented tumor boards. The radiotherapy (Pr Deutsch, Dr Levy) department is strongly connected to DITEP and the surgery departments participate according to specifjc needs, especially with the HNSCC Tumor Board (Dr Temam). Strong links with other French Early Drug Development Centers (CLIP² centers) and networks of international centers in Europe (VHIO, NKI, Cambridge, DKFZ, KI within the Cancer Core Europe consortium headed by Pr Eggermont and Pr Calvo).

RELATIONSHIP WITH INTERNAL (RCP) AND EXTERNAL ONCOLOGISTS

25

Early Drug Development @ DITEP

MECHANISMS OF RESISTANCE

• L. Friboulet
• B. Besse
• C. Massard

IMMUNOLOGY & IMMUNO- MONITORING

• L. Zitvogel
• A. Marabelle
• N. Chaput

BIOPATHOLOGY & BIOLOGICAL RESOURCES

• JY. Scoazec

DNA REPAIR EPIGENETIC

• S. Postel-Vinay

BIOINFORMATICS

• D. Gautheret
• L. Verlingue
• Dir. Prof. E. Deutsch

MOLECULAR RADIOTHERAPY

• E. Deutsch

CLINICAL RESEARCH TRANSLATIONAL RESEARCH BASIC RESEARCH

Strong interactions with the Clinical Research Division (DRC), headed by Pr Vassal for the initiation and conduct of Gustave Roussy-sponsored early clinical trials & Investigator-initiated Studies (ISS). The DRC encompasses different entities: the SPEC, headed by Ms Vuillier, in charge of the regulatory affairs and monitoring of investigation sites; the SBE, headed by Dr Benhamou, in charge of early clinical trial biostatistics design (Dr Lanoy, Dr Paoletti), medically-driven data management and analyses of ISS; the UFPV headed by Dr Laghouati, is in charge

• f

the pharmacovigilance declarations and of immune-related SAE, a specifjc registry (REISAMIC) of immune- checkpoint treatments. Active contribution in early clinical trials

• f multiple experts: Biopathology/CRB

and Translational Research Platforms (Pr Scoazec) including high-throughput molecular profjling (Dr Lacroix), IHC (Dr Adam), circulating cells (Dr Farace), immunomonitoring (Pr Chaput-Gras), bioinformatics (Mr Meurice); Functional Imaging (Dr Balleyguier, Dr Ammary, Dr Lassau); Nuclear Medicine (Dr Dercle) with a specifjc innovative program of PET-MRI; Interventional Radiology (Pr De Baere) for sequential biopsies in precision medicine programs; Pharmacology & pharmacokinetics (Dr Paci).

RELATIONSHIP WITH PLATFORMS & RESEARCH TEAMS

The development of collaborations and partnerships with industry are a major

• bjective for Gustave Roussy, and espe-

cially DITEP. This objective is supported by an active policy of attracting global phar- maceutical and biotechnology companies. It is based on the value of our medical and scientifjc expertise, our operational skills and our clinical and biological resources. Through industry partnerships, our priority is to have access to the most innovative and potentially effective agents for our patients early in their development. Our teams are able to propose ancillary projects to optimize development of these molecules, establish the mechanism of their action or defjne predictive biomarkers

• f their effectiveness. This is also the
• pportunity to collaborate on preclinical

and translational studies in biology or ima- ging, connecting academic and industrial researchers and clinicians, thus genera- ting signifjcant benefjts in terms of patents and know-how. Finally, these collaborations are accompa- nied by signifjcant funding to retain skilled personnel and develop new methods. To this end, DITEP promotes privileged partnerships with pharmaceutical compa- nies likely to give us a substantial portfolio

• f molecules and early trials.

Contact: Dr Angevin, Alliance Manager eric.angevin@gustaveroussy.fr

INDUSTRIAL PARTNERSHIPS

CV OF DITEP PRINCIPAL INVESTIGATORS & SUB-INVESTIGATORS

Christophe Massard General background

Christophe Massard (MD, PhD) medical oncologist, is Chair of Drug Development Department (DITEP), Gustave Roussy , Villejuif, France. He is Consultant Medical Oncologist and full time cancer specialist at Gustave Roussy , half time at Drug Development department (DDD) and joined the faculty in 2006. He is primarily involved in translational cancer research and the design and conduct

• f early-phase biomarker-driven clinical trials, with a

special interest in Genito urinary cancer and Central Nervous System tumor . Dr Massard received his medical degree from PARIS XI University in 2006, and he got a MSc and PhD from PARIS XI University in 2013. He completed his residency training in Paris Hospital, followed by his fellowship in medical

• ncology at Gustave Roussy. He is board-certifjed in

Medical Oncology. He did a post-doctoral fellowship in Prof DeBono’s lab at the Royal Marsden Hospital of London and Institute of Cancer Research (London). Dr Massard is member of ESMO, ASCO, AACR. Over the last 5 years, he was the principal investigators of 15 phase I trials, 1 phase II trial (prostate cancer), and sub- investigator of more than 80 clinical trials (phase 1 trials and GU cancers). He is also involved in translational research aspects related to precision medicine(MOSCATO, MATCH R and PETRUS program). Dr Massard has contributed to

• ver 180 peer-reviewed publications, including publications

in European Urology, Annals of Oncology and Journal of Clinical Oncology. . He is also a member of the editorial boards of Bulletin du Cancer , Investigational New Drugs, and European Journal of Cancer . Research axes: early clinical trials, precision medicine, GU cancers (prostate cancer , bladder cancer and testis), glioma, and circulating biomarkers.

• First-in-human study of LY3039478, an
• ral Notch signaling inhibitor in advanced or

• Safety and effjcacy of durvalumab (MEDI4736), a

• Dose escalation study of ODM-203, a selective

• Massard C, Mateo J, Loriot Y, Pezaro C, Albiges

• J. Phase I/II trial of cabazitaxel plus abiraterone

• Massard C, Gordon MS, Sharma S, Rafji S,

• Massard C, Michiels S, Ferte C, Le Deley MC,

• f the MOSCATO 01 Trial. Cancer Discov. 2017

• Massard C, Borget I, Farace F, Aspeslagh S, Le

• Massard C, Chi KN, Castellano D, de Bono J,

MD PhD

29

General background

Eric Deutsch, MD, PhD, full-Professor in Radiation Oncology at South-Paris University, head of the Inserm Unit 1030 « Molecular Radiology Laboratory » and Head

• f the Radiation Oncology Department in Villejuif, France.

He is teaching radiobiology and medical physics at the Medical School of South-Paris University. Eric Deutsch’s research has been dedicated to combination

• f novel anticancer drugs either used alone or in

combination to radiotherapy. His interest focuses on cell death mecanisms, HPV related tumours and the tumour- stroma interplay , on the clinical side, he is versed into the fjeld of translational research and early clinical trials. He has investigated several fjrst in human novel drugs- radiotherapy combinations such as mTOR inhibitors, antiviral agents, immune modifyers and nanoparticles. Research axes: Early clinical trials and phase I, novel anticancer drugs, radiation biology, HPVs related tumors, combination with new drugs and Radiotherapy.

• Phase I trial evaluating the antiviral agent

• Desing of clinical trials integrating local

• Combination of vascular disrupting agents and

• Bonvalot S, Le Pechoux C, De Baere T, Kantor G,

• Deutsch E, Cohen-Jonathan Moyal E, Gregorc V,

• Levy A, Massard C, Soria JC, Deutsch E.

• Deutsch E, Haie-Meder C, Bayar MA, Mondini M,

• Deutsch E, Le Péchoux C, Faivre L, Rivera S, Tao

• JC. Phase I trial of everolimus in combination with

• cancer. Ann Oncol. 2015;26(6):1223-9.

Eric Deutsch

MD PhD

General background

Vincent Ribrag attended the University of Science and Medical School of South-Paris University between 1978 and 1985. In 1990-1991 he obtained his Master of Science in Molecular Biology , with Professor JC Kaplan. In the years 1990-1992 he also received his Diplôme d’Études Approfondies in molecular and cellular pharmacology at the Pierre et Marie Curie (Paris Vl) University with Professor Ascher . He obtained his board certifjcation in Hematology and discussed a thesis (silver medal) at the Paris Xl Faculty of Medicine entitled “VIP (etoposide,ifosfamide, cisplatinum) as a salvage intensifjcation program in relapsed or refractory Hodgkin’s disease.” Dr Ribrag is a tenure-track specialist at Gustave-Roussy lnstitute and has been nominated head of the Hematology multidisciplinary committee in Gustave-Roussy. Among numerous experimental activities, he counts a Laboratoire in clinical pharmacology (URA 147 CNRS, U-140 INSERM) with Dr A Gouyette; works in enzymology , the ICGM: INSERM U-363 at the Hôpital Cochin in Paris; the Unité INSERM U U1170: Animal MCL models and drug discovery and is head of the translational research lab in hematology. Dr Ribrag is member of several international cancer societies, namely the American Association for Cancer Research (AACR), the American Society of Hematology (ASH), the Société Française de Greffe de Moelle (SFGM), the Société Française d’Hématologie (SFH), the Groupe Français des Myélodysplasies (GFM) where he serves as scientifjc secretary since 1998. He is also part of the Lysa Scientifjc and Administrative Committees and of the European Scientifjc Committee of the Mantle Cell Lymphoma study group since 2001 and associated Head of early trials with Martin Dreyling.

• Phase 1 Study of Tazemetostat (EPZ-6438), an

• Safety and Effjcacy of Abexinostat, a Pan-

• Phase 1 fjrst-in-human study of the enhancer
• f zeste-homolog 2 (EZH2) histone methyl

• Zinzani PL, Ribrag V, Moskowitz CH, Michot

• f pembrolizumab in patients with relapsed/

• lymphoma. Blood. 2017 Jul 20;130(3):267-270.
• Ribrag V, Kim WS, Bouabdallah R, Lim

• f abexinostat, a pan-histone deacetylase

• Haematologica. 2017 May;102(5):903-909.
• Ribrag V, Koscielny S, Bosq J, Leguay T,

• Armand P, Shipp MA, Ribrag V, Michot JM,

• CH. Programmed Death-1 Blockade With

• Failure. J Clin Oncol. 2016 Jun 27. pii: JCO673467

• Infante JR, Cassier PA, Gerecitano JF, Witteveen

• GI. A Phase I Study of the Cyclin-Dependent

Vincent Ribrag

MD

31

General background

Aurélien Marabelle MD, PhD, is a Senior Medical Oncologist in the Drug Development Department (DITEP), a group leader in Prof Laurence Zitvogel’s lab (INSERM U1015) and the Clinical Director of the Cancer Immunotherapy Program at Gustave Roussy. He joined the faculty in Oct 2014. He got a MSc & PhD in Oncology & Immunology from Ecole Normale Supérieure de Lyon, King’s College London & University of Lyon. He did a post-doctoral fellowship in Prof Ronald Levy’s lab at Stanford University, California. He trained at the University of Paris VI medical school and received his medical degree from the University of Clermont-Ferrand. He completed his residency training in between Clermont-Ferrand & Lyon, followed by a clinical fellowship at Léon Bérard Cancer Center in Lyon. Dr Marabelle is a member of ASCO & AACR. Dr Marabelle is board-certifjed in Pediatric Oncology & Cell Therapy. Research axes: Cancer Immunotherapy & Early Phase Studies

• Phase I study of E7046, a novel PGE2-receptor

• n myeloid- and T-lymphoid cell-mediated

• Understanding the relevant immune

• Prioritisation of potential immunotherapy

• “Novel Immunostimulatory Antibodies: What’s

• Champiat S, Dercle L, Ammari S, Massard C,

• Marabelle A, Aspeslagh S, Postel-Vinay S, Soria
• JC. JAK Mutations as Escape Mechanisms to Anti-

• Aspeslagh S, Postel-Vinay S, Rusakiewicz S,

• Boutros C, Tarhini A, Routier E, Lambotte O,

• Postel-Vinay S, Aspeslagh S, Lanoy E, Robert C,

• Jacquelot N, Roberti MP, Enot DP, Rusakiewicz

• Commun. 2017 Sep 19;8(1):592.
• Shekarian T, Valsesia-Wittmann S, Brody J,

Aurélien Marabelle

MD PhD

General background

Eric Angevin obtained his medical and biology degree at Paris VI University and a PhD degree of cancerology and tumor immunology at South Paris XI University, while being appointed at Gustave Roussy as medical oncologist in 1995 in the Immunotherapy and Novel Therapies unit of the Medical Oncology Department. In 2006, he was appointed Assistant Director of Clinical Research in charge of innovation and valorisation, and joins the newly created Early Clinical Trial/phase I Department (DITEP). He has been involved as principal or sub- investigator of more than 200 clinical trials during the last 15 years, including FIH phase I studies across all tumor

• types. With a specifjc expertise in immunotherapy and

targeted molecules, both at the clinical and translational research levels, he published more than 100 papers in international peer-reviewed journals. As GR Alliance Manager , he is also in charge of the industrial partnering and collaboration initiatives with pharma/biotech companies at the institutional level. He has been invited to several advisory boards and is an active member of the French Cancer Institute Early Clinical Trials working group (INCA-CLIP²) and of ASCO, AACR, ESMO, EORTC-NCI-AACR and TAT international meetings.

• First-In-Human Phase 1 Study of ABBV-399, an

• First-in-human phase I administration of YS110,

• A fjrst-in-human (FIH) phase I study of

• Angevin E, Spitaleri G, Rodon J, Dotti K,

• Angevin E, Cassier PA, Italiano A, Gonçalves A,

• study. Eur J Cancer. 2017;83:194-202.
• Angevin E, Isambert N, Trillet-Lenoir V, You B,

• Angevin E, Tabernero J, Elez E, Cohen SJ,

• Angevin E, Lopez-Martin JA, Lin CC, Gschwend

• f dovitinib (TKI258), an oral FGFR, VEGFR, and

Eric Angevin

MD PhD

33

General background

Antoine Hollebecque (M.D.) is a senior medical physician at Gustave Roussy Cancer Center in Paris. He received his medical degree from Lille2 University in 2008. He completed his residency training followed by his fellowship in hepato-gastroenterology at Lille2 University. He spent 2 years as an Assistant Professor in the Drug Development Department at Gustave Roussy Cancer Center in 2012-2013. He completed his training with a one-year post-doctoral fellowship in the Clinical and Experimental Pharmacology (CEP) (Pr C. Dive), Manchester Institute, Cancer Research UK, Manchester where he worked on cell-free DNA. Over the last 5 years, Dr Hollebecque was the principal investigator of 20 phase I trials and sub-investigator of more than 100 phase I. He has contributed to over 64 peer-reviewed publications, including publications in New England Journal of Medicine, Journal of Clinical Oncology, European Journal of Cancer , Gastroenterology, Hepatology. Dr Hollebecque is a member of the European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR). Research axes: early phase studies, gastro-intestinal cancers, cell-free DNA, Next Generation Sequencing.

• An Open-Label, Multicohort, Phase 1/2 Study of

• Molecular screening for cancer treatment optimization

• A phase Ib trial of LY2584702 tosylate, a p70 S6

• Tacher V, Le Deley MC, Hollebecque A, Deschamps F,

• T. Factors associated with success of image-guided

• Jovelet C, Ileana E, Le Deley M-C, Motte N, Rosellini

• Isambert N, Delord JP, Soria JC, Hollebecque A,

• f a fjrst-in-man dose-escalation study with a fjxeddose

• Infante JR, Hollebecque A, Postel-Vinay S, Bauer

• Temam S, Spicer J, Farzaneh F, Soria JC, Oppenheim

• Hollebecque A, Bahleda R, Faivre L, Adam J,

Antoine Hollebecque

MD

General background

Andreea Varga, MD, Senior Medical Oncologist in the Drug Development Department of Gustave Roussy Cancer Campus since 2011. She received her medical degree from Medical Faculty Cluj-Napoca Rumania in 2004. She started her training in Medical Oncology at Cluj- Napoca University (2005-2010) in oncology, cardiology, internal medecine and radiology units ,then at Paul Brousse Hospital in Paris (2008-2009) and breast cancer unit of Institut Gustave Roussy (2009-2010). She continued her clinical research residency at IGR (2009-2010) and became medical oncologist of phase I Unit (Pr Soria) in 2011. In september 2017, she was appointed Head of the DITEP out-patient day care unit. Dr Varga is board-certifjed in Medical Oncology since 2010. Research axes: phase I trials, drug development, targeted and personalized therapy of breast cancer , lung and other solid tumors.

• A fjrst-in-human phase I study to

• Antitumor activity and safety of

• Activity of rociletinib in EGFR mutant

• Massard C, Mateo J, Loriot Y, Pezaro C,

• Oncol. 2016 Oct 18. pii: mdw441 [Epub

• Jung J, Lee JS, Dickson MA, Schwartz

• Morschhauser F, Terriou L, Coiffjer

• f the oral histone deacetylase inhibitor

• Bahleda R, Sessa C, Del Conte G,

• f ombrabulin (AVE8062) combined

• Frenel JS, Le Tourneau C, O’Neil B, Ott

Andrea Varga

MD

35

General background

Rastislav Bahleda, MD, Senior Medical Oncologist in the Drug Development Department of Gustave Roussy Cancer Campus since 2007. He received his medical degree from Medical Faculty of Comenius University in Bratislava (1995) and completed his clinical residency in Internal Medicine (1998). He continued his training to complete a fellowship in Clinical Oncology at Comenius University and National Cancer Institut in Bratislava (1995-2001). He continued clinical and molecular research (Inserm U 268) in sarcomas at Institut Gustave Roussy (2002-2003) and received University Diploma in Clinical Research from University of Paris XI. He continued his clinical research residency at IGR (2003- 2006) and became medical oncologist at the Medical Oncology Department (2007), and the Drug Development Department (2013). Dr Bahleda is board-certifjed in Internal Medicine and Medical Oncology and a member of ASCO. Research axes: phase I trials, drug development,

• ncogenic mutations, FGFR pathway

, personnalized and molecular targeted therapy.

• Long-Term Safety and Clinical Outcomes of

• Phase 1 study of JNJ-42756493, a pan-fjbroblast

• Bahleda R, Varga A, Berge Y, Soria JC, Schnell D,

• pen-label study of afatinib plus vinorelbine in patients

• Bahleda R, Baker J, Massard C, Gadgeel SM, Rogers

• Malignancies. Oncology. 2016;90(1):10-20.
• Awada A, Campone M, Varga A, Aftimos P, Frenel

• Calvo E, Soria JC, Ma WW, Wang T, Bahleda R,

• Res. 2017 Mar 1;23(5):1177-1185.
• Bahleda R, Grilley-Olson JE, Govindan R, Barlesi

• f roniciclib, a pan-cyclin-dependent kinase inhibitor,

Rastislav Bahleda

MD

General background

Anas Gazzah, MD, Senior Medical Oncologist in the Drug Development Department of Gustave Roussy Cancer Campus since 2010. He received his medical degree from Medical Faculty Sousse Tunisia in 2004. He continued his training to complete a fellowship in Medical Oncology at Paris University VII (Denis Diderot) and VI (Pierre et Marie Curie) from 2005 to 2009. He completed training in

• nco-hematology

and radiotherapy (2006-2007) and continued his clinical residency training (Institut Gustave Roussy , Assistance Publique Hôpitaux de Paris, Centre René Huguenin). He continued his clinical research training at Gustave Roussy (2008-2010) and became medical oncologist within the Drug Development Department (Pr Soria) in 2010. Dr Gazzah is board-certifjed in Medical Oncology since 2009. Research axes: phase I trials, drug development, targeted and personnalized therapy of lung cancer .

• First-in-human phase I trial of the

• Phase Ib study of afatinib plus

• Phase Ib study of afatinib plus

• Tabernero J, Bahleda R, Dienstmann

• Remon J, Gazzah A, Besse B, Soria
• JC. Crizotinib Improves Osteoarthritis

• Hollebecque A, Deutsch E, Massard

• r lymphoma. Invest New Drugs.

• Gazzah A, Gonzales DB, Levy A,

• Hollebecque A, Bahleda R, Faivre L,

Anas Gazzah

MD

37

General background

Jean-Marie Michot is a full-time medical internist at Gustave Roussy. He was fjrst trained in Normandy at the University of Rouen until 2004. He began his training in Paris in 2004 at the University Paris Diderot and obtained a Master 2 specialization in Immunology from the Pasteur Institute of Paris in 2009. He is certifjed in Internal Medicine and received the Silver Medal from the Faculty of Medicine of Paris in 2010. Dr. Michot is affjliated with the Department of Internal Medicine and Clinical Immunology at University Paris-South Hospital since 2010. He joined the Hematology Unit of Gustave Roussy in 2013 where he developed phase 1 hematology clinical trials with Vincent Ribrag and Stéphane De Botton. He had a focus for new treatments in lymphoproliferative

• disorders. His wish is to advance new therapies, and to

develop personalized medicine approaches. He aims to improve the management of immunological related adverse events of new immune-checkpoint inhibitors.

• Phase Ib study of CC-122 in combination with
• binutuzumab (GA101): relapsed or refractory (R/R)

• Phase IB study of CC-122 and obinutuzumab in

• Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani

• Michot JM, Mazeron R, Dercle L, Ammari S, Canova

• Thijssen R, Ter Burg J, Garrick B, van Bochove GG,

• Aftimos P, Rolfo C, Rottey S, Offner F, Bron D,

• Zinzani PL, Ribrag V, Moskowitz CH, Michot JM,

Jean-Marie Michot

MD

General background

Sophie Postel-Vinay (MD, Ph.D), is currently Physician Scientist at the Drug Development Department and U981 INSERM research unit of Gustave Roussy Cancer Campus, where she leads an independent research group as of January 2018 thanks to the ATIP-Avenir INSERM/ CNRS grant. She received her medical degree from the Université René Descartes Paris V in 2010, and joined the faculty in November 2013 after completion of her PhD. She completed her residency training in Paris, and spent 18 months at the Royal Marsden Hospital of London in Pr Stan Kaye Drug Development Unit. Dr Postel-Vinay is member of AACR and ASCO, from which she received a merit award in 2010. She is also an ESMO member, has been representative of the French Young Oncologist at the Young Oncologists Committee from 2013-2016, and received the ESMO translational research fellowship for her PhD that was performed at the Institute of Cancer Research (London) in Pr Alan Ashworth laboratory, focusing on DNA repair and synthetic lethality. Dr Postel-Vinay has a physician scientist position since 2016, which allows her to have a fundamental research activity within the INSERM Unit 981 (80% of her time), in parallel of her clinical drug development activity (phase 1 trials). She obtained in 2017 the ATIP- Avenir “Young Group Leader” grant from INSERM/ CNRS, which now allows her to develop her own group as an independent research team. Her research activity focuses on chromatin remodeling and its interplay with DNA damage repair and immune modulation in solid tumor cancer models. Her research interests include DNA repair, chromatin remodeling and synthetic lethality, sarcoma, drug development, predictive biomarkers and emerging targets.

• First-in-human phase I dose escalation study of

• First-in-human study of oral S 49076, a MET/

• Towards new methods for the determination of

• f Molecularly Targeted Agents

• Infante JR, Hollebecque A, Postel-Vinay S,

• Postel-Vinay S, Aspeslagh S, Lanoy E, Robert

• Postel-Vinay S, Boursin Y, Massard C,

• Dercle L, Ammari S, Champiat S, Massard C,

• Shaw AT, Felip E, Bauer TM, Besse B, Navarro

• pen-label, single-arm fjrst-in-man phase 1 trial.

Sophie Postel-Vinay

MD PhD

39

General background

Stéphane Champiat MD, PhDc is currently Assistant Professor at the Drug Development Department of Gustave Roussy Cancer Campus. He trained at the University of Paris VI medical school and received his medical degree from the University of Nantes in 2014. He completed his residency training in Medical Oncology at the Institute of Cancer Research in Nantes and at Gustave Roussy Cancer Center . He joined the faculty in November 2017. Dr Champiat worked for one year as a postdoctoral researcher at University California San Francisco focusing

• n T cell immunity. He started in 2014 a PhD at Paris XI

University in the INSERM Unit 981 “Predictive biomarkers and new therapeutic strategies” research group. He has been working since 2012 at Gustave Roussy where he is growing clinical experience with immunomodulatory antibodies in cancer patients. He is particularly involved in the strategy for managing immune-related toxicities and has setup the immune-related toxicities management program (iTOX program) at Gustave Roussy. Dr Champiat is a member

• f

the European Society

• f

Medical Oncology (ESMO) and the Society for Immunotherapy of Cancer (SITC). Research axes: thoracic oncology, early phase studies and cancer immunotherapy.

MD

• Champiat S, Dercle L, Ammari S, Massard C,

• f immune checkpoint blockade dysimmune toxicities:

Stéphane Champiat

MD PhD

General background

Capucine Baldini (MD) is a medical oncologist working at the Drug Development Department (DITEP), Gustave Roussy ,Villejuif, France. She is involved in early phase trials with a special interest in geriatric oncology, gastro-intestinal cancer , genito urinary cancer , Central Nervous System tumor. Dr Baldini received her medical degree from Lille II University in 2014 and got a MSc from PARIS XI University in 2013. She completed her fellowship in medical oncology at Lille University Hospital with a specialization in geriatric

• ncology and at Gustave Roussy in early phase trials at

DITEP. She is a member of ESMO, ASCO, AACR, SIOG, SoFOG and involved in young SIOG and SoFOG interest group

• leadership. She is working on early phase trials and

immunotherapy in older patients. She is a subinvestigator of more than 80 clinical trials (phase 1 trials). Research axes: early clinical trials, geriatric oncology, GU cancers (prostate cancer , bladder cancer), glioma.

• Setting up a geriatric oncology unit

• Immunotherapy phase I trials in patients over 70

• FOLFIRINAGE : Tolerance and effjcacy of

• Baldini C, Le Saux O, Helissey C, Aspeslagh S,

• Loh KP, Soto-Perez-de-Celis E, Hsu T, de Glas

• Bigot F, Castanon E, Baldini C, Hollebecque A,

• Baldini C, Escande A, Bouché O, El Hajbi F, Volet

• Mislang AR, Wildes TM, Kanesvaran R, Baldini

• lder adults: The International Society of Geriatric

Capucine Baldini

MD

41

Dr Jean-Pierre Armand focuses his cancer research in the fjeld of new mechanism of

• ncogenese and early drug development. Jean-Pierre Armand MD, MSc, is certifjed in

Medical Oncology (University of Toulouse III and Paris XI). He is presently senior consultant at Gustave Roussy. He was General Director of the Institut Claudius Regaud in Toulouse (2007 -2012). Over the last years he has been in charge of the construction of a new cancer center, in a European research hub created in the Toulouse cancer campus (Institut Universitaire du Cancer). Although expert in breast, head&neck, and neuro-oncology, the fjrst fjeld of Dr Armand was very early drug development in phase 1 and 2. He has been the founder of the IGR Phase I Unit in the early 80s. He did the fjrst in human phase I in the world at IGR of numerous drugs, including classicals cytotoxics, (Irinotecan, Oxaliplatin, Taxotere, Navelbine, Vinfmunine), and more recently targeted therapies, (Sutent, Sorafenib, Temsirolismus...)

• Prof. Jean-Charles Soria, M.D., Ph.D., is since September 2017, Senior Vice President and

Head of the Oncology Innovative Medicines unit (iMED) at MedImmune.

• Prof. Soria served as a Professor of Medicine and Medical Oncology at South-Paris

University and a Cancer Specialist at Gustave Roussy. Prof. Soria was Chair of the Drug Development Department at Gustave Roussy and was a member of the lung cancer unit with a focus on targeted therapies. His main research interests are early clinical development, phase I trials across solid tumors, pharmacodynamic biomarkers, lung cancer and personalized medicine.

• Prof. Soria trained as a medical oncologist and obtained the Silver medal from Paris Medical

School in 1997. He gained a PhD degree in the fundamental basis of oncogenesis in 2001, and completed his training with a two-year postdoctoral fellowship in the Department

• f Thoracic Head and Neck Medical Oncology at MD Anderson Cancer Center, Houston,

USA, where he has held an Adjunct Professorship in 2012. He has contributed to over 550 peer-reviewed publications, including publications as fjrst

• r last author in the New England Journal of Medicine, Lancet Oncology, JCO, Annals of
• Oncology. He has been appointed Editor in Chief of Annals of Oncology for 2014-2018.

MD

Jean-Pierre Armand Jean-Charles Soria PAST LEADERS IN EARLY DRUG DEVELOPMENT AT GUSTAVE ROUSSY

MD MD PhD

DITEP EXECUTIVE SUMMARY & DEVELOPMENT PROJECT

Mission/core identity of the DITEP Our mission is to provoke radical changes, qualitative and quantitative strides forward in cancer care. The DITEP team embodies, develops and promotes clinical research that is conceived as patient-centered care and based on offering the greatest number of patients’ access to innovative therapies and to early clinical trials. The innovation is placed at the crossroads between early clinical trials and tumor bio- logy, especially precision medicine. The DITEP is a key player in the develop- ment of immunotherapy, innovative mole- cules in hematological malignancies and combinations to radiotherapy. Institutional anchoring The DITEP is structurally and functionally integrated within Gustave Roussy. This integration is implemented as a dyna- mic process of interactions with the other medical departments, research units and technical platforms along the whole drug development path. Development dynamics Our goal is to remain in the group of the world leaders in drug development, and to be a key player, driver and facilitator in the evaluation of tomorrow’s medicine in onco- logy. The way to do so is to maintain and to spread enthusiasm, open intelligence and proactive practices regarding future medi- cal and scientifjc evolutions. Activity model and quality management Since November 2016, the DITEP is certi- fjed ISO 9001v2015 (Quality Management System) for its activities of access to the- rapeutic innovations, management of early clinical trials, and scientifjc outreach. Our managerial values are to establish solidarity and cooperation between DITEP professionals and jobs a cornerstone of our practices. The strategic stakes are to ensure and develop the quality of our partnerships, both private and public with industrial and academic teams.

/ DRUG DEVELOPMENT DEPARTMENT 114, rue Édouard-Vaillant 94805 Villejuif Cedex - France Tél. : 01 42 11 42 11 Fax : 01 42 11 53 00

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